You are here

Weinberg, Joe Brice

Overview:

Dr. Weinberg is a board-certified hematologist and medical oncologist who serves as Professor of Medicine and Immunology and Associate Professor of Obstetrics and Gynecology at the Duke University Medical Center, and staff physician in hematology-oncology at the Durham V.A. Medical Center. His clinical interests are in hematology and oncology, and his research focuses on blood cells, nitric oxide (NO), and leukemia. The work includes studies of resistance to infection, pathways of inflammation, and regulation of normal and leukemic cell life and death. His current work includes studies of leukemia (primarily chronic lymphocytic leukemia); the roles of NO and arginine in the resistance to malaria; and the interactions of NO, prostaglandins, and mechanical force in inflammation and arthritis.

Positions:

Professor of Medicine

Medicine, Hematology
School of Medicine

Professor of Immunology

Immunology
School of Medicine

Associate Professor of Obstetrics and Gynecology

Obstetrics and Gynecology
School of Medicine

Affiliate, Duke Global Health Institute

Duke Global Health Institute
Institutes and Provost's Academic Units

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

B.S. 1966

B.S. — University of Arkansas, Fayetteville

M.D. 1969

M.D. — University of Arkansas at Little Rock

Internship & Residency

University of Arkansas at Little Rock

Fellowship, Hematology Oncology

University of Utah School of Medicine

News:

Grants:

Transfusion Medicine and Hematology

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Preceptor
Start Date
July 01, 1975
End Date
June 30, 2021

The Effect of Reducing Posttraumatic Stress Disorder Symptoms on Cardiovascular Risk

Administered By
Psychiatry & Behavioral Sciences, Behavioral Medicine
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
February 06, 2016
End Date
January 31, 2021

Interdisciplinary Research Training Program in AIDS

Administered By
Medicine, Infectious Diseases
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 01, 2010
End Date
August 31, 2020

Nitric Oxide and Microvascular Dysfunction in Severe Malaria

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 15, 2015
End Date
May 31, 2019

Training Program in Inflammatory and Immunological Diseases

Administered By
Medicine, Rheumatology and Immunology
AwardedBy
National Institutes of Health
Role
Preceptor
Start Date
September 30, 1980
End Date
August 31, 2017

Burroughs Wellcome Travel Fund-Assessment of endothelial glycocalyz in normal children in a malaria endemic area of Africa

Administered By
Medicine, Hematology
AwardedBy
Burroughs Wellcome Fund
Role
Principal Investigator
Start Date
September 01, 2016
End Date
August 18, 2017

Obesity, Biomechanics, and Inflammation in Osteoarthritis

Administered By
Orthopaedics
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
September 30, 2013
End Date
January 31, 2016

Clinical Oncology Research Career Development Program

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 29, 2009
End Date
July 31, 2015

Arginine, Nitric Oxide, and Severe Malaria

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 30, 1997
End Date
July 31, 2015

Nitric Oxide and Malaria

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 03, 2012
End Date
July 31, 2014

IPA - Robert Nielsen

Administered By
Medicine, Hematology
AwardedBy
Durham Veterans Affairs Medical Center
Role
Principal Investigator
Start Date
July 01, 2012
End Date
June 30, 2014

IPA - Stephen H. Johnson

Administered By
Medicine, Hematology
AwardedBy
Durham Veterans Affairs Medical Center
Role
Principal Investigator
Start Date
July 01, 2012
End Date
June 30, 2014

Molecular Pathogenesis of Monoclonal B Cell Lymphocytosis and CLL

Administered By
Medicine, Hematological Malignancies
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
August 01, 2011
End Date
December 18, 2013

Intrinsic Repair of the Knee Meniscus

Administered By
Orthopaedics
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 01, 2007
End Date
August 31, 2013

IPA - Youwei Chen

Administered By
Medicine, Hematology
AwardedBy
Veterans Administration Medical Center
Role
Principal Investigator
Start Date
April 01, 2011
End Date
October 01, 2011

IPA - Youwei Chen

Administered By
Medicine, Hematology
AwardedBy
Veterans Administration Medical Center
Role
Principal Investigator
Start Date
April 01, 2010
End Date
March 31, 2011

Nitric Oxide, Oxygen and Mechanical Stress in Cartilage

Administered By
Orthopaedics
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
August 01, 2004
End Date
February 01, 2010

Prevention of Chronic Lymphocytic Leukemia (CLL)

Administered By
Medicine, Rheumatology and Immunology
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
September 01, 2007
End Date
August 31, 2009

Training in Biomolecular and Tissue Engineering

Administered By
Orthopaedics
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 20, 2003
End Date
June 30, 2009

IPA - Robert A. Nielsen

Administered By
Medicine, Hematology
AwardedBy
Veterans Administration Medical Center
Role
Principal Investigator
Start Date
February 01, 2007
End Date
July 01, 2007

Inducible NOS as a Treatment Target in CLL

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
June 01, 2001
End Date
May 31, 2007

Does NO mediate clinical anti-VEGF vascular effects

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
September 26, 2003
End Date
August 31, 2006

Mechanical Stress and Prostaglandins in Cartilage

Administered By
Orthopaedics
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
August 01, 2001
End Date
May 31, 2004

Hyaluronan-mediated Nitric Oxide Production by Macrophages

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 20, 1999
End Date
June 30, 2002

Specialized center of research (SCOR) in Rheumatoid Arthritis

Administered By
Medicine, Rheumatology and Immunology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 30, 1987
End Date
August 31, 2001

Nitric Oxide And Severe Malaria

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 30, 1997
End Date
August 31, 1999

Specialized Center Of Research In Rheumatoid Arthritis

Administered By
Medicine, Rheumatology and Immunology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 01, 1987
End Date
August 31, 1999

Specialized Center Of Research In Rheumatoid Arthritis

Administered By
Medicine, Rheumatology and Immunology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 30, 1987
End Date
August 31, 1997
Show More

Publications:

Enhanced CDC of B cell chronic lymphocytic leukemia cells mediated by rituximab combined with a novel anti-complement factor H antibody.

Rituximab therapy for B cell chronic lymphocytic leukemia (B-CLL) has met with mixed success. Among several factors to which resistance can be attributed is failure to activate complement dependent cytotoxicity (CDC) due to protective complement regulatory proteins, including the soluble regulator complement factor H (CFH). We hypothesized that rituximab killing of non-responsive B-CLL cells could be augmented by a novel human monoclonal antibody against CFH. The B cells from 11 patients with B-CLL were tested ex vivo in CDC assays with combinations of CFH monoclonal antibody, rituximab, and a negative control antibody. CDC of rituximab non-responsive malignant B cells from CLL patients could in some cases be augmented by the CFH monoclonal antibody. Antibody-mediated cytotoxicity of cells was dependent upon functional complement. In one case where B-CLL cells were refractory to CDC by the combination of rituximab plus CFH monoclonal antibody, additionally neutralizing the membrane complement regulatory protein CD59 allowed CDC to occur. Inhibiting CDC regulatory proteins such as CFH holds promise for overcoming resistance to rituximab therapy in B-CLL.

Authors
Winkler, MT; Bushey, RT; Gottlin, EB; Campa, MJ; Guadalupe, ES; Volkheimer, AD; Weinberg, JB; Patz, EF
MLA Citation
Winkler, MT, Bushey, RT, Gottlin, EB, Campa, MJ, Guadalupe, ES, Volkheimer, AD, Weinberg, JB, and Patz, EF. "Enhanced CDC of B cell chronic lymphocytic leukemia cells mediated by rituximab combined with a novel anti-complement factor H antibody." PloS one 12.6 (January 2017): e0179841-.
PMID
28658265
Source
epmc
Published In
PloS one
Volume
12
Issue
6
Publish Date
2017
Start Page
e0179841
DOI
10.1371/journal.pone.0179841

Nitric Oxide-Dependent Endothelial Dysfunction and Reduced Arginine Bioavailability in Plasmodium vivax Malaria but No Greater Increase in Intravascular Hemolysis in Severe Disease.

 Pathogenesis of severe Plasmodium vivax malaria is poorly understood. Endothelial dysfunction and reduced nitric oxide (NO) bioavailability characterize severe falciparum malaria, but have not been assessed in severe vivax malaria. In patients with severe vivax malaria (n = 9), patients with nonsevere vivax malaria (n = 58), and healthy controls (n = 79), we measured NO-dependent endothelial function by using reactive hyperemia-peripheral arterial tonometry (RH-PAT) and assessed associations with arginine, asymmetric dimethylarginine (ADMA), and hemolysis. The L-arginine level and the L-arginine to ADMA ratio (a measure of L-arginine bioavailability) were reduced in patients with severe vivax malaria and those with nonsevere vivax malaria, compared with healthy controls (median L-arginine level, 65, 66, and 98 µmol/mL, respectively [P = .0001]; median L-arginine to ADMA ratio, 115, 125, and 187, respectively [P = .0001]). Endothelial function was impaired in proportion to disease severity (median RH-PAT index, 1.49, 1.73, and 1.97 in patients with severe vivax malaria, those with nonsevere vivax malaria, and healthy controls, respectively; P = .018) and was associated with the L-arginine to ADMA ratio. While the posttreatment fall in hemoglobin level was greater in severe vivax malaria as compared to nonsevere vivax malaria (2.5 vs 1 g/dL; P = .0001), markers of intravascular hemolysis were not higher in severe disease. Endothelial function is impaired in nonsevere and severe vivax malaria, is associated with reduced L-arginine bioavailability, and may contribute to microvascular pathogenesis. Severe disease appears to be more associated with extravascular hemolysis than with intravascular hemolysis.

Authors
Barber, BE; William, T; Grigg, MJ; Piera, KA; Chen, Y; Wang, H; Weinberg, JB; Yeo, TW; Anstey, NM
MLA Citation
Barber, BE, William, T, Grigg, MJ, Piera, KA, Chen, Y, Wang, H, Weinberg, JB, Yeo, TW, and Anstey, NM. "Nitric Oxide-Dependent Endothelial Dysfunction and Reduced Arginine Bioavailability in Plasmodium vivax Malaria but No Greater Increase in Intravascular Hemolysis in Severe Disease." The Journal of infectious diseases 214.10 (November 2016): 1557-1564.
PMID
27630198
Source
epmc
Published In
Journal of Infectious Diseases
Volume
214
Issue
10
Publish Date
2016
Start Page
1557
End Page
1564
DOI
10.1093/infdis/jiw427

An investigation of vago-regulatory and health-behavior accounts for increased inflammation in posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) has been linked to chronic inflammation, a condition that poses a risk for cardiovascular disease. Attenuated vagal activity has been proposed as a potential mediator of PTSD and inflammation, although associated behavioral health risks-namely cigarette smoking and alcohol dependence-might also account for that link.Inflammation was quantified by fasting serum concentrations of C-reactive protein (CRP), tumor necrosis factor (TNF)-α, interleukin (IL)-10, and thymus- and activation-regulated chemokine (TARC)/CCL17 collected from 85 participants with PTSD and 82 without PTSD. Latent variable modeling was used to assess the relationship between PTSD symptom severity and inflammation along with potential mediators vagal activity (respiratory sinus arrhythmia; RSA), smoking status, and lifetime alcohol dependence.PTSD symptom severity was associated with increased inflammation (β=.18, p=.02). However, this association was reduced in models that adjusted for RSA, smoking status, and lifetime alcohol dependence. Independent mediation effects were deemed significant via bootstrapping analyses. Together, RSA, smoking status, and lifetime alcohol dependence accounted for 95% of the effect of PTSD symptom severity on inflammation.Although RSA accounted for a modest proportion of the association between posttraumatic stress and pro-inflammatory responses, behavioral factors-specifically cigarette smoking and alcohol dependence-proved to be larger mediators. The benefits of PTSD treatment may be enhanced by additional interventions aimed at modifying these health behaviors.

Authors
Dennis, PA; Weinberg, JB; Calhoun, PS; Watkins, LL; Sherwood, A; Dennis, MF; Beckham, JC
MLA Citation
Dennis, PA, Weinberg, JB, Calhoun, PS, Watkins, LL, Sherwood, A, Dennis, MF, and Beckham, JC. "An investigation of vago-regulatory and health-behavior accounts for increased inflammation in posttraumatic stress disorder." Journal of psychosomatic research 83 (April 2016): 33-39.
PMID
27020074
Source
epmc
Published In
Journal of Psychosomatic Research
Volume
83
Publish Date
2016
Start Page
33
End Page
39
DOI
10.1016/j.jpsychores.2016.02.008

Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 × 10(-11)), 6p25.2 (rs73718779, SERPINB6, P=1.97 × 10(-8)) and 3q28 (rs9815073, LPP, P=3.62 × 10(-8)), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 × 10(-11)) in the combined analysis. We find suggestive evidence (P<5 × 10(-7)) for two additional new loci at 4q24 (rs10028805, BANK1, P=7.19 × 10(-8)) and 3p22.2 (rs1274963, CSRNP1, P=2.12 × 10(-7)). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility.

Authors
Berndt, SI; Camp, NJ; Skibola, CF; Vijai, J; Wang, Z; Gu, J; Nieters, A; Kelly, RS; Smedby, KE; Monnereau, A; Cozen, W; Cox, A; Wang, SS; Lan, Q; Teras, LR; Machado, M; Yeager, M; Brooks-Wilson, AR; Hartge, P; Purdue, MP; Birmann, BM; Vajdic, CM; Cocco, P; Zhang, Y; Giles, GG; Zeleniuch-Jacquotte, A; Lawrence, C; Montalvan, R; Burdett, L; Hutchinson, A; Ye, Y; Call, TG; Shanafelt, TD; Novak, AJ; Kay, NE; Liebow, M; Cunningham, JM; Allmer, C; Hjalgrim, H; Adami, H-O; Melbye, M; Glimelius, B et al.
MLA Citation
Berndt, SI, Camp, NJ, Skibola, CF, Vijai, J, Wang, Z, Gu, J, Nieters, A, Kelly, RS, Smedby, KE, Monnereau, A, Cozen, W, Cox, A, Wang, SS, Lan, Q, Teras, LR, Machado, M, Yeager, M, Brooks-Wilson, AR, Hartge, P, Purdue, MP, Birmann, BM, Vajdic, CM, Cocco, P, Zhang, Y, Giles, GG, Zeleniuch-Jacquotte, A, Lawrence, C, Montalvan, R, Burdett, L, Hutchinson, A, Ye, Y, Call, TG, Shanafelt, TD, Novak, AJ, Kay, NE, Liebow, M, Cunningham, JM, Allmer, C, Hjalgrim, H, Adami, H-O, Melbye, M, and Glimelius, B et al. "Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia." Nature communications 7 (March 9, 2016): 10933-.
PMID
26956414
Source
epmc
Published In
Nature Communications
Volume
7
Publish Date
2016
Start Page
10933
DOI
10.1038/ncomms10933

Abstract A24: The dual PI3K δ/γ inhibitor, RP6530, in combination with ibrutinib or fludarabine, synergistically enhances cytotoxicity in primary CLL cells in vitro.

Authors
Vakkalanka, S; Penmetsa, KV; Chasse, D; Chen, Y; Viswanadha, S; Friedman, DR; Weinberg, JB
MLA Citation
Vakkalanka, S, Penmetsa, KV, Chasse, D, Chen, Y, Viswanadha, S, Friedman, DR, and Weinberg, JB. "Abstract A24: The dual PI3K δ/γ inhibitor, RP6530, in combination with ibrutinib or fludarabine, synergistically enhances cytotoxicity in primary CLL cells in vitro." September 1, 2015.
Source
crossref
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
21
Issue
17 Supplement
Publish Date
2015
Start Page
A24
End Page
A24
DOI
10.1158/1557-3265.HEMMAL14-A24

Set alpha/beta-mrna isoform ratio by a novel qpcr assay has prognostic significance in chronic lymphocytic leukemia and may be modulated by treatment

Authors
Brander, D; Christensen, D; Volkheimer, A; Stewart, T; Chen, Y; Friedman, D; Weinberg, JB
MLA Citation
Brander, D, Christensen, D, Volkheimer, A, Stewart, T, Chen, Y, Friedman, D, and Weinberg, JB. "Set alpha/beta-mrna isoform ratio by a novel qpcr assay has prognostic significance in chronic lymphocytic leukemia and may be modulated by treatment." LEUKEMIA & LYMPHOMA 56 (September 1, 2015): 121-122.
Source
wos-lite
Published In
Leukemia & Lymphoma (Informa)
Volume
56
Publish Date
2015
Start Page
121
End Page
122

Pan-caspase peptide inhibitor to induce primary chronic lymphocytic leukemia (CLL) cell death through a non-apoptotic and non-necroptotic mechanism

Authors
Friedman, DR; Stewart, T; Guadalupe, E; Brander, DM; Pisetsky, DS; Weinberg, JB
MLA Citation
Friedman, DR, Stewart, T, Guadalupe, E, Brander, DM, Pisetsky, DS, and Weinberg, JB. "Pan-caspase peptide inhibitor to induce primary chronic lymphocytic leukemia (CLL) cell death through a non-apoptotic and non-necroptotic mechanism." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

Impaired systemic tetrahydrobiopterin bioavailability and increased dihydrobiopterin in adult falciparum malaria: association with disease severity, impaired microvascular function and increased endothelial activation.

Tetrahydrobiopterin (BH₄) is a co-factor required for catalytic activity of nitric oxide synthase (NOS) and amino acid-monooxygenases, including phenylalanine hydroxylase. BH4 is unstable: during oxidative stress it is non-enzymatically oxidized to dihydrobiopterin (BH₂), which inhibits NOS. Depending on BH₄ availability, NOS oscillates between NO synthase and NADPH oxidase: as the BH₄/BH₂ ratio decreases, NO production falls and is replaced by superoxide. In African children and Asian adults with severe malaria, NO bioavailability decreases and plasma phenylalanine increases, together suggesting possible BH₄ deficiency. The primary three biopterin metabolites (BH₄, BH₂ and B₀ [biopterin]) and their association with disease severity have not been assessed in falciparum malaria. We measured pterin metabolites in urine of adults with severe falciparum malaria (SM; n=12), moderately-severe malaria (MSM, n=17), severe sepsis (SS; n=5) and healthy subjects (HC; n=20) as controls. In SM, urinary BH₄ was decreased (median 0.16 ¼mol/mmol creatinine) compared to MSM (median 0.27), SS (median 0.54), and HC (median 0.34)]; p<0.001. Conversely, BH₂ was increased in SM (median 0.91 ¼mol/mmol creatinine), compared to MSM (median 0.67), SS (median 0.39), and HC (median 0.52); p<0.001, suggesting increased oxidative stress and insufficient recycling of BH2 back to BH4 in severe malaria. Overall, the median BH₄/BH₂ ratio was lowest in SM [0.18 (IQR: 0.04-0.32)] compared to MSM (0.45, IQR 0.27-61), SS (1.03; IQR 0.54-2.38) and controls (0.66; IQR 0.43-1.07); p<0.001. In malaria, a lower BH₄/BH₂ ratio correlated with decreased microvascular reactivity (r=0.41; p=0.03) and increased ICAM-1 (r=-0.52; p=0.005). Decreased BH4 and increased BH₂ in severe malaria (but not in severe sepsis) uncouples NOS, leading to impaired NO bioavailability and potentially increased oxidative stress. Adjunctive therapy to regenerate BH4 may have a role in improving NO bioavailability and microvascular perfusion in severe falciparum malaria.

Authors
Yeo, TW; Lampah, DA; Kenangalem, E; Tjitra, E; Price, RN; Weinberg, JB; Hyland, K; Granger, DL; Anstey, NM
MLA Citation
Yeo, TW, Lampah, DA, Kenangalem, E, Tjitra, E, Price, RN, Weinberg, JB, Hyland, K, Granger, DL, and Anstey, NM. "Impaired systemic tetrahydrobiopterin bioavailability and increased dihydrobiopterin in adult falciparum malaria: association with disease severity, impaired microvascular function and increased endothelial activation." PLoS Pathogens 11.3 (March 12, 2015): e1004667-.
PMID
25764397
Source
epmc
Published In
PLoS pathogens
Volume
11
Issue
3
Publish Date
2015
Start Page
e1004667
DOI
10.1371/journal.ppat.1004667

Impaired systemic tetrahydrobiopterin bioavailability and increased oxidized biopterins in pediatric falciparum malaria: association with disease severity.

Decreased bioavailability of nitric oxide (NO) is a major contributor to the pathophysiology of severe falciparum malaria. Tetrahydrobiopterin (BH4) is an enzyme cofactor required for NO synthesis from L-arginine. We hypothesized that systemic levels of BH₄ would be decreased in children with cerebral malaria, contributing to low NO bioavailability. In an observational study in Tanzania, we measured urine levels of biopterin in its various redox states (fully reduced [BH₄] and the oxidized metabolites, dihydrobiopterin [BH₂] and biopterin [B₀]) in children with uncomplicated malaria (UM, n = 55), cerebral malaria (CM, n = 45), non-malaria central nervous system conditions (NMC, n = 48), and in 111 healthy controls (HC). Median urine BH4 concentration in CM (1.10 [IQR:0.55-2.18] μmol/mmol creatinine) was significantly lower compared to each of the other three groups - UM (2.10 [IQR:1.32-3.14];p<0.001), NMC (1.52 [IQR:1.01-2.71];p = 0.002), and HC (1.60 [IQR:1.15-2.23];p = 0.005). Oxidized biopterins were increased, and the BH4:BH2 ratio markedly decreased in CM. In a multivariate logistic regression model, each Log10-unit decrease in urine BH4 was independently associated with a 3.85-fold (95% CI:1.89-7.61) increase in odds of CM (p<0.001). Low systemic BH4 levels and increased oxidized biopterins contribute to the low NO bioavailability observed in CM. Adjunctive therapy to regenerate BH4 may have a role in improving NO bioavailability and microvascular perfusion in severe falciparum malaria.

Authors
Rubach, MP; Mukemba, J; Florence, S; Lopansri, BK; Hyland, K; Volkheimer, AD; Yeo, TW; Anstey, NM; Weinberg, JB; Mwaikambo, ED; Granger, DL
MLA Citation
Rubach, MP, Mukemba, J, Florence, S, Lopansri, BK, Hyland, K, Volkheimer, AD, Yeo, TW, Anstey, NM, Weinberg, JB, Mwaikambo, ED, and Granger, DL. "Impaired systemic tetrahydrobiopterin bioavailability and increased oxidized biopterins in pediatric falciparum malaria: association with disease severity." PLoS pathogens 11.3 (March 12, 2015): e1004655-.
PMID
25764173
Source
epmc
Published In
PLoS pathogens
Volume
11
Issue
3
Publish Date
2015
Start Page
e1004655
DOI
10.1371/journal.ppat.1004655

Final Clinical Results with Laboratory Correlates in the Phase I Trial of Lenalidomide Plus Plerixafor in Previously Treated Chronic Lymphocytic Leukemia (CLL)

Authors
Brander, DM; Allgood, SD; Rizzieri, DA; Stewart, T; Weinberg, JB; Lanasa, MC
MLA Citation
Brander, DM, Allgood, SD, Rizzieri, DA, Stewart, T, Weinberg, JB, and Lanasa, MC. "Final Clinical Results with Laboratory Correlates in the Phase I Trial of Lenalidomide Plus Plerixafor in Previously Treated Chronic Lymphocytic Leukemia (CLL)." December 6, 2014.
Source
wos-lite
Published In
Blood
Volume
124
Issue
21
Publish Date
2014

Double IGHV Gene Rearrangements in Chronic Lymphocytic Leukemia

Authors
Heyman, BM; Volkheimer, AD; Weinberg, JB; Lanasa, M
MLA Citation
Heyman, BM, Volkheimer, AD, Weinberg, JB, and Lanasa, M. "Double IGHV Gene Rearrangements in Chronic Lymphocytic Leukemia." December 6, 2014.
Source
wos-lite
Published In
Blood
Volume
124
Issue
21
Publish Date
2014

Decreased endothelial nitric oxide bioavailability, impaired microvascular function, and increased tissue oxygen consumption in children with falciparum malaria.

Endothelial nitric oxide (NO) bioavailability, microvascular function, and host oxygen consumption have not been assessed in pediatric malaria. We measured NO-dependent endothelial function by using peripheral artery tonometry to determine the reactive hyperemia index (RHI), and microvascular function and oxygen consumption (VO2) using near infrared resonance spectroscopy in 13 Indonesian children with severe falciparum malaria and 15 with moderately severe falciparum malaria. Compared with 19 controls, children with severe malaria and those with moderately severe malaria had lower RHIs (P = .03); 12% and 8% lower microvascular function, respectively (P = .03); and 29% and 25% higher VO2, respectively. RHIs correlated with microvascular function in all children with malaria (P < .001) and all with severe malaria (P < .001). Children with malaria have decreased endothelial and microvascular function and increased oxygen consumption, likely contributing to the pathogenesis of the disease.

Authors
Yeo, TW; Lampah, DA; Kenangalem, E; Tjitra, E; Weinberg, JB; Granger, DL; Price, RN; Anstey, NM
MLA Citation
Yeo, TW, Lampah, DA, Kenangalem, E, Tjitra, E, Weinberg, JB, Granger, DL, Price, RN, and Anstey, NM. "Decreased endothelial nitric oxide bioavailability, impaired microvascular function, and increased tissue oxygen consumption in children with falciparum malaria." The Journal of infectious diseases 210.10 (November 2014): 1627-1632.
PMID
24879801
Source
epmc
Published In
Journal of Infectious Diseases
Volume
210
Issue
10
Publish Date
2014
Start Page
1627
End Page
1632
DOI
10.1093/infdis/jiu308

The role of alternatively activated (M2) monocytes in limiting NO bioavailability in falciparum malaria

Authors
Weinberg, JB; Volkheimer, AD; Chen, Y; Rubach, MP; Mwaikambo, ED; Mukemba, J; Florence, S; Yeo, TW; Granger, DL; Anstey, NM
MLA Citation
Weinberg, JB, Volkheimer, AD, Chen, Y, Rubach, MP, Mwaikambo, ED, Mukemba, J, Florence, S, Yeo, TW, Granger, DL, and Anstey, NM. "The role of alternatively activated (M2) monocytes in limiting NO bioavailability in falciparum malaria." Nitric Oxide 42 (November 2014): 101-101.
Source
crossref
Published In
Nitric Oxide: Biology and Chemistry
Volume
42
Publish Date
2014
Start Page
101
End Page
101
DOI
10.1016/j.niox.2014.09.012

Dimethylarginines: endogenous inhibitors of nitric oxide synthesis in children with falciparum malaria.

Nitric oxide (NO) bioavailability is impaired in children and adults with severe falciparum malaria (SM). Asymmetric-dimethylarginine (ADMA) limits NO production by inhibiting NO synthase and is increased in adult SM. The role of ADMA in the pathogenesis of childhood SM is unknown.We studied Tanzanian children ages 4-8 years with malaria. Plasma levels of arginine, arginase, cell-free hemoglobin, ADMA, symmetric-dimethylarginine (SDMA), histidine-rich protein-2, and angiopoietin-2 were measured.ADMA was low in children with SM relative to controls. Nevertheless, arginine and arginine:ADMA ratios were very low in SM. SDMA was high in children with SM. With treatment, arginine and the arginine:ADMA ratio normalized, but SDMA did not. Arginine:ADMA ratios, but not arginine, were significantly and inde-pendent-ly inversely associated with lactate and angiopoietin-2. Plasma arginase was not elevated in those with malaria, and plasma free hemoglobin was elevated only in patients with cerebral malaria.In contrast to adults, plasma ADMA is reduced in SM in children, but hypoargininemia is more severe. Arginine bioavailability (reflected by low arginine:ADMA ratios) is therefore comparably low in SM in children as in adults. Therapies to increase NO bioavailability in malaria may be useful as adjunctive treatment of severe malaria in children.

Authors
Weinberg, JB; Yeo, TW; Mukemba, JP; Florence, SM; Volkheimer, AD; Wang, H; Chen, Y; Rubach, M; Granger, DL; Mwaikambo, ED; Anstey, NM
MLA Citation
Weinberg, JB, Yeo, TW, Mukemba, JP, Florence, SM, Volkheimer, AD, Wang, H, Chen, Y, Rubach, M, Granger, DL, Mwaikambo, ED, and Anstey, NM. "Dimethylarginines: endogenous inhibitors of nitric oxide synthesis in children with falciparum malaria." The Journal of infectious diseases 210.6 (September 2014): 913-922.
PMID
24620026
Source
epmc
Published In
Journal of Infectious Diseases
Volume
210
Issue
6
Publish Date
2014
Start Page
913
End Page
922
DOI
10.1093/infdis/jiu156

Quantification of Plasmodium falciparum histidine-rich protein-2 in cerebrospinal spinal fluid from cerebral malaria patients.

A cerebrospinal fluid (CSF) biomarker for cerebral malaria (CM) has not been validated. We examined the detection, semiquantification, and clinical use of the Plasmodium falciparum histidine-rich protein-2 (PfHRP-2) as a parasite antigen biomarker for CM. The PfHRP-2 was detected in archival CSF samples from CM patients from Tanzania both by a newly developed sensitive and specific immuno-polymerase chain reaction (72 of 73) and by rapid diagnostic tests (62 of 73). The geometric mean PfHRP-2 CSF concentration was 8.76 ng/mL with no differences in those who survived (9.2 ng/mL), those who died (11.1 ng/mL), and those with neurologic sequelae (10.8 ng/mL). All aparasitemic endemic and nonendemic control samples had undetectable CSF PfHRP-2. In a separate group of 11 matched plasma and CSF cerebral malaria patient samples, the ratio of plasma to CSF PfHRP-2 was 175. The CSF PfHRP-2 reflects elevated plasma PfHRP-2 rather than elevated CM-specific CSF ratios, falling short of a validated biomarker.

Authors
Mikita, K; Thakur, K; Anstey, NM; Piera, KA; Pardo, CA; Weinberg, JB; Mukemba, J; Florence, S; Mwaikambo, ED; Granger, DL; Sullivan, DJ
MLA Citation
Mikita, K, Thakur, K, Anstey, NM, Piera, KA, Pardo, CA, Weinberg, JB, Mukemba, J, Florence, S, Mwaikambo, ED, Granger, DL, and Sullivan, DJ. "Quantification of Plasmodium falciparum histidine-rich protein-2 in cerebrospinal spinal fluid from cerebral malaria patients." The American journal of tropical medicine and hygiene 91.3 (September 2014): 486-492.
PMID
24980497
Source
epmc
Published In
American Journal of Tropical Medicine and Hygiene
Volume
91
Issue
3
Publish Date
2014
Start Page
486
End Page
492
DOI
10.4269/ajtmh.14-0210

Perifosine treatment in chronic lymphocytic leukemia: results of a phase II clinical trial and in vitro studies.

Abstract Because of the importance of the phosphoinositide 3-kinase (PI3K)/AKT pathway in chronic lymphocytic leukemia (CLL), we evaluated in vitro cytotoxicity induced by perifosine, an AKT inhibitor, in CLL lymphocytes and found that the mean 50% effective dose (ED50) was 313 nM. We then performed a phase II trial of perifosine in patients with relapsed/refractory CLL to assess response, outcomes, toxicity and ex vivo correlative measures. After 3 months of treatment, six of eight patients showed stable disease, one achieved a partial response and one had progressive disease. Median event-free survival and overall survival in all patients treated were 3.9 and 9.7 months. Adverse events included hematologic, infectious/fever, pain, gastrointestinal and constitutional toxicities. Unexpectedly, AKT phosphorylation in CLL lymphocytes from treated patients was not correlated with response. Additionally, perifosine did not inhibit AKT phosphorylation in cultured CLL lymphocytes. Perifosine is cytotoxic to CLL cells in vitro, and largely induces stabilized disease in vivo, with an AKT-independent mechanism.

Authors
Friedman, DR; Lanasa, MC; Davis, PH; Allgood, SD; Matta, KM; Brander, DM; Chen, Y; Davis, ED; Volkheimer, AD; Moore, JO; Gockerman, JP; Sportelli, P; Weinberg, JB
MLA Citation
Friedman, DR, Lanasa, MC, Davis, PH, Allgood, SD, Matta, KM, Brander, DM, Chen, Y, Davis, ED, Volkheimer, AD, Moore, JO, Gockerman, JP, Sportelli, P, and Weinberg, JB. "Perifosine treatment in chronic lymphocytic leukemia: results of a phase II clinical trial and in vitro studies." Leukemia & lymphoma 55.5 (May 2014): 1067-1075.
PMID
23863122
Source
epmc
Published In
Leukemia & Lymphoma (Informa)
Volume
55
Issue
5
Publish Date
2014
Start Page
1067
End Page
1075
DOI
10.3109/10428194.2013.824080

Increased plasma arginase activity in human sepsis: association with increased circulating neutrophils.

BACKGROUND: The pathophysiology of sepsis is incompletely understood. Impaired bioavailability of L-arginine, the substrate for NO synthesis, is linked to sepsis severity, and plasma arginase has been linked to hypoargininemia in other disease states. Circulating neutrophils are increased in sepsis and constitutively express arginase. We investigated whether plasma arginase activity is increased in human sepsis and whether this is associated with neutrophil numbers and activation. METHODS: We used HPLC and a radiometric assay to evaluate plasma amino acid concentrations and plasma arginase activity. The relationships between plasma arginase activity, neutrophil count, neutrophil activity and plasma L-arginine and arginine metabolites were evaluated in 44 sepsis patients and 25 controls. RESULTS: Plasma arginase activity was increased in sepsis patients, correlated with neutrophil count (r=0.44; p=0.003), but was independent of sepsis severity (SOFA or APACHE II score). Plasma HNP1-3 correlated with neutrophil count (r=0.31; p=0.04), was elevated in shock (median 180 ng/mL vs. 83 ng/mL sepsis without shock, p=0.0006) and correlated with SOFA score. Sepsis patients with high neutrophil counts had significantly higher plasma HNP1-3 and arginase activity and lower plasma L-arginine concentrations than those with lower neutrophil counts and controls. CONCLUSIONS: Plasma arginase activity, potentially derived in part from neutrophil activation, is elevated in sepsis, and may contribute to impaired bioavailability of L-arginine in sepsis.

Authors
Darcy, CJ; Woodberry, T; Davis, JS; Piera, KA; McNeil, YR; Chen, Y; Yeo, TW; Weinberg, JB; Anstey, NM
MLA Citation
Darcy, CJ, Woodberry, T, Davis, JS, Piera, KA, McNeil, YR, Chen, Y, Yeo, TW, Weinberg, JB, and Anstey, NM. "Increased plasma arginase activity in human sepsis: association with increased circulating neutrophils." Clin Chem Lab Med 52.4 (April 2014): 573-581.
PMID
24166672
Source
pubmed
Published In
Clinical Chemistry and Laboratory Medicine
Volume
52
Issue
4
Publish Date
2014
Start Page
573
End Page
581
DOI
10.1515/cclm-2013-0698

Neutrophils with myeloid derived suppressor function deplete arginine and constrain T cell function in septic shock patients.

INTRODUCTION: Impaired T cell function in sepsis is associated with poor outcome, but the mechanisms are unclear. In cancer, arginase-expressing myeloid derived suppressor cells (MDSCs) deplete arginine, impair T cell receptor CD3 zeta-chain expression and T cell function and are linked to poor clinical outcome, but their role during acute human infectious disease and in particular sepsis remains unknown. Hypoarginemia is prevalent in sepsis. This study aimed to determine whether neutrophils that co-purify with PBMC express arginase, and if arginine depletion constrains T cell CD3 zeta-chain expression and function in human sepsis. METHODS: Using flow cytometry, cell culture, HPLC, arginase activity and mRNA detection, our study examined whether neutrophils, with reduced buoyant density isolated in the Ficoll interface, metabolise L-arginine and suppress T cell proliferation in sepsis. A total of 35 sepsis patients (23 with septic shock) and 12 hospital controls in a tertiary referral hospital in tropical Australia were evaluated. RESULTS: Only sepsis patients had interphase neutrophils, neutrophils co-purifying with mononuclear cells (≤1.077 specific gravity). The percentage of interphase neutrophils in sepsis was proportional to sepsis severity and correlated with plasma IL-6 concentrations. Ex vivo, sepsis-derived interphase neutrophils expressed arginase, metabolised culture L-arginine and suppressed T cell proliferation and CD3 zeta-chain expression. In vivo, in septic shock there was a longitudinal inverse association between interphase neutrophil number and CD3 zeta-chain expression. Depletion or inhibition of interphase neutrophils in vitro restored zeta-chain expression and T cell function. CONCLUSIONS: For the first time during an acute human infection, interphase neutrophils that express arginase were found to circulate in sepsis, in proportion to disease severity. These neutrophil-MDSCs impair T cell CD3 zeta-chain expression and T cell function via L-arginine metabolism, and likely contribute to the T cell dysfunction seen in sepsis. Modulation of neutrophil-MDSC or their downstream effects warrant consideration as targets for novel adjunctive therapies in sepsis.

Authors
Darcy, CJ; Minigo, G; Piera, KA; Davis, JS; McNeil, YR; Chen, Y; Volkheimer, AD; Weinberg, JB; Anstey, NM; Woodberry, T
MLA Citation
Darcy, CJ, Minigo, G, Piera, KA, Davis, JS, McNeil, YR, Chen, Y, Volkheimer, AD, Weinberg, JB, Anstey, NM, and Woodberry, T. "Neutrophils with myeloid derived suppressor function deplete arginine and constrain T cell function in septic shock patients." Critical care (London, England) 18.4 (January 2014): R163-.
PMID
25084831
Source
epmc
Published In
Critical Care
Volume
18
Issue
4
Publish Date
2014
Start Page
R163
DOI
10.1186/cc14003

CD38 variation as a prognostic factor in chronic lymphocytic leukemia.

Authors
Nipp, RD; Volkheimer, AD; Davis, ED; Chen, Y; Weinberg, JB; Friedman, DR
MLA Citation
Nipp, RD, Volkheimer, AD, Davis, ED, Chen, Y, Weinberg, JB, and Friedman, DR. "CD38 variation as a prognostic factor in chronic lymphocytic leukemia." Leuk Lymphoma 55.1 (January 2014): 191-194. (Letter)
PMID
23510236
Source
pubmed
Published In
Leukemia & Lymphoma (Informa)
Volume
55
Issue
1
Publish Date
2014
Start Page
191
End Page
194
DOI
10.3109/10428194.2013.786070

Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia.

Genome-wide association studies (GWAS) have previously identified 13 loci associated with risk of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL). To identify additional CLL susceptibility loci, we conducted the largest meta-analysis for CLL thus far, including four GWAS with a total of 3,100 individuals with CLL (cases) and 7,667 controls. In the meta-analysis, we identified ten independent associated SNPs in nine new loci at 10q23.31 (ACTA2 or FAS (ACTA2/FAS), P=1.22×10(-14)), 18q21.33 (BCL2, P=7.76×10(-11)), 11p15.5 (C11orf21, P=2.15×10(-10)), 4q25 (LEF1, P=4.24×10(-10)), 2q33.1 (CASP10 or CASP8 (CASP10/CASP8), P=2.50×10(-9)), 9p21.3 (CDKN2B-AS1, P=1.27×10(-8)), 18q21.32 (PMAIP1, P=2.51×10(-8)), 15q15.1 (BMF, P=2.71×10(-10)) and 2p22.2 (QPCT, P=1.68×10(-8)), as well as an independent signal at an established locus (2q13, ACOXL, P=2.08×10(-18)). We also found evidence for two additional promising loci below genome-wide significance at 8q22.3 (ODF1, P=5.40×10(-8)) and 5p15.33 (TERT, P=1.92×10(-7)). Although further studies are required, the proximity of several of these loci to genes involved in apoptosis suggests a plausible underlying biological mechanism.

Authors
Berndt, SI; Skibola, CF; Joseph, V; Camp, NJ; Nieters, A; Wang, Z; Cozen, W; Monnereau, A; Wang, SS; Kelly, RS; Lan, Q; Teras, LR; Chatterjee, N; Chung, CC; Yeager, M; Brooks-Wilson, AR; Hartge, P; Purdue, MP; Birmann, BM; Armstrong, BK; Cocco, P; Zhang, Y; Severi, G; Zeleniuch-Jacquotte, A; Lawrence, C; Burdette, L; Yuenger, J; Hutchinson, A; Jacobs, KB; Call, TG; Shanafelt, TD; Novak, AJ; Kay, NE; Liebow, M; Wang, AH; Smedby, KE; Adami, H-O; Melbye, M; Glimelius, B; Chang, ET; Glenn, M et al.
MLA Citation
Berndt, SI, Skibola, CF, Joseph, V, Camp, NJ, Nieters, A, Wang, Z, Cozen, W, Monnereau, A, Wang, SS, Kelly, RS, Lan, Q, Teras, LR, Chatterjee, N, Chung, CC, Yeager, M, Brooks-Wilson, AR, Hartge, P, Purdue, MP, Birmann, BM, Armstrong, BK, Cocco, P, Zhang, Y, Severi, G, Zeleniuch-Jacquotte, A, Lawrence, C, Burdette, L, Yuenger, J, Hutchinson, A, Jacobs, KB, Call, TG, Shanafelt, TD, Novak, AJ, Kay, NE, Liebow, M, Wang, AH, Smedby, KE, Adami, H-O, Melbye, M, Glimelius, B, Chang, ET, and Glenn, M et al. "Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia." Nat Genet 45.8 (August 2013): 868-876.
PMID
23770605
Source
pubmed
Published In
Nature Genetics
Volume
45
Issue
8
Publish Date
2013
Start Page
868
End Page
876
DOI
10.1038/ng.2652

Mapping of the IRF8 gene identifies a 3'UTR variant associated with risk of chronic lymphocytic leukemia but not other common non-Hodgkin lymphoma subtypes.

BACKGROUND: Our genome-wide association study (GWAS) of chronic lymphocytic leukemia (CLL) identified 4 highly correlated intronic variants within the IRF8 gene that were associated with CLL. These results were further supported by a recent meta-analysis of our GWAS with two other GWAS of CLL, supporting the IRF8 gene as a strong candidate for CLL risk. METHODS: To refine the genetic association of CLL risk, we conducted Sanger sequencing of IRF8 in 94 CLL cases and 96 controls. We then conducted fine mapping by genotyping 39 variants (of which 10 were identified from sequencing) in 745 CLL cases and 1,521 controls. We also assessed these associations with risk of other non-Hodgkin lymphoma (NHL) subtypes. RESULTS: The strongest association with CLL risk was observed with a common single-nucleotide polymorphism (SNP) located within the 3' untranslated region (UTR) of IRF8 (rs1044873, log additive OR = 0.7, P = 1.81 × 10(-6)). This SNP was not associated with the other NHL subtypes (all P > 0.05). CONCLUSIONS: We provide evidence that rs1044873 in the IRF8 gene accounts for the initial GWAS signal for CLL risk. This association appears to be unique to CLL with little support for association with other common NHL subtypes. Future work is needed to assess functional role of IRF8 in CLL etiology. IMPACT: These data provide support that a functional variant within the 3'UTR of IRF8 may be driving the GWAS signal seen on 16q24.1 for CLL risk.

Authors
Slager, SL; Achenbach, SJ; Asmann, YW; Camp, NJ; Rabe, KG; Goldin, LR; Call, TG; Shanafelt, TD; Kay, NE; Cunningham, JM; Wang, AH; Weinberg, JB; Norman, AD; Link, BK; Leis, JF; Vachon, CM; Lanasa, MC; Caporaso, NE; Novak, AJ; Cerhan, JR
MLA Citation
Slager, SL, Achenbach, SJ, Asmann, YW, Camp, NJ, Rabe, KG, Goldin, LR, Call, TG, Shanafelt, TD, Kay, NE, Cunningham, JM, Wang, AH, Weinberg, JB, Norman, AD, Link, BK, Leis, JF, Vachon, CM, Lanasa, MC, Caporaso, NE, Novak, AJ, and Cerhan, JR. "Mapping of the IRF8 gene identifies a 3'UTR variant associated with risk of chronic lymphocytic leukemia but not other common non-Hodgkin lymphoma subtypes." Cancer Epidemiol Biomarkers Prev 22.3 (March 2013): 461-466.
PMID
23307532
Source
pubmed
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
22
Issue
3
Publish Date
2013
Start Page
461
End Page
466
DOI
10.1158/1055-9965.EPI-12-1217

Chronic lymphocytic leukemia and regulatory B cells share IL-10 competence and immunosuppressive function.

Chronic lymphocytic leukemia (CLL) can be immunosuppressive in humans and mice, and CLL cells share multiple phenotypic markers with regulatory B cells that are competent to produce interleukin (IL)-10 (B10 cells). To identify functional links between CLL cells and regulatory B10 cells, the phenotypes and abilities of leukemia cells from 93 patients with overt CLL to express IL-10 were assessed. CD5(+) CLL cells purified from 90% of the patients were IL-10-competent and secreted IL-10 following appropriate ex vivo stimulation. Serum IL-10 levels were also significantly elevated in CLL patients. IL-10-competent cell frequencies were higher among CLLs with IgV(H) mutations, and correlated positively with TCL1 expression. In the TCL1-transgenic (TCL1-Tg) mouse model of CLL, IL-10-competent B cells with the cell surface phenotype of B10 cells expanded significantly with age, preceding the development of overt, CLL-like leukemia. Malignant CLL cells in TCL1-Tg mice also shared immunoregulatory functions with mouse and human B10 cells. Serum IL-10 levels varied in TCL1-Tg mice, but in vivo low-dose lipopolysaccharide treatment induced IL-10 expression in CLL cells and high levels of serum IL-10. Thus, malignant IL-10-competent CLL cells exhibit regulatory functions comparable to normal B10 cells that may contribute to the immunosuppression observed in patients and TCL1-Tg mice.

Authors
DiLillo, DJ; Weinberg, JB; Yoshizaki, A; Horikawa, M; Bryant, JM; Iwata, Y; Matsushita, T; Matta, KM; Chen, Y; Venturi, GM; Russo, G; Gockerman, JP; Moore, JO; Diehl, LF; Volkheimer, AD; Friedman, DR; Lanasa, MC; Hall, RP; Tedder, TF
MLA Citation
DiLillo, DJ, Weinberg, JB, Yoshizaki, A, Horikawa, M, Bryant, JM, Iwata, Y, Matsushita, T, Matta, KM, Chen, Y, Venturi, GM, Russo, G, Gockerman, JP, Moore, JO, Diehl, LF, Volkheimer, AD, Friedman, DR, Lanasa, MC, Hall, RP, and Tedder, TF. "Chronic lymphocytic leukemia and regulatory B cells share IL-10 competence and immunosuppressive function." Leukemia 27.1 (January 2013): 170-182.
PMID
22713648
Source
pubmed
Published In
Leukemia
Volume
27
Issue
1
Publish Date
2013
Start Page
170
End Page
182
DOI
10.1038/leu.2012.165

Clinical and biological relevance of genomic heterogeneity in chronic lymphocytic leukemia.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is typically regarded as an indolent B-cell malignancy. However, there is wide variability with regards to need for therapy, time to progressive disease, and treatment response. This clinical variability is due, in part, to biological heterogeneity between individual patients' leukemias. While much has been learned about this biological variation using genomic approaches, it is unclear whether such efforts have sufficiently evaluated biological and clinical heterogeneity in CLL. METHODS: To study the extent of genomic variability in CLL and the biological and clinical attributes of genomic classification in CLL, we evaluated 893 unique CLL samples from fifteen publicly available gene expression profiling datasets. We used unsupervised approaches to divide the data into subgroups, evaluated the biological pathways and genetic aberrations that were associated with the subgroups, and compared prognostic and clinical outcome data between the subgroups. RESULTS: Using an unsupervised approach, we determined that approximately 600 CLL samples are needed to define the spectrum of diversity in CLL genomic expression. We identified seven genomically-defined CLL subgroups that have distinct biological properties, are associated with specific chromosomal deletions and amplifications, and have marked differences in molecular prognostic markers and clinical outcomes. CONCLUSIONS: Our results indicate that investigations focusing on small numbers of patient samples likely provide a biased outlook on CLL biology. These findings may have important implications in identifying patients who should be treated with specific targeted therapies, which could have efficacy against CLL cells that rely on specific biological pathways.

Authors
Friedman, DR; Lucas, JE; Weinberg, JB
MLA Citation
Friedman, DR, Lucas, JE, and Weinberg, JB. "Clinical and biological relevance of genomic heterogeneity in chronic lymphocytic leukemia." PLoS One 8.2 (2013): e57356-.
PMID
23468975
Source
pubmed
Published In
PloS one
Volume
8
Issue
2
Publish Date
2013
Start Page
e57356
DOI
10.1371/journal.pone.0057356

Chronic lymphocytic leukemia and regulatory B cells share IL-10 competence and immunosuppressive function

Chronic lymphocytic leukemia (CLL) can be immunosuppressive in humans and mice, and CLL cells share multiple phenotypic markers with regulatory B cells that are competent to produce interleukin (IL)-10 (B10 cells). To identify functional links between CLL cells and regulatory B10 cells, the phenotypes and abilities of leukemia cells from 93 patients with overt CLL to express IL-10 were assessed. CD5 + CLL cells purified from 90% of the patients were IL-10-competent and secreted IL-10 following appropriate ex vivo stimulation. Serum IL-10 levels were also significantly elevated in CLL patients. IL-10-competent cell frequencies were higher among CLLs with IgV H mutations, and correlated positively with TCL1 expression. In the TCL1-transgenic (TCL1-Tg) mouse model of CLL, IL-10-competent B cells with the cell surface phenotype of B10 cells expanded significantly with age, preceding the development of overt, CLL-like leukemia. Malignant CLL cells in TCL1-Tg mice also shared immunoregulatory functions with mouse and human B10 cells. Serum IL-10 levels varied in TCL1-Tg mice, but in vivo low-dose lipopolysaccharide treatment induced IL-10 expression in CLL cells and high levels of serum IL-10. Thus, malignant IL-10-competent CLL cells exhibit regulatory functions comparable to normal B10 cells that may contribute to the immunosuppression observed in patients and TCL1-Tg mice. © 2013 Macmillan Publishers Limited All rights reserved.

Authors
Dilillo, DJ; Weinberg, JB; Yoshizaki, A; Horikawa, M; Bryant, JM; Iwata, Y; Matsushita, T; Matta, KM; Chen, Y; Venturi, GM; Russo, G; Gockerman, JP; Moore, JO; Diehl, LF; Volkheimer, AD; Friedman, DR; Lanasa, MC; Hall, RP; Tedder, TF
MLA Citation
Dilillo, DJ, Weinberg, JB, Yoshizaki, A, Horikawa, M, Bryant, JM, Iwata, Y, Matsushita, T, Matta, KM, Chen, Y, Venturi, GM, Russo, G, Gockerman, JP, Moore, JO, Diehl, LF, Volkheimer, AD, Friedman, DR, Lanasa, MC, Hall, RP, and Tedder, TF. "Chronic lymphocytic leukemia and regulatory B cells share IL-10 competence and immunosuppressive function." Leukemia 27.1 (2013): 170-182.
Source
scival
Published In
Leukemia
Volume
27
Issue
1
Publish Date
2013
Start Page
170
End Page
182
DOI
10.1038/leu.2012.165

The inhibition by interleukin 1 of MSC chondrogenesis and the development of biomechanical properties in biomimetic 3D woven PCL scaffolds.

Tissue-engineered constructs designed to treat large cartilage defects or osteoarthritic lesions may be exposed to significant mechanical loading as well as an inflammatory environment upon implantation in an injured or diseased joint. We hypothesized that a three-dimensionally (3D) woven poly(ε-caprolactone) (PCL) scaffold seeded with bone marrow-derived mesenchymal stem cells (MSCs) would provide biomimetic mechanical properties in early stages of in vitro culture as the MSCs assembled a functional, cartilaginous extracellular matrix (ECM). We also hypothesized that these properties would be maintained even in the presence of the pro-inflammatory cytokine interleukin-1 (IL-1), which is found at high levels in injured or diseased joints. MSC-seeded 3D woven scaffolds cultured in chondrogenic conditions synthesized a functional ECM rich in collagen and proteoglycan content, reaching an aggregate modulus of ~0.75 MPa within 14 days of culture. However, the presence of pathophysiologically relevant levels of IL-1 limited matrix accumulation and inhibited any increase in mechanical properties over baseline values. On the other hand, the mechanical properties of constructs cultured in chondrogenic conditions for 4 weeks prior to IL-1 exposure were protected from deleterious effects of the cytokine. These findings demonstrate that IL-1 significantly inhibits the chondrogenic development and maturation of MSC-seeded constructs; however, the overall mechanical functionality of the engineered tissue can be preserved through the use of a 3D woven scaffold designed to recreate the mechanical properties of native articular cartilage.

Authors
Ousema, PH; Moutos, FT; Estes, BT; Caplan, AI; Lennon, DP; Guilak, F; Weinberg, JB
MLA Citation
Ousema, PH, Moutos, FT, Estes, BT, Caplan, AI, Lennon, DP, Guilak, F, and Weinberg, JB. "The inhibition by interleukin 1 of MSC chondrogenesis and the development of biomechanical properties in biomimetic 3D woven PCL scaffolds." Biomaterials 33.35 (December 2012): 8967-8974.
PMID
22999467
Source
pubmed
Published In
Biomaterials
Volume
33
Issue
35
Publish Date
2012
Start Page
8967
End Page
8974
DOI
10.1016/j.biomaterials.2012.08.045

Common variants within 6p21.31 locus are associated with chronic lymphocytic leukaemia and, potentially, other non-Hodgkin lymphoma subtypes.

A recent meta-analysis of three genome-wide association studies of chronic lymphocytic leukaemia (CLL) identified two common variants at the 6p21.31 locus that are associated with CLL risk. To verify and further explore the association of these variants with other non-Hodgkin lymphoma (NHL) subtypes, we genotyped 1196 CLL cases, 1699 NHL cases, and 2410 controls. We found significant associations between the 6p21.31 variants and CLL risk (rs210134: P = 0·01; rs210142: P = 6·8 × 10(-3)). These variants also showed a trend towards association with some of the other NHL subtypes. Our results validate the prior work and support specific genetic pathways for risk among NHL subtypes.

Authors
Slager, SL; Camp, NJ; Conde, L; Shanafelt, TD; Achenbach, SJ; Rabe, KG; Kay, NE; Novak, AJ; Call, TG; Bracci, PM; Sille, FMC; Sanchez, S; Akers, NK; Cunningham, JM; Serie, DJ; McDonnell, SK; Leis, JF; Wang, AH; Weinberg, JB; Glenn, M; Link, B; Vachon, CM; Lanasa, MC; Skibola, CF; Cerhan, JR
MLA Citation
Slager, SL, Camp, NJ, Conde, L, Shanafelt, TD, Achenbach, SJ, Rabe, KG, Kay, NE, Novak, AJ, Call, TG, Bracci, PM, Sille, FMC, Sanchez, S, Akers, NK, Cunningham, JM, Serie, DJ, McDonnell, SK, Leis, JF, Wang, AH, Weinberg, JB, Glenn, M, Link, B, Vachon, CM, Lanasa, MC, Skibola, CF, and Cerhan, JR. "Common variants within 6p21.31 locus are associated with chronic lymphocytic leukaemia and, potentially, other non-Hodgkin lymphoma subtypes." Br J Haematol 159.5 (December 2012): 572-576.
PMID
23025533
Source
pubmed
Published In
British Journal of Haematology
Volume
159
Issue
5
Publish Date
2012
Start Page
572
End Page
576
DOI
10.1111/bjh.12070

CD38 Variation in Chronic Lymphocytic Leukemia

Authors
Nipp, RD; Weinberg, JB; Volkheimer, AD; Davis, ED; Chen, Y; Friedman, DR
MLA Citation
Nipp, RD, Weinberg, JB, Volkheimer, AD, Davis, ED, Chen, Y, and Friedman, DR. "CD38 Variation in Chronic Lymphocytic Leukemia." November 16, 2012.
Source
wos-lite
Published In
Blood
Volume
120
Issue
21
Publish Date
2012

Chronic lymphocytic leukemia in African Americans.

Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in the United States with almost 4390 attributable deaths per year. Epidemiologic data compiled by the Surveillance, Epidemiology and End Results (SEER) program identifies important differences in incidence and survival for African Americans with CLL. Although the incidence of CLL is lower among African Americans than among Caucasians (4.6 and 6.2 per 100 000 men, respectively), age-adjusted survival is inferior. African American patients with CLL are almost twice as likely to die from a CLL-related complication in the first 5 years after diagnosis as are Caucasian patients with CLL. The biologic basis for these observations is almost entirely unexplored, and a comprehensive clinical analysis of African American patients with CLL is lacking. This is the subject of the present review.

Authors
Coombs, CC; Falchi, L; Weinberg, JB; Ferrajoli, A; Lanasa, MC
MLA Citation
Coombs, CC, Falchi, L, Weinberg, JB, Ferrajoli, A, and Lanasa, MC. "Chronic lymphocytic leukemia in African Americans." Leuk Lymphoma 53.11 (November 2012): 2326-2329. (Review)
PMID
22646816
Source
pubmed
Published In
Leukemia & Lymphoma (Informa)
Volume
53
Issue
11
Publish Date
2012
Start Page
2326
End Page
2329
DOI
10.3109/10428194.2012.698276

Single nucleotide polymorphisms and inherited risk of chronic lymphocytic leukemia among African Americans.

The incidence of chronic lymphocytic leukemia (CLL) is significantly lower in African Americans than whites, but overall survival is inferior. The biologic basis for these observations remains unexplored. We hypothesized that germline genetic predispositions differ between African Americans and whites with CLL and yield inferior clinical outcomes among African Americans. We examined a discovery cohort of 42 African American CLL patients ascertained at Duke University and found that the risk allele frequency of most single nucleotide polymorphisms known to confer risk of development for CLL is significantly lower among African Americans than whites. We then confirmed our results in a distinct cohort of 68 African American patients ascertained by the CLL Research Consortium. These results provide the first evidence supporting differential genetic risk for CLL between African Americans compared with whites. A fuller understanding of differential genetic risk may improve prognostication and therapeutic decision making for all CLL patients.

Authors
Coombs, CC; Rassenti, LZ; Falchi, L; Slager, SL; Strom, SS; Ferrajoli, A; Weinberg, JB; Kipps, TJ; Lanasa, MC
MLA Citation
Coombs, CC, Rassenti, LZ, Falchi, L, Slager, SL, Strom, SS, Ferrajoli, A, Weinberg, JB, Kipps, TJ, and Lanasa, MC. "Single nucleotide polymorphisms and inherited risk of chronic lymphocytic leukemia among African Americans." Blood 120.8 (August 23, 2012): 1687-1690.
PMID
22745306
Source
pubmed
Published In
Blood
Volume
120
Issue
8
Publish Date
2012
Start Page
1687
End Page
1690
DOI
10.1182/blood-2012-02-408799

Common variation at 6p21.31 (BAK1) influences the risk of chronic lymphocytic leukemia.

We performed a meta-analysis of 3 genome-wide association studies to identify additional common variants influencing chronic lymphocytic leukemia (CLL) risk. The discovery phase was composed of genome-wide association study data from 1121 cases and 3745 controls. Replication analysis was performed in 861 cases and 2033 controls. We identified a novel CLL risk locus at 6p21.33 (rs210142; intronic to the BAK1 gene, BCL2 antagonist killer 1; P = 9.47 × 10(-16)). A strong relationship between risk genotype and reduced BAK1 expression was shown in lymphoblastoid cell lines. This finding provides additional support for polygenic inheritance to CLL and provides further insight into the biologic basis of disease development.

Authors
Slager, SL; Skibola, CF; Di Bernardo, MC; Conde, L; Broderick, P; McDonnell, SK; Goldin, LR; Croft, N; Holroyd, A; Harris, S; Riby, J; Serie, DJ; Kay, NE; Call, TG; Bracci, PM; Halperin, E; Lanasa, MC; Cunningham, JM; Leis, JF; Morrison, VA; Spector, LG; Vachon, CM; Shanafelt, TD; Strom, SS; Camp, NJ; Weinberg, JB; Matutes, E; Caporaso, NE; Wade, R; Dyer, MJS; Dearden, C; Cerhan, JR; Catovsky, D; Houlston, RS
MLA Citation
Slager, SL, Skibola, CF, Di Bernardo, MC, Conde, L, Broderick, P, McDonnell, SK, Goldin, LR, Croft, N, Holroyd, A, Harris, S, Riby, J, Serie, DJ, Kay, NE, Call, TG, Bracci, PM, Halperin, E, Lanasa, MC, Cunningham, JM, Leis, JF, Morrison, VA, Spector, LG, Vachon, CM, Shanafelt, TD, Strom, SS, Camp, NJ, Weinberg, JB, Matutes, E, Caporaso, NE, Wade, R, Dyer, MJS, Dearden, C, Cerhan, JR, Catovsky, D, and Houlston, RS. "Common variation at 6p21.31 (BAK1) influences the risk of chronic lymphocytic leukemia." Blood 120.4 (July 26, 2012): 843-846.
PMID
22700719
Source
pubmed
Published In
Blood
Volume
120
Issue
4
Publish Date
2012
Start Page
843
End Page
846
DOI
10.1182/blood-2012-03-413591

Phase II study of cenersen, an antisense inhibitor of p53, in combination with fludarabine, cyclophosphamide and rituximab for high-risk chronic lymphocytic leukemia.

Patients with chronic lymphocytic leukemia (CLL) with deletion or mutation of TP53 have exceedingly poor clinical outcomes. Cenersen, an oligonucleotide targeting TP53, has been shown to abrogate the activity of TP53 gain-of-function mutants and to increase sensitivity of lymphoma cells to cytotoxic chemotherapy in vitro. We combined cenersen with fludarabine, cyclophosphamide and rituximab (FCR) as treatment for patients with high-risk CLL. The purpose of this phase II study was to determine the overall response rate, response duration and toxicity of cenersen administered in combination with FCR. Twenty patients with relapsed or high-risk CLL were evaluated. Nineteen patients were previously treated. The complete response rate was 18%; the overall response rate was 53%. Median progression-free and overall survival was 5.3 and 10.6 months, respectively. The most common serious adverse events were neutropenia and thrombocytopenia. In this single arm phase II study, cenersen combined with FCR yielded clinical responses with acceptable toxicity in patients with high-risk CLL.

Authors
Lanasa, MC; Davis, PH; Datto, M; Li, Z; Gockerman, JP; Moore, JO; DeCastro, CM; Friedman, DR; Diehl, LF; Rehder, C; Cook, H; Daugherty, FJ; Matta, KMB; Weinberg, JB; Rizzieri, D
MLA Citation
Lanasa, MC, Davis, PH, Datto, M, Li, Z, Gockerman, JP, Moore, JO, DeCastro, CM, Friedman, DR, Diehl, LF, Rehder, C, Cook, H, Daugherty, FJ, Matta, KMB, Weinberg, JB, and Rizzieri, D. "Phase II study of cenersen, an antisense inhibitor of p53, in combination with fludarabine, cyclophosphamide and rituximab for high-risk chronic lymphocytic leukemia." Leuk Lymphoma 53.2 (February 2012): 218-224.
PMID
21827374
Source
pubmed
Published In
Leukemia & Lymphoma (Informa)
Volume
53
Issue
2
Publish Date
2012
Start Page
218
End Page
224
DOI
10.3109/10428194.2011.610012

Plasma Plasmodium falciparum histidine-rich protein-2 concentrations are associated with malaria severity and mortality in Tanzanian children.

Plasma Plasmodium falciparum histidine-rich protein-2 (PfHRP-2) concentrations, a measure of parasite biomass, have been correlated with malaria severity in adults, but not yet in children. We measured plasma PfHRP-2 in Tanzanian children with uncomplicated (n = 61) and cerebral malaria (n = 45; 7 deaths). Median plasma PfHRP-2 concentrations were higher in cerebral malaria (1008 [IQR 342-2572] ng/mL) than in uncomplicated malaria (465 [IQR 36-1426] ng/mL; p = 0.017). In cerebral malaria, natural log plasma PfHRP-2 was associated with coma depth (r = -0.42; p = 0.006) and mortality (OR: 3.0 [95% CI 1.03-8.76]; p = 0.04). In this relatively small cohort study in a mesoendemic transmission area of Africa, plasma PfHRP-2 was associated with pediatric malaria severity and mortality. Further studies among children in areas of Africa with higher malaria transmission and among children with different clinical manifestations of severe malaria will help determine the wider utility of quantitative PfHRP-2 as a measure of parasite biomass and prognosis in sub-Saharan Africa.

Authors
Rubach, MP; Mukemba, J; Florence, S; John, B; Crookston, B; Lopansri, BK; Yeo, TW; Piera, KA; Alder, SC; Weinberg, JB; Anstey, NM; Granger, DL; Mwaikambo, ED
MLA Citation
Rubach, MP, Mukemba, J, Florence, S, John, B, Crookston, B, Lopansri, BK, Yeo, TW, Piera, KA, Alder, SC, Weinberg, JB, Anstey, NM, Granger, DL, and Mwaikambo, ED. "Plasma Plasmodium falciparum histidine-rich protein-2 concentrations are associated with malaria severity and mortality in Tanzanian children." PLoS One 7.5 (2012): e35985-.
PMID
22586457
Source
pubmed
Published In
PloS one
Volume
7
Issue
5
Publish Date
2012
Start Page
e35985
DOI
10.1371/journal.pone.0035985

SET oncoprotein overexpression in B-cell chronic lymphocytic leukemia and non-Hodgkin lymphoma: a predictor of aggressive disease and a new treatment target.

B-cell chronic lymphocytic leukemia (CLL), an incurable leukemia, is characterized by defective apoptosis. We found that the SET oncoprotein, a potent inhibitor of the protein phosphatase 2A (PP2A) tumor suppressor, is overexpressed in primary CLL cells and B-cell non-Hodgkin lymphoma (NHL) cell line cells. In CLL, increased levels of SET correlated significantly with disease severity (shorter time to treatment and overall survival). We developed SET antagonist peptides that bound SET, increased cellular PP2A activity, decreased Mcl-1 expression, and displayed selective cytotoxicity for CLL and NHL cells in vitro. In addition, shRNA for SET was cytotoxic for NHL cells in vitro. The SET antagonist peptide COG449 inhibited growth of NHL tumor xenografts in mice. These data demonstrate that SET is a new treatment target in B-cell malignancies and that SET antagonists represent novel agents for treatment of CLL and NHL.

Authors
Christensen, DJ; Chen, Y; Oddo, J; Matta, KM; Neil, J; Davis, ED; Volkheimer, AD; Lanasa, MC; Friedman, DR; Goodman, BK; Gockerman, JP; Diehl, LF; de Castro, CM; Moore, JO; Vitek, MP; Weinberg, JB
MLA Citation
Christensen, DJ, Chen, Y, Oddo, J, Matta, KM, Neil, J, Davis, ED, Volkheimer, AD, Lanasa, MC, Friedman, DR, Goodman, BK, Gockerman, JP, Diehl, LF, de Castro, CM, Moore, JO, Vitek, MP, and Weinberg, JB. "SET oncoprotein overexpression in B-cell chronic lymphocytic leukemia and non-Hodgkin lymphoma: a predictor of aggressive disease and a new treatment target." Blood 118.15 (October 13, 2011): 4150-4158.
PMID
21844565
Source
pubmed
Published In
Blood
Volume
118
Issue
15
Publish Date
2011
Start Page
4150
End Page
4158
DOI
10.1182/blood-2011-04-351072

Immunophenotypic and gene expression analysis of monoclonal B-cell lymphocytosis shows biologic characteristics associated with good prognosis CLL.

Monoclonal B-cell lymphocytosis (MBL) is a hematologic condition wherein small B-cell clones can be detected in the blood of asymptomatic individuals. Most MBL have an immunophenotype similar to chronic lymphocytic leukemia (CLL), and 'CLL-like' MBL is a precursor to CLL. We used flow cytometry to identify MBL from unaffected members of CLL kindreds. We identified 101 MBL cases from 622 study subjects; of these, 82 individuals with MBL were further characterized. In all, 91 unique MBL clones were detected: 73 CLL-like MBL (CD5(+)CD20(dim)sIg(dim)), 11 atypical MBL (CD5(+)CD20(+)sIg(+)) and 7 CD5(neg) MBL (CD5(neg)CD20(+)sIg(neg)). Extended immunophenotypic characterization of these MBL subtypes was performed, and significant differences in cell surface expression of CD23, CD49d, CD79b and FMC-7 were observed among the groups. Markers of risk in CLL such as CD38, ZAP70 and CD49d were infrequently expressed in CLL-like MBL, but were expressed in the majority of atypical MBL. Interphase cytogenetics was performed in 35 MBL cases, and del 13q14 was most common (22/30 CLL-like MBL cases). Gene expression analysis using oligonucleotide arrays was performed on seven CLL-like MBL, and showed activation of B-cell receptor associated pathways. Our findings underscore the diversity of MBL subtypes and further clarify the relationship between MBL and other lymphoproliferative disorders.

Authors
Lanasa, MC; Allgood, SD; Slager, SL; Dave, SS; Love, C; Marti, GE; Kay, NE; Hanson, CA; Rabe, KG; Achenbach, SJ; Goldin, LR; Camp, NJ; Goodman, BK; Vachon, CM; Spector, LG; Rassenti, LZ; Leis, JF; Gockerman, JP; Strom, SS; Call, TG; Glenn, M; Cerhan, JR; Levesque, MC; Weinberg, JB; Caporaso, NE
MLA Citation
Lanasa, MC, Allgood, SD, Slager, SL, Dave, SS, Love, C, Marti, GE, Kay, NE, Hanson, CA, Rabe, KG, Achenbach, SJ, Goldin, LR, Camp, NJ, Goodman, BK, Vachon, CM, Spector, LG, Rassenti, LZ, Leis, JF, Gockerman, JP, Strom, SS, Call, TG, Glenn, M, Cerhan, JR, Levesque, MC, Weinberg, JB, and Caporaso, NE. "Immunophenotypic and gene expression analysis of monoclonal B-cell lymphocytosis shows biologic characteristics associated with good prognosis CLL." Leukemia 25.9 (September 2011): 1459-1466.
PMID
21617698
Source
pubmed
Published In
Leukemia
Volume
25
Issue
9
Publish Date
2011
Start Page
1459
End Page
1466
DOI
10.1038/leu.2011.117

Immunoglobulin class switch recombination in chronic lymphocytic leukemia.

During B lymphocyte maturation, a subset of B cells undergo class switch recombination (CSR), a process wherein the heavy chain constant region is changed to a different immunoglobulin isotype without introduction of variable region mutations. CSR thus allows for the production of various antibody isotypes with different effector functions. Similar to naive B cells, chronic lymphocytic leukemia (CLL) cells co-express surface immunoglobulin (Ig) M and D (IgM+IgD+), though a minority of cases express terminally differentiated isotypes. In this brief report, we discuss the capacity of CLL to undergo CSR and the relevance of CSR to the clinical behavior of CLL.

Authors
Lanasa, MC; Weinberg, JB
MLA Citation
Lanasa, MC, and Weinberg, JB. "Immunoglobulin class switch recombination in chronic lymphocytic leukemia." Leuk Lymphoma 52.7 (July 2011): 1398-1400. (Review)
PMID
21699386
Source
pubmed
Published In
Leukemia & Lymphoma (Informa)
Volume
52
Issue
7
Publish Date
2011
Start Page
1398
End Page
1400
DOI
10.3109/10428194.2011.568076

Immunologic aspects of monoclonal B-cell lymphocytosis.

Monoclonal B-cell lymphocytosis (MBL) is a preclinical hematologic condition wherein small numbers of clonal B cells can be detected in the blood of otherwise healthy individuals. Most MBL have a surface immunophenotype nearly identical to that of chronic lymphocytic leukemia (CLL), though other phenotypes can also be identified. MBL has been shown to be a precursor state for CLL, but most MBL clones are quite small and apparently have minimal potential to progress of CLL or other B-cell lymphoproliferative disorder (B-LPD). The investigation of MBL as a precursor state for CLL will likely lead to important insights into mechanisms of disease pathogenesis. The review will cover clinical and translational aspects of MBL, with a particular emphasis on the prevalence of MBL; the relationship between MBL, CLL, and other B-LPDs; and the capacity of MBL to modulate the normal B- and T-cell compartments.

Authors
Lanasa, MC; Weinberg, JB
MLA Citation
Lanasa, MC, and Weinberg, JB. "Immunologic aspects of monoclonal B-cell lymphocytosis." Immunol Res 49.1-3 (April 2011): 269-280. (Review)
PMID
21161696
Source
pubmed
Published In
Immunologic Research
Volume
49
Issue
1-3
Publish Date
2011
Start Page
269
End Page
280
DOI
10.1007/s12026-010-8188-4

Genome-wide association study identifies a novel susceptibility locus at 6p21.3 among familial CLL.

Prior genome-wide association (GWA) studies have identified 10 susceptibility loci for risk of chronic lymphocytic leukemia (CLL). To identify additional loci, we performed a GWA study in 407 CLL cases (of which 102 had a family history of CLL) and 296 controls. Moreover, given the strong familial risk of CLL, we further subset our GWA analysis to the CLL cases with a family history of CLL to identify loci specific to these familial CLL cases. Our top hits from these analyses were evaluated in an additional sample of 252 familial CLL cases and 965 controls. Using all available data, we identified and confirmed an independent association of 4 single-nucleotide polymorphisms (SNPs) that met genome-wide statistical significance within the IRF8 (interferon regulatory factor 8) gene (combined P values ≤ 3.37 × 10(-8)), located in the previously identified 16q24.1 locus. Subsetting to familial CLL cases, we identified and confirmed a new locus on chromosome 6p21.3 (combined P value = 6.92 × 10(-9)). This novel region harbors the HLA-DQA1 and HLA-DRB5 genes. Finally, we evaluated the 10 previously reported SNPs in the overall sample and replicated 8 of them. Our findings support the hypothesis that familial CLL cases have additional genetic variants not seen in sporadic CLL. Additional loci among familial CLL cases may be identified through larger studies.

Authors
Slager, SL; Rabe, KG; Achenbach, SJ; Vachon, CM; Goldin, LR; Strom, SS; Lanasa, MC; Spector, LG; Rassenti, LZ; Leis, JF; Camp, NJ; Glenn, M; Kay, NE; Cunningham, JM; Hanson, CA; Marti, GE; Weinberg, JB; Morrison, VA; Link, BK; Call, TG; Caporaso, NE; Cerhan, JR
MLA Citation
Slager, SL, Rabe, KG, Achenbach, SJ, Vachon, CM, Goldin, LR, Strom, SS, Lanasa, MC, Spector, LG, Rassenti, LZ, Leis, JF, Camp, NJ, Glenn, M, Kay, NE, Cunningham, JM, Hanson, CA, Marti, GE, Weinberg, JB, Morrison, VA, Link, BK, Call, TG, Caporaso, NE, and Cerhan, JR. "Genome-wide association study identifies a novel susceptibility locus at 6p21.3 among familial CLL." Blood 117.6 (February 10, 2011): 1911-1916.
PMID
21131588
Source
pubmed
Published In
Blood
Volume
117
Issue
6
Publish Date
2011
Start Page
1911
End Page
1916
DOI
10.1182/blood-2010-09-308205

Interleukin-1, tumor necrosis factor-alpha, and transforming growth factor-beta 1 and integrative meniscal repair: influences on meniscal cell proliferation and migration.

Interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) are up-regulated in injured and osteoarthritic knee joints. IL-1 and TNF-α inhibit integrative meniscal repair; however, the mechanisms by which this inhibition occurs are not fully understood. Transforming growth factor-β1 (TGF-β1) increases meniscal cell proliferation and accumulation, and enhances integrative meniscal repair. An improved understanding of the mechanisms modulating meniscal cell proliferation and migration will help to improve approaches for enhancing intrinsic or tissue-engineered repair of the meniscus. The goal of this study was to examine the hypothesis that IL-1 and TNF-α suppress, while TGF-β1 enhances, cellular proliferation and migration in cell and tissue models of meniscal repair.A micro-wound assay was used to assess meniscal cell migration and proliferation in response to the following treatments for 0, 24, or 48 hours: 0 to 10 ng/mL IL-1, TNF-α, or TGF-β1, in the presence or absence of 10% serum. Proliferated and total cells were fluorescently labeled and imaged using confocal laser scanning microscopy and the number of proliferated, migrated, and total cells was determined in the micro-wound and edges of each image. Meniscal cell proliferation was also assessed throughout meniscal repair model explants treated with 0 or 10 ng/mL IL-1, TNF-α, or TGF-β1 for 14 days. At the end of the culture period, biomechanical testing and histological analyses were also performed. Statistical differences were assessed using an ANOVA and Newman-Keuls post hoc test.IL-1 and TNF-α decreased cell proliferation in both cell and tissue models of meniscal repair. In the presence of serum, TGF-β1 increased outer zone cell proliferation in the micro-wound and in the cross section of meniscal repair model explants. Both IL-1 and TNF-α decreased the integrative shear strength of repair and extracellular matrix deposition in the meniscal repair model system, while TGF-β1 had no effect on either measure.Meniscal cell proliferation in vivo may be diminished following joint injury due to the up-regulation of inflammatory cytokines, thereby limiting native cellular repair of meniscal lesions. Therefore, therapies that can promote meniscal cell proliferation have promise to enhance meniscal repair and improve tissue engineering strategies.

Authors
Riera, KM; Rothfusz, NE; Wilusz, RE; Weinberg, JB; Guilak, F; McNulty, AL
MLA Citation
Riera, KM, Rothfusz, NE, Wilusz, RE, Weinberg, JB, Guilak, F, and McNulty, AL. "Interleukin-1, tumor necrosis factor-alpha, and transforming growth factor-beta 1 and integrative meniscal repair: influences on meniscal cell proliferation and migration." Arthritis research & therapy 13.6 (January 2011): R187-.
PMID
22087734
Source
epmc
Published In
Arthritis Research and Therapy
Volume
13
Issue
6
Publish Date
2011
Start Page
R187
DOI
10.1186/ar3515

Erratum: Inhibition of nitric oxide synthase by cobalamins and cobinamides (Free Radical Biology & Medicine (2009) 46 (1626-1632))

Authors
Weinberg, JB; Chen, Y; Jiang, N; Beasley, BE; Salerno, JC; Ghosh, DK
MLA Citation
Weinberg, JB, Chen, Y, Jiang, N, Beasley, BE, Salerno, JC, and Ghosh, DK. "Erratum: Inhibition of nitric oxide synthase by cobalamins and cobinamides (Free Radical Biology & Medicine (2009) 46 (1626-1632))." Free Radical Biology and Medicine 51.7 (2011): 1471--.
Source
scival
Published In
Free Radical Biology & Medicine
Volume
51
Issue
7
Publish Date
2011
Start Page
1471-
DOI
10.1016/j.freeradbiomed.2011.07.010

Deep sequencing of the small RNA transcriptome of normal and malignant human B cells identifies hundreds of novel microRNAs.

A role for microRNA (miRNA) has been recognized in nearly every biologic system examined thus far. A complete delineation of their role must be preceded by the identification of all miRNAs present in any system. We elucidated the complete small RNA transcriptome of normal and malignant B cells through deep sequencing of 31 normal and malignant human B-cell samples that comprise the spectrum of B-cell differentiation and common malignant phenotypes. We identified the expression of 333 known miRNAs, which is more than twice the number previously recognized in any tissue type. We further identified the expression of 286 candidate novel miRNAs in normal and malignant B cells. These miRNAs were validated at a high rate (92%) using quantitative polymerase chain reaction, and we demonstrated their application in the distinction of clinically relevant subgroups of lymphoma. We further demonstrated that a novel miRNA cluster, previously annotated as a hypothetical gene LOC100130622, contains 6 novel miRNAs that regulate the transforming growth factor-β pathway. Thus, our work suggests that more than a third of the miRNAs present in most cellular types are currently unknown and that these miRNAs may regulate important cellular functions.

Authors
Jima, DD; Zhang, J; Jacobs, C; Richards, KL; Dunphy, CH; Choi, WWL; Au, WY; Srivastava, G; Czader, MB; Rizzieri, DA; Lagoo, AS; Lugar, PL; Mann, KP; Flowers, CR; Bernal-Mizrachi, L; Naresh, KN; Evens, AM; Gordon, LI; Luftig, M; Friedman, DR; Weinberg, JB; Thompson, MA; Gill, JI; Liu, Q; How, T; Grubor, V; Gao, Y; Patel, A; Wu, H; Zhu, J; Blobe, GC; Lipsky, PE; Chadburn, A; Dave, SS; Hematologic Malignancies Research Consortium,
MLA Citation
Jima, DD, Zhang, J, Jacobs, C, Richards, KL, Dunphy, CH, Choi, WWL, Au, WY, Srivastava, G, Czader, MB, Rizzieri, DA, Lagoo, AS, Lugar, PL, Mann, KP, Flowers, CR, Bernal-Mizrachi, L, Naresh, KN, Evens, AM, Gordon, LI, Luftig, M, Friedman, DR, Weinberg, JB, Thompson, MA, Gill, JI, Liu, Q, How, T, Grubor, V, Gao, Y, Patel, A, Wu, H, Zhu, J, Blobe, GC, Lipsky, PE, Chadburn, A, Dave, SS, and Hematologic Malignancies Research Consortium, . "Deep sequencing of the small RNA transcriptome of normal and malignant human B cells identifies hundreds of novel microRNAs." Blood 116.23 (December 2, 2010): e118-e127.
PMID
20733160
Source
pubmed
Published In
Blood
Volume
116
Issue
23
Publish Date
2010
Start Page
e118
End Page
e127
DOI
10.1182/blood-2010-05-285403

Targeting Destruction of Mcl-1 by Activation of Protein Phosphatase 2A In CLL and B-Cell Lymphomas

Authors
Christensen, DJ; Oddo, J; Bond, K; Volkheimer, A; Chen, Y; Davis, E; Gockerman, JP; Diehl, LF; III, DCC; Moore, JO; Vitek, MP; Weinberg, JB
MLA Citation
Christensen, DJ, Oddo, J, Bond, K, Volkheimer, A, Chen, Y, Davis, E, Gockerman, JP, Diehl, LF, III, DCC, Moore, JO, Vitek, MP, and Weinberg, JB. "Targeting Destruction of Mcl-1 by Activation of Protein Phosphatase 2A In CLL and B-Cell Lymphomas." November 19, 2010.
Source
wos-lite
Published In
Blood
Volume
116
Issue
21
Publish Date
2010
Start Page
1703
End Page
1704

Investigation of CLL-Susceptibility Loci with Monoclonal B-Cell Lymphocytosis (MBL) Risk and Confirmation of Recently Reported CLL-Susceptibility Loci

Authors
Slager, S; Rabe, K; Achenbach, S; Vachon, C; Goldin, L; Strom, S; Lanasa, MC; Spector, LG; Rassenti, LZ; Leis, J; Camp, N; Glenn, M; Kay, NE; Cunningham, JM; Hanson, CA; Marti, GE; Weinberg, JB; Morrison, VA; Link, B; Call, T; Caporaso, N; Cerhan, J
MLA Citation
Slager, S, Rabe, K, Achenbach, S, Vachon, C, Goldin, L, Strom, S, Lanasa, MC, Spector, LG, Rassenti, LZ, Leis, J, Camp, N, Glenn, M, Kay, NE, Cunningham, JM, Hanson, CA, Marti, GE, Weinberg, JB, Morrison, VA, Link, B, Call, T, Caporaso, N, and Cerhan, J. "Investigation of CLL-Susceptibility Loci with Monoclonal B-Cell Lymphocytosis (MBL) Risk and Confirmation of Recently Reported CLL-Susceptibility Loci." November 19, 2010.
Source
wos-lite
Published In
Blood
Volume
116
Issue
21
Publish Date
2010
Start Page
1014
End Page
1014

A study of the TNF/LTA/LTB locus and susceptibility to severe malaria in highland papuan children and adults.

BACKGROUND: Severe malaria (SM) syndromes caused by Plasmodium falciparum infection result in major morbidity and mortality each year. However, only a fraction of P. falciparum infections develop into SM, implicating host genetic factors as important determinants of disease outcome. Previous studies indicate that tumour necrosis factor (TNF) and lymphotoxin alpha (LTα) may be important for the development of cerebral malaria (CM) and other SM syndromes. METHODS: An extensive analysis was conducted of single nucleotide polymorphisms (SNPs) in the TNF, LTA and LTB genes in highland Papuan children and adults, a population historically unexposed to malaria that has migrated to a malaria endemic region. Generated P-values for SNPs spanning the LTA/TNF/LTB locus were corrected for multiple testing of all the SNPs and haplotype blocks within the region tested through 10,000 permutations. A global P-value of < 0.05 was considered statistically significant. RESULTS: No associations between SNPs in the TNF/LTA/LTB locus and susceptibility to SM in highland Papuan children and adults were found. CONCLUSIONS: These results support the notion that unique selective pressure on the TNF/LTA/LTB locus in different populations has influenced the contribution of the gene products from this region to SM susceptibility.

Authors
Randall, LM; Kenangalem, E; Lampah, DA; Tjitra, E; Mwaikambo, ED; Handojo, T; Piera, KA; Zhao, ZZ; de Labastida Rivera, F; Zhou, Y; McSweeney, KM; Le, L; Amante, FH; Haque, A; Stanley, AC; Woodberry, T; Salwati, E; Granger, DL; Hobbs, MR; Price, RN; Weinberg, JB; Montgomery, GW; Anstey, NM; Engwerda, CR
MLA Citation
Randall, LM, Kenangalem, E, Lampah, DA, Tjitra, E, Mwaikambo, ED, Handojo, T, Piera, KA, Zhao, ZZ, de Labastida Rivera, F, Zhou, Y, McSweeney, KM, Le, L, Amante, FH, Haque, A, Stanley, AC, Woodberry, T, Salwati, E, Granger, DL, Hobbs, MR, Price, RN, Weinberg, JB, Montgomery, GW, Anstey, NM, and Engwerda, CR. "A study of the TNF/LTA/LTB locus and susceptibility to severe malaria in highland papuan children and adults. (Published online)" Malar J 9 (October 29, 2010): 302-.
PMID
21029472
Source
pubmed
Published In
Malaria Journal
Volume
9
Publish Date
2010
Start Page
302
DOI
10.1186/1475-2875-9-302

Common occurrence of monoclonal B-cell lymphocytosis among members of high-risk CLL families.

Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic haematological condition characterized by low absolute levels of B-cell clones with a surface immunophenotype similar to that of chronic lymphocytic leukaemia (CLL). In the general population, MBL increases with age with a prevalence of 5-9% in individuals over age 60 years. It has been reported to be higher among first-degree relatives from CLL families. We report results of multi-parameter flow cytometry among 505 first-degree relatives with no personal history of lymphoproliferative disease from 140 families having at least two cases of CLL. Seventeen percent of relatives had MBL. Age was the most important determinant where the probability for developing MBL by age 90 years was 61%. MBL clustered in certain families but clustering was independent of the number of known CLL cases in a family. As is the case with CLL, males had a significantly higher risk for MBL than did females (P = 0·04). MBL patients had significantly higher mean absolute lymphocyte counts (2·4 × 10(9) /l) and B-cell counts (0·53 × 10(9) /l) than those with a normal B-cell immuno-phenotype. Our findings show that MBL occurs at a very high rate in high risk CLL families. Both the age and gender distribution of MBL are parallel to CLL, implying a shared inherited risk.

Authors
Goldin, LR; Lanasa, MC; Slager, SL; Cerhan, JR; Vachon, CM; Strom, SS; Camp, NJ; Spector, LG; Leis, JF; Morrison, VA; Glenn, M; Rabe, KG; Achenbach, SJ; Algood, SD; Abbasi, F; Fontaine, L; Yau, M; Rassenti, LZ; Kay, NE; Call, TG; Hanson, CA; Weinberg, JB; Marti, GE; Caporaso, NE
MLA Citation
Goldin, LR, Lanasa, MC, Slager, SL, Cerhan, JR, Vachon, CM, Strom, SS, Camp, NJ, Spector, LG, Leis, JF, Morrison, VA, Glenn, M, Rabe, KG, Achenbach, SJ, Algood, SD, Abbasi, F, Fontaine, L, Yau, M, Rassenti, LZ, Kay, NE, Call, TG, Hanson, CA, Weinberg, JB, Marti, GE, and Caporaso, NE. "Common occurrence of monoclonal B-cell lymphocytosis among members of high-risk CLL families." Br J Haematol 151.2 (October 2010): 152-158.
PMID
20738309
Source
pubmed
Published In
British Journal of Haematology
Volume
151
Issue
2
Publish Date
2010
Start Page
152
End Page
158
DOI
10.1111/j.1365-2141.2010.08339.x

LMP-420: a novel purine nucleoside analog with potent cytotoxic effects for CLL cells and minimal toxicity for normal hematopoietic cells.

B-cell chronic lymphocytic leukemia (CLL) is characterized by slow accumulation of malignant cells, which are supported in the microenvironment by cell-cell interactions and soluble cytokines such as tumor necrosis factor (TNF). We evaluated the effect of the small molecule TNF inhibitor LMP-420 on primary CLL cells. The mean concentration of LMP-420 required to induce 50% cytotoxicity (ED50) at 72 h was 245 n. LMP-420-induced time- and dose-dependent apoptosis, as shown by annexin V staining, caspase activation and DNA fragmentation. These changes were associated with decreased expression of anti-apoptotic proteins Mcl-1, Bcl-xL and Bcl-2. CLL cells from patients with poor prognostic indicators showed LMP-420 sensitivity equal to that for cells from patients with favorable characteristics. In addition, LMP-420 potentiated the cytotoxic effect of fludarabine and inhibited in vitro proliferation of stimulated CLL cells. Gene expression profiling indicated that the mechanism of action of LMP-420 may involve suppression of nuclear factor-kappaB and immune response pathways in CLL cells. LMP-420 had minimal effects on normal peripheral blood mononuclear cell, B- and T-cell function, and hematopoietic colony formation. Our data suggest that LMP-420 may be a useful treatment for CLL with negligible hematologic toxicities.

Authors
Mowery, YM; Weinberg, JB; Kennedy, MN; Bond, KM; Moore, JO; Lanasa, MC; Gockerman, JP; Diehl, LF; Pizzo, SV; Cianciolo, GJ; Friedman, DR
MLA Citation
Mowery, YM, Weinberg, JB, Kennedy, MN, Bond, KM, Moore, JO, Lanasa, MC, Gockerman, JP, Diehl, LF, Pizzo, SV, Cianciolo, GJ, and Friedman, DR. "LMP-420: a novel purine nucleoside analog with potent cytotoxic effects for CLL cells and minimal toxicity for normal hematopoietic cells." Leukemia 24.9 (September 2010): 1580-1587.
PMID
20613784
Source
epmc
Published In
Leukemia
Volume
24
Issue
9
Publish Date
2010
Start Page
1580
End Page
1587
DOI
10.1038/leu.2010.150

Monoclonal B cell lymphocytosis.

Monoclonal B lymphocytosis (MBL) is an asymptomatic clinical syndrome wherein small B cell clones are detectable in the peripheral blood. MBL is common in the adult population, with an estimated prevalence of greater than 3% among individuals over age 50. Most MBLs have an immunophenotype similar to chronic lymphocytic leukemia (CLL). Recently, MBL has been shown to be a precursor state for CLL, though most MBLs presumably do not progress to CLL. Therefore, there has been considerable interest in the biology of MBL to better understand the mechanisms of CLL leukemogenesis. We have investigated immunoglobulin heavy chain gene usage and clonality in MBL. These investigations reveal that most MBLs use mutated heavy chains typically associated with good-risk CLL, and that MBLs are frequently oligoclonal, rather than monoclonal. Deletion of chromosome 13q14 is also commonly observed. These and other ongoing studies may help illuminate the pathogenesis of CLL.

Authors
Lanasa, MC; Allgood, SD; Weinberg, JB
MLA Citation
Lanasa, MC, Allgood, SD, and Weinberg, JB. "Monoclonal B cell lymphocytosis." Leuk Lymphoma 51.8 (August 2010): 1386-1388.
PMID
20629528
Source
pubmed
Published In
Leukemia & Lymphoma (Informa)
Volume
51
Issue
8
Publish Date
2010
Start Page
1386
End Page
1388
DOI
10.3109/10428194.2010.496018

Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32.

To identify susceptibility loci for non-Hodgkin lymphoma subtypes, we conducted a three-stage genome-wide association study. We identified two variants associated with follicular lymphoma at 6p21.32 (rs10484561, combined P = 1.12 x 10(-29) and rs7755224, combined P = 2.00 x 10(-19); r(2) = 1.0), supporting the idea that major histocompatibility complex genetic variation influences follicular lymphoma susceptibility. We also found confirmatory evidence of a previously reported association between chronic lymphocytic leukemia/small lymphocytic lymphoma and rs735665 (combined P = 4.24 x 10(-9)).

Authors
Conde, L; Halperin, E; Akers, NK; Brown, KM; Smedby, KE; Rothman, N; Nieters, A; Slager, SL; Brooks-Wilson, A; Agana, L; Riby, J; Liu, J; Adami, H-O; Darabi, H; Hjalgrim, H; Low, H-Q; Humphreys, K; Melbye, M; Chang, ET; Glimelius, B; Cozen, W; Davis, S; Hartge, P; Morton, LM; Schenk, M; Wang, SS; Armstrong, B; Kricker, A; Milliken, S; Purdue, MP; Vajdic, CM; Boyle, P; Lan, Q; Zahm, SH; Zhang, Y; Zheng, T; Becker, N; Benavente, Y; Boffetta, P; Brennan, P; Butterbach, K; Cocco, P; Foretova, L et al.
MLA Citation
Conde, L, Halperin, E, Akers, NK, Brown, KM, Smedby, KE, Rothman, N, Nieters, A, Slager, SL, Brooks-Wilson, A, Agana, L, Riby, J, Liu, J, Adami, H-O, Darabi, H, Hjalgrim, H, Low, H-Q, Humphreys, K, Melbye, M, Chang, ET, Glimelius, B, Cozen, W, Davis, S, Hartge, P, Morton, LM, Schenk, M, Wang, SS, Armstrong, B, Kricker, A, Milliken, S, Purdue, MP, Vajdic, CM, Boyle, P, Lan, Q, Zahm, SH, Zhang, Y, Zheng, T, Becker, N, Benavente, Y, Boffetta, P, Brennan, P, Butterbach, K, Cocco, P, and Foretova, L et al. "Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32." Nat Genet 42.8 (August 2010): 661-664.
PMID
20639881
Source
pubmed
Published In
Nature Genetics
Volume
42
Issue
8
Publish Date
2010
Start Page
661
End Page
664
DOI
10.1038/ng.626

Age-related susceptibility to severe malaria associated with galectin-2 in highland Papuans.

BACKGROUND: Age and host genetics are important determinants of malaria severity. Lymphotoxin-alpha (LTalpha) has been associated with the development of cerebral malaria (CM) and other severe malaria (SM) syndromes. Mutations in genes regulating LTalpha production contribute to other acute vascular diseases and may contribute to malaria pathogenesis. METHODS: We tested the association between rs7291467, a single-nucleotide polymorphism (SNP) in the LTalpha-related gene encoding galectin-2 (LGALS2), disease severity, and function in a case-control study of ethnic Highland Papuan adults and children with SM (n = 380) and asymptomatic malaria-exposed controls (n = 356) originating from a non-malaria-endemic region but residing in a lowland malaria-endemic area of Papua, Indonesia. RESULTS: The LGALS2 SNP showed a significant association with susceptibility to SM (including CM), in children (odds ratio, 2.02 [95% confidence interval, 1.14-3.57]) but not in adults. In SM, the C allele at rs7291467 was associated with enhanced galectin-2 transcript levels. In a separate group of Tanzanian children originating from a malaria-endemic region, we found preservation of the major ancestral LGALS2 allele and no association with susceptibility to CM. CONCLUSIONS: Results suggest differences in the inflammatory contribution to the development of SM between children and adults in the same population and potential differences between individuals originating from malaria-endemic and non-malaria-endemic areas.

Authors
Randall, LM; Kenangalem, E; Lampah, DA; Tjitra, E; Mwaikambo, ED; Handojo, T; Piera, KA; Zhao, ZZ; de Labastida Rivera, F; Zhou, Y; McSweeney, KM; Le, L; Amante, FH; Haque, A; Stanley, AC; Woodberry, T; Salwati, E; Granger, DL; Hobbs, MR; Price, RN; Weinberg, JB; Montgomery, GW; Anstey, NM; Engwerda, CR
MLA Citation
Randall, LM, Kenangalem, E, Lampah, DA, Tjitra, E, Mwaikambo, ED, Handojo, T, Piera, KA, Zhao, ZZ, de Labastida Rivera, F, Zhou, Y, McSweeney, KM, Le, L, Amante, FH, Haque, A, Stanley, AC, Woodberry, T, Salwati, E, Granger, DL, Hobbs, MR, Price, RN, Weinberg, JB, Montgomery, GW, Anstey, NM, and Engwerda, CR. "Age-related susceptibility to severe malaria associated with galectin-2 in highland Papuans." J Infect Dis 202.1 (July 1, 2010): 117-124.
PMID
20500087
Source
pubmed
Published In
Journal of Infectious Diseases
Volume
202
Issue
1
Publish Date
2010
Start Page
117
End Page
124
DOI
10.1086/653125

Dynamic loading enhances integrative meniscal repair in the presence of interleukin-1.

Meniscal tears are a common knee injury and increased levels of interleukin-1 (IL-1) have been measured in injured and degenerated joints. Studies have shown that IL-1 decreases the shear strength, cell accumulation, and tissue formation in meniscal repair interfaces. While mechanical stress and IL-1 modulate meniscal biosynthesis and degradation, the effects of dynamic loading on meniscal repair are unknown. The purpose of this study was to determine the effects of mechanical compression on meniscal repair under normal and inflammatory conditions.Explants were harvested from porcine medial menisci. To simulate a full-thickness defect, a central core was removed and reinserted. Explants were loaded for 4h/day at 1 Hz and 0%-26% strain for 14 days in the presence of 0 or 100 pg/mL of IL-1. Media were assessed for matrix metalloproteinase (MMP) activity, aggrecanase activity, sulfated glycosaminoglycan (S-GAG) release, and nitric oxide (NO) production. After 14 days, biomechanical testing and histological analyses were performed.IL-1 increased MMP activity, S-GAG release, and NO production, while decreasing the shear strength and tissue repair in the interface. Dynamic loading antagonized IL-1-mediated inhibition of repair at all strain amplitudes. Neither IL-1 treatment nor strain altered aggrecanase activity. Additionally, strain alone did not alter meniscal healing, except at the highest strain magnitude (26%), a level that enhanced the strength of repair.Dynamic loading blocked the catabolic effects of IL-1 on meniscal repair, suggesting that joint loading through physical therapy may be beneficial in promoting healing of meniscal lesions under inflammatory conditions.

Authors
McNulty, AL; Estes, BT; Wilusz, RE; Weinberg, JB; Guilak, F
MLA Citation
McNulty, AL, Estes, BT, Wilusz, RE, Weinberg, JB, and Guilak, F. "Dynamic loading enhances integrative meniscal repair in the presence of interleukin-1." Osteoarthritis and cartilage 18.6 (June 2010): 830-838.
PMID
20202487
Source
epmc
Published In
Osteoarthritis and Cartilage
Volume
18
Issue
6
Publish Date
2010
Start Page
830
End Page
838
DOI
10.1016/j.joca.2010.02.009

A single tube, four-color flow cytometry assay for evaluation of ZAP-70 and CD38 expression in chronic lymphocytic leukemia.

We describe a simple and robust flow cytometry assay for ZAP-70 and CD38 expression. The steps required to validate this assay in a clinical flow cytometry laboratory are described. Two criteria were used to characterize ZAP-70 expression into positive, negative, and indeterminate categories and applied to 111 cases of chronic lymphocytic leukemia (CLL) resulting in 29.7% positive, 56.8% negative, and 13.5% indeterminate cases. A sensitivity-specificity crossover plot between ZAP-70 and CD38 suggested a cutoff of 12.5% for defining CD38 positivity. ZAP-70+ cases were significantly more likely to be at a higher clinical stage and, together with CD38+ cases, were more likely to have unmutated IgV(H). However, for individual patients, the concordance between these markers was not perfect. It may be necessary to evaluate several prognostic markers simultaneously in CLL, and availability of convenient assays for ZAP-70 and CD38 is desirable for optimal clinical decision making.

Authors
Hassanein, NM; Perkinson, KR; Alcancia, F; Goodman, BK; Weinberg, JB; Lagoo, AS
MLA Citation
Hassanein, NM, Perkinson, KR, Alcancia, F, Goodman, BK, Weinberg, JB, and Lagoo, AS. "A single tube, four-color flow cytometry assay for evaluation of ZAP-70 and CD38 expression in chronic lymphocytic leukemia." Am J Clin Pathol 133.5 (May 2010): 708-717.
PMID
20395517
Source
pubmed
Published In
American Journal of Clinical Pathology
Volume
133
Issue
5
Publish Date
2010
Start Page
708
End Page
717
DOI
10.1309/AJCPQS4OXJJSZ5KN

Increased asymmetric dimethylarginine in severe falciparum malaria: association with impaired nitric oxide bioavailability and fatal outcome.

Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is a predictor of mortality in critical illness. Severe malaria (SM) is associated with decreased NO bioavailability, but the contribution of ADMA to the pathogenesis of impaired NO bioavailability and adverse outcomes in malaria is unknown. In adults with and without falciparum malaria, we tested the hypotheses that plasma ADMA would be: 1) increased in proportion to disease severity, 2) associated with impaired vascular and pulmonary NO bioavailability and 3) independently associated with increased mortality. We assessed plasma dimethylarginines, exhaled NO concentrations and endothelial function in 49 patients with SM, 78 with moderately severe malaria (MSM) and 19 healthy controls (HC). Repeat ADMA and endothelial function measurements were performed in patients with SM. Multivariable regression was used to assess the effect of ADMA on mortality and NO bioavailability. Plasma ADMA was increased in SM patients (0.85 microM; 95% CI 0.74-0.96) compared to those with MSM (0.54 microM; 95%CI 0.5-0.56) and HCs (0.64 microM; 95%CI 0.58-0.70; p<0.001). ADMA was an independent predictor of mortality in SM patients with each micromolar elevation increasing the odds of death 18 fold (95% CI 2.0-181; p = 0.01). ADMA was independently associated with decreased exhaled NO (r(s) = -0.31) and endothelial function (r(s) = -0.32) in all malaria patients, and with reduced exhaled NO (r(s) = -0.72) in those with SM. ADMA is increased in SM and associated with decreased vascular and pulmonary NO bioavailability. Inhibition of NOS by ADMA may contribute to increased mortality in severe malaria.

Authors
Yeo, TW; Lampah, DA; Tjitra, E; Gitawati, R; Darcy, CJ; Jones, C; Kenangalem, E; McNeil, YR; Granger, DL; Lopansri, BK; Weinberg, JB; Price, RN; Duffull, SB; Celermajer, DS; Anstey, NM
MLA Citation
Yeo, TW, Lampah, DA, Tjitra, E, Gitawati, R, Darcy, CJ, Jones, C, Kenangalem, E, McNeil, YR, Granger, DL, Lopansri, BK, Weinberg, JB, Price, RN, Duffull, SB, Celermajer, DS, and Anstey, NM. "Increased asymmetric dimethylarginine in severe falciparum malaria: association with impaired nitric oxide bioavailability and fatal outcome. (Published online)" PLoS Pathog 6.4 (April 22, 2010): e1000868-.
PMID
20421938
Source
pubmed
Published In
PLoS pathogens
Volume
6
Issue
4
Publish Date
2010
Start Page
e1000868
DOI
10.1371/journal.ppat.1000868

Genetic susceptibility variants for chronic lymphocytic leukemia.

BACKGROUND: There is strong and consistent evidence that a genetic component contributes to the etiology of chronic lymphocytic leukemia (CLL). A recent genome-wide association study of CLL identified seven genetic variants that increased the risk of CLL within a European population. METHODS: We evaluated the association of these variants, or variants in linkage disequilibrium with these variants, with CLL risk in an independent sample of 438 CLL cases and 328 controls. RESULTS: Of these seven single nucleotide polymorphisms (SNP), six had P trend < 0.05 and had estimated odds ratios (OR) that were strikingly comparable to those of the previous study. Associations were seen for rs9378805 [OR, 1.47; 95% confidence intervals (CI), 1.19-1.80; P trend = 0.0003] near IRF4 and rs735665 near GRAMD1B (OR, 1.47; 95% CI, 1.14-1.89; P trend = 0.003). However, no associations (P > 0.05) were found for rs11083846, nor were any found for any SNP in linkage disequilibrium with rs11083846. CONCLUSIONS: Our results confirm the previous findings and further support the role of a genetic basis in the etiology of CLL; however, more research is needed to elucidate the causal SNP(s) and the potential manner in which these SNPs or linked SNPs function in CLL pathogenesis.

Authors
Slager, SL; Goldin, LR; Strom, SS; Lanasa, MC; Spector, LG; Rassenti, L; Leis, JF; Camp, NJ; Kay, NE; Vachon, CM; Glenn, M; Weinberg, JB; Rabe, KG; Cunningham, JM; Achenbach, SJ; Hanson, CA; Marti, GE; Call, TG; Caporaso, NE; Cerhan, JR
MLA Citation
Slager, SL, Goldin, LR, Strom, SS, Lanasa, MC, Spector, LG, Rassenti, L, Leis, JF, Camp, NJ, Kay, NE, Vachon, CM, Glenn, M, Weinberg, JB, Rabe, KG, Cunningham, JM, Achenbach, SJ, Hanson, CA, Marti, GE, Call, TG, Caporaso, NE, and Cerhan, JR. "Genetic susceptibility variants for chronic lymphocytic leukemia." Cancer Epidemiol Biomarkers Prev 19.4 (April 2010): 1098-1102.
PMID
20332261
Source
pubmed
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
19
Issue
4
Publish Date
2010
Start Page
1098
End Page
1102
DOI
10.1158/1055-9965.EPI-09-1217

Malaria severity and human nitric oxide synthase type 2 (NOS2) promoter haplotypes.

Nitric oxide (NO) mediates host resistance to severe malaria and other infectious diseases. NO production and mononuclear cell expression of the NO producing enzyme-inducible nitric oxide synthase (NOS2) have been associated with protection from severe falciparum malaria. The purpose of this study was to identify single nucleotide polymorphisms (SNPs) and haplotypes in the NOS2 promoter, to identify associations of these haplotypes with malaria severity and to test the effects of these polymorphisms on promoter activity. We identified 34 SNPs in the proximal 7.3 kb region of the NOS2 promoter and inferred NOS2 promoter haplotypes based on genotyping 24 of these SNPs in a population of Tanzanian children with and without cerebral malaria. We identified 71 haplotypes; 24 of these haplotypes comprised 82% of the alleles. We determined whether NOS2 promoter haplotypes were associated with malaria severity in two groups of subjects from Dar es Salaam (N = 185 and N = 250) and in an inception cohort of children from Muheza-Tanga, Tanzania (N = 883). We did not find consistent associations of NOS2 promoter haplotypes with malaria severity or malarial anemia, although interpretation of these results was potentially limited by the sample size of each group. Furthermore, cytokine-induced NOS2 promoter activity determined using luciferase reporter constructs containing the proximal 7.3 kb region of the NOS2 promoter and the G-954C or C-1173T SNPs did not differ from NOS2 promoter constructs that lacked these polymorphisms. Taken together, these studies suggest that the relationship between NOS2 promoter polymorphisms and malaria severity is more complex than previously described.

Authors
Levesque, MC; Hobbs, MR; O'Loughlin, CW; Chancellor, JA; Chen, Y; Tkachuk, AN; Booth, J; Patch, KB; Allgood, S; Pole, AR; Fernandez, CA; Mwaikambo, ED; Mutabingwa, TK; Fried, M; Sorensen, B; Duffy, PE; Granger, DL; Anstey, NM; Weinberg, JB
MLA Citation
Levesque, MC, Hobbs, MR, O'Loughlin, CW, Chancellor, JA, Chen, Y, Tkachuk, AN, Booth, J, Patch, KB, Allgood, S, Pole, AR, Fernandez, CA, Mwaikambo, ED, Mutabingwa, TK, Fried, M, Sorensen, B, Duffy, PE, Granger, DL, Anstey, NM, and Weinberg, JB. "Malaria severity and human nitric oxide synthase type 2 (NOS2) promoter haplotypes." Hum Genet 127.2 (February 2010): 163-182.
PMID
19859740
Source
pubmed
Published In
Human Genetics
Volume
127
Issue
2
Publish Date
2010
Start Page
163
End Page
182
DOI
10.1007/s00439-009-0753-3

Single-cell analysis reveals oligoclonality among 'low-count' monoclonal B-cell lymphocytosis.

Monoclonal B-cell lymphocytosis (MBL) is a preclinical hematologic syndrome characterized by small accumulations of CD5(+) B lymphocytes. Most MBL share phenotypic characteristics with chronic lymphocytic leukemia (CLL). Although some MBL progress to CLL, most MBL have apparently limited potential for progression to CLL, particularly those MBL with normal absolute B-cell counts ('low-count' MBL). Most CLL are monoclonal and it is not known whether MBL are monoclonal or oligoclonal; this is important because it is unclear whether MBL represent indolent CLL or represent a distinct premalignant precursor before the development of CLL. We used flow cytometry analysis and sorting to determine immunophenotypic characteristics, clonality and molecular features of MBL from familial CLL kindreds. Single-cell analysis indicated four of six low-count MBL consisted of two or more unrelated clones; the other two MBL were monoclonal. 87% of low-count MBL clones had mutated immunoglobulin genes, and no immunoglobulin heavy-chain rearrangements of V(H) family 1 were observed. Some MBL were diversified, clonally related populations with evidence of antigen drive. We conclude that although low-count MBL share many phenotypic characteristics with CLL, many MBL are oligoclonal. This supports a model for step-wise development of MBL into CLL.

Authors
Lanasa, MC; Allgood, SD; Volkheimer, AD; Gockerman, JP; Whitesides, JF; Goodman, BK; Moore, JO; Weinberg, JB; Levesque, MC
MLA Citation
Lanasa, MC, Allgood, SD, Volkheimer, AD, Gockerman, JP, Whitesides, JF, Goodman, BK, Moore, JO, Weinberg, JB, and Levesque, MC. "Single-cell analysis reveals oligoclonality among 'low-count' monoclonal B-cell lymphocytosis." Leukemia 24.1 (January 2010): 133-140.
PMID
19946263
Source
pubmed
Published In
Leukemia
Volume
24
Issue
1
Publish Date
2010
Start Page
133
End Page
140
DOI
10.1038/leu.2009.192

Increased asymmetric dimethylarginine in severe falciparum malaria: Association with impaired nitric oxide bioavailability and fatal outcome

Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is a predictor of mortality in critical illness. Severe malaria (SM) is associated with decreased NO bioavailability, but the contribution of ADMA to the pathogenesis of impaired NO bioavailability and adverse outcomes in malaria is unknown. In adults with and without falciparum malaria, we tested the hypotheses that plasma ADMA would be: 1) increased in proportion to disease severity, 2) associated with impaired vascular and pulmonary NO bioavailability and 3) independently associated with increased mortality. We assessed plasma dimethylarginines, exhaled NO concentrations and endothelial function in 49 patients with SM, 78 with moderately severe malaria (MSM) and 19 healthy controls (HC). Repeat ADMA and endothelial function measurements were performed in patients with SM. Multivariable regression was used to assess the effect of ADMA on mortality and NO bioavailability. Plasma ADMA was increased in SM patients (0.85 μM; 95% CI 0.74-0.96) compared to those with MSM (0.54 μM; 95%CI 0.5-0.56) and HCs (0.64 μM; 95%CI 0.58-0.70; p<0.001). ADMA was an independent predictor of mortality in SM patients with each micromolar elevation increasing the odds of death 18 fold (95% CI 2.0-181; p = 0.01). ADMA was independently associated with decreased exhaled NO (rs =20.31) and endothelial function (rs =20.32) in all malaria patients, and with reduced exhaled NO (rs =-0.72) in those with SM. ADMA is increased in SM and associated with decreased vascular and pulmonary NO bioavailability. Inhibition of NOS by ADMA may contribute to increased mortality in severe malaria.

Authors
Yeo, TW; Lampah, DA; Tjitra, E; Gitawati, R; Darcy, CJ; Jones, C; Kenangalem, E; McNeil, YR; Granger, DL; Lopansri, BK; Weinberg, JB; Price, RN; Duffull, SB; Celermajer, DS; Anstey, NM
MLA Citation
Yeo, TW, Lampah, DA, Tjitra, E, Gitawati, R, Darcy, CJ, Jones, C, Kenangalem, E, McNeil, YR, Granger, DL, Lopansri, BK, Weinberg, JB, Price, RN, Duffull, SB, Celermajer, DS, and Anstey, NM. "Increased asymmetric dimethylarginine in severe falciparum malaria: Association with impaired nitric oxide bioavailability and fatal outcome." PLoS Pathogens 6.4 (2010): 1-8.
Source
scival
Published In
PLoS pathogens
Volume
6
Issue
4
Publish Date
2010
Start Page
1
End Page
8
DOI
10.1371/journal.ppat.1000868

Monoclonal B cell lymphocytosis: Clinical and population perspectives

Monoclonal B Cell Lymphocytosis (MBL) refers to clones of CLL-like cells that exhibit CLL characteristics that fall short of the numbers required for CLL diagnosis. Data from large CLL kindreds document increased prevalence of MBL suggesting a genetic contribution to its etiology. The molecular features that favor progression of MBL to CLL are poorly understood but an elevated B-cell count is a risk factor for progression. An important consideration when evaluating volunteers from CLL families who are willing to donate bone marrow is that MBL be ruled out since the MBL donor clone could result in a second CLL in the recipient. Further studies of MBL are needed to identify the molecular features and how they evolve during progression.

Authors
Caporaso, NE; Marti, GE; Landgren, O; Azzato, E; Weinberg, JB; Goldin, L; Shanafelt, T
MLA Citation
Caporaso, NE, Marti, GE, Landgren, O, Azzato, E, Weinberg, JB, Goldin, L, and Shanafelt, T. "Monoclonal B cell lymphocytosis: Clinical and population perspectives." Cytometry Part B - Clinical Cytometry 78.SUPPL. 1 (2010): S115-S119.
PMID
20839332
Source
scival
Published In
Cytometry
Volume
78
Issue
SUPPL. 1
Publish Date
2010
Start Page
S115
End Page
S119
DOI
10.1002/cyto.b.20555

Statin use and need for therapy in chronic lymphocytic leukemia

Authors
Friedman, DR; Magura, LA; Warren, HAC; Harrison, JD; Diehl, LF; Weinberg, JB
MLA Citation
Friedman, DR, Magura, LA, Warren, HAC, Harrison, JD, Diehl, LF, and Weinberg, JB. "Statin use and need for therapy in chronic lymphocytic leukemia." Leukemia and Lymphoma 51.12 (2010): 2295-2298.
PMID
20929315
Source
scival
Published In
Leukemia & Lymphoma (Informa)
Volume
51
Issue
12
Publish Date
2010
Start Page
2295
End Page
2298
DOI
10.3109/10428194.2010.520050

A Comprehensive Identification of the Microrna Transcriptome and Its Application in B Cell Malignancies

Authors
Jacobs, CL; Jima, DD; Zhang, J; Dunphy, C; Richards, KL; Choi, WWL; Srivastava, G; Evens, AM; Gordon, LI; Czader, M; Rizzieri, DA; Lagoo, AS; Mann, KP; Flowers, CR; Naresh, K; Luftig, M; Friedman, DR; Weinberg, JB; Thompson, MA; Gill, J; Kahl, BS; Chadburn, A; Dave, S
MLA Citation
Jacobs, CL, Jima, DD, Zhang, J, Dunphy, C, Richards, KL, Choi, WWL, Srivastava, G, Evens, AM, Gordon, LI, Czader, M, Rizzieri, DA, Lagoo, AS, Mann, KP, Flowers, CR, Naresh, K, Luftig, M, Friedman, DR, Weinberg, JB, Thompson, MA, Gill, J, Kahl, BS, Chadburn, A, and Dave, S. "A Comprehensive Identification of the Microrna Transcriptome and Its Application in B Cell Malignancies." November 20, 2009.
Source
wos-lite
Published In
Blood
Volume
114
Issue
22
Publish Date
2009
Start Page
948
End Page
949

A genomic approach to improve prognosis and predict therapeutic response in chronic lymphocytic leukemia.

PURPOSE: Chronic lymphocytic leukemia (CLL) is a B-cell malignancy characterized by a variable clinical course. Several parameters have prognostic capabilities but are associated with altered response to therapy in only a small subset of patients. EXPERIMENTAL DESIGN: We used gene expression profiling methods to generate predictors of therapy response and prognosis. Genomic signatures that reflect progressive disease and responses to chemotherapy or chemoimmunotherapy were created using cancer cell lines and patient leukemia cell samples. We validated and applied these three signatures to independent clinical data from four cohorts, representing a total of 301 CLL patients. RESULTS: A genomic signature of prognosis created from patient leukemic cell gene expression data coupled with clinical parameters significantly differentiated patients with stable disease from those with progressive disease in the training data set. The progression signature was validated in two independent data sets, showing a capacity to accurately identify patients at risk for progressive disease. In addition, genomic signatures that predict response to chlorambucil or pentostatin, cyclophosphamide, and rituximab were generated and could accurately distinguish responding and nonresponding CLL patients. CONCLUSIONS: Thus, microarray analysis of CLL lymphocytes can be used to refine prognosis and predict response to different therapies. These results have implications for standard and investigational therapeutics in CLL patients.

Authors
Friedman, DR; Weinberg, JB; Barry, WT; Goodman, BK; Volkheimer, AD; Bond, KM; Chen, Y; Jiang, N; Moore, JO; Gockerman, JP; Diehl, LF; Decastro, CM; Potti, A; Nevins, JR
MLA Citation
Friedman, DR, Weinberg, JB, Barry, WT, Goodman, BK, Volkheimer, AD, Bond, KM, Chen, Y, Jiang, N, Moore, JO, Gockerman, JP, Diehl, LF, Decastro, CM, Potti, A, and Nevins, JR. "A genomic approach to improve prognosis and predict therapeutic response in chronic lymphocytic leukemia." Clin Cancer Res 15.22 (November 15, 2009): 6947-6955.
PMID
19861443
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
15
Issue
22
Publish Date
2009
Start Page
6947
End Page
6955
DOI
10.1158/1078-0432.CCR-09-1132

Relationship of cell-free hemoglobin to impaired endothelial nitric oxide bioavailability and perfusion in severe falciparum malaria.

BACKGROUND: Hemolysis causes anemia in falciparum malaria, but its contribution to microvascular pathology in severe malaria (SM) is not well characterized. In other hemolytic diseases, release of cell-free hemoglobin causes nitric oxide (NO) quenching, endothelial activation, and vascular complications. We examined the relationship of plasma hemoglobin and myoglobin to endothelial dysfunction and disease severity in malaria. METHODS: Cell-free hemoglobin (a potent NO quencher), reactive hyperemia peripheral arterial tonometry (RH-PAT) (a measure of endothelial NO bioavailability), and measures of perfusion and endothelial activation were quantified in adults with moderately severe (n = 78) or severe (n = 49) malaria and control subjects (n = 16) from Papua, Indonesia. RESULTS: Cell-free hemoglobin concentrations in patients with SM (median, 5.4 micromol/L; interquartile range [IQR], 3.2-7.4 micromol/L) were significantly higher than in those with moderately severe malaria (2.6 micromol/L; IQR, 1.3-4.5 micromol/L) or controls (1.2 micromol/L; IQR, 0.9-2.4 micromol/L; P < .001). Multivariable regression analysis revealed that cell-free hemoglobin remained inversely associated with RH-PAT, and in patients with SM, there was a significant longitudinal association between improvement in RH-PAT index and decreasing levels of cell-free hemoglobin (P = .047). Cell-free hemoglobin levels were also independently associated with lactate, endothelial activation, and proinflammatory cytokinemia. CONCLUSIONS: Hemolysis in falciparum malaria results in NO quenching by cell-free hemoglobin, and may exacerbate endothelial dysfunction, adhesion receptor expression and impaired tissue perfusion. Treatments that increase NO bioavailability may have potential as adjunctive therapies in SM.

Authors
Yeo, TW; Lampah, DA; Tjitra, E; Gitawati, R; Kenangalem, E; Piera, K; Granger, DL; Lopansri, BK; Weinberg, JB; Price, RN; Duffull, SB; Celermajer, DS; Anstey, NM
MLA Citation
Yeo, TW, Lampah, DA, Tjitra, E, Gitawati, R, Kenangalem, E, Piera, K, Granger, DL, Lopansri, BK, Weinberg, JB, Price, RN, Duffull, SB, Celermajer, DS, and Anstey, NM. "Relationship of cell-free hemoglobin to impaired endothelial nitric oxide bioavailability and perfusion in severe falciparum malaria." J Infect Dis 200.10 (November 15, 2009): 1522-1529.
PMID
19803726
Source
pubmed
Published In
Journal of Infectious Diseases
Volume
200
Issue
10
Publish Date
2009
Start Page
1522
End Page
1529
DOI
10.1086/644641

NOS2A, TLR4, and IFNGR1 interactions influence pulmonary tuberculosis susceptibility in African-Americans.

Tuberculosis (TB) has substantial mortality worldwide with 5-10% of those exposed progressing to active TB disease. Studies in mice and humans indicate that the inducible nitric oxide synthase (iNOS) molecule plays an important role in immune response to TB. A mixed case-control association study of individuals with TB, relatives, or close contact controls was performed in 726 individuals (279 case and 166 control African-Americans; 198 case and 123 control Caucasians). Thirty-nine single nucleotide polymorphisms (SNPs) were selected from the NOS2A gene for single SNP, haplotype, and multilocus interaction analyses with other typed candidate genes using generalized estimating equations. In African-Americans, ten NOS2A SNPs were associated with TB. The strongest associations were observed at rs2274894 (odds ratio (OR) = 1.84, 95% confidence interval (CI) [1.23-2.77], p = 0.003) and rs7215373 (OR = 1.67, 95% CI [1.17-2.37], p = 0.004), both of which passed a false discovery rate correction for multiple comparisons (q* = 0.20). The strongest gene-gene interactions were observed between NOS2A rs2248814 and IFNGR1 rs1327474 (p = 0.0004) and NOS2A rs944722 and IFNGR1 rs1327474 (p = 0.0006). Three other SNPs in NOS2A interacted with TLR4 rs5030729 and five other NOS2A SNPs interacted with IFNGR1 rs1327474. No significant associations were observed in Caucasians. These results suggest that NOS2A variants may contribute to TB susceptibility, particularly in individuals of African descent, and may act synergistically with SNPs in TLR4 and IFNGR1.

Authors
Velez, DR; Hulme, WF; Myers, JL; Weinberg, JB; Levesque, MC; Stryjewski, ME; Abbate, E; Estevan, R; Patillo, SG; Gilbert, JR; Hamilton, CD; Scott, WK
MLA Citation
Velez, DR, Hulme, WF, Myers, JL, Weinberg, JB, Levesque, MC, Stryjewski, ME, Abbate, E, Estevan, R, Patillo, SG, Gilbert, JR, Hamilton, CD, and Scott, WK. "NOS2A, TLR4, and IFNGR1 interactions influence pulmonary tuberculosis susceptibility in African-Americans." Hum Genet 126.5 (November 2009): 643-653.
PMID
19575238
Source
pubmed
Published In
Human Genetics
Volume
126
Issue
5
Publish Date
2009
Start Page
643
End Page
653
DOI
10.1007/s00439-009-0713-y

Inhibition of nitric oxide synthase by cobalamins and cobinamides.

Cobalamins are important cofactors for methionine synthase and methylmalonyl-CoA mutase. Certain corrins also bind nitric oxide (NO), quenching its bioactivity. To determine if corrins would inhibit NO synthase (NOS), we measured their effects on -L-[(14)C]arginine-to-L-[(14)C]citrulline conversion by NOS1, NOS2, and NOS3. Hydroxocobalamin (OH-Cbl), cobinamide, and dicyanocobinamide (CN(2)-Cbi) potently inhibited all isoforms, whereas cyanocobalamin, methylcobalamin, and adenosylcobalamin had much less effect. OH-Cbl and CN(2)-Cbi prevented binding of the oxygen analog carbon monoxide (CO) to the reduced NOS1 and NOS2 heme active site. CN(2)-Cbi did not react directly with NO or CO. Spectral perturbation analysis showed that CN(2)-Cbi interacted directly with the purified NOS1 oxygenase domain. NOS inhibition by corrins was rapid and not reversed by dialysis with L-arginine or tetrahydrobiopterin. Molecular modeling indicated that corrins could access the unusually large heme- and substrate-binding pocket of NOS. Best fits were obtained in the "base-off" conformation of the lower axial dimethylbenzimidazole ligand. CN(2)-Cbi inhibited interferon-gamma-activated Raw264.7 mouse macrophage NO production. We show for the first time that certain corrins directly inhibit NOS, suggesting that these agents (or their derivatives) may have pharmacological utility. Endogenous cobalamins and cobinamides might play important roles in regulating NOS activity under normal and pathological conditions.

Authors
Weinberg, JB; Chen, Y; Jiang, N; Beasley, BE; Salerno, JC; Ghosh, DK
MLA Citation
Weinberg, JB, Chen, Y, Jiang, N, Beasley, BE, Salerno, JC, and Ghosh, DK. "Inhibition of nitric oxide synthase by cobalamins and cobinamides." Free Radic Biol Med 46.12 (June 15, 2009): 1626-1632.
PMID
19328848
Source
pubmed
Published In
Free Radical Biology and Medicine
Volume
46
Issue
12
Publish Date
2009
Start Page
1626
End Page
1632
DOI
10.1016/j.freeradbiomed.2009.03.017

Inhibition of matrix metalloproteinases enhances in vitro repair of the meniscus.

Damage or injury of the meniscus is associated with onset and progression of knee osteoarthritis (OA). The intrinsic repair capacity of the meniscus is inhibited by inflammatory cytokines, such as interleukin-1 (IL-1). Using an in vitro meniscal repair model system, we examined the hypothesis that inhibition of matrix metalloproteinases (MMPs) in the presence of IL-1 will enhance repair of meniscal lesions. Integrative repair of the meniscus was examined between two concentric explants cultured with IL-1 and various MMP inhibitors for 14 days. Throughout the culture period, we assessed total specific MMP activity in the media. At harvest, biomechanical testing to assess the strength of repair and histologic staining were performed. IL-1 decreased the shear strength of repair, as compared with control explants. In the presence of IL-1, the broad-spectrum MMP inhibitor GM 6001 decreased the MMP activity in the media, increased the shear strength of repair, and enhanced tissue repair in the interface. However, individual MMP inhibitors did not alter the shear strength of repair in either the presence or absence of IL-1. These findings suggest IL-1 may inhibit meniscal repair through upregulation of MMPs, but inhibition of multiple MMPs may be necessary to promote integrative meniscal repair.

Authors
McNulty, AL; Weinberg, JB; Guilak, F
MLA Citation
McNulty, AL, Weinberg, JB, and Guilak, F. "Inhibition of matrix metalloproteinases enhances in vitro repair of the meniscus." Clinical Orthopaedics and Related Research 467.6 (June 2009): 1557-1567.
PMID
18975039
Source
epmc
Published In
Clinical Orthopaedics and Related Research ®
Volume
467
Issue
6
Publish Date
2009
Start Page
1557
End Page
1567
DOI
10.1007/s11999-008-0596-6

Patterns of microRNA expression characterize stages of human B-cell differentiation.

Mature B-cell differentiation provides an important mechanism for the acquisition of adaptive immunity. Malignancies derived from mature B cells constitute the majority of leukemias and lymphomas. These malignancies often maintain the characteristics of the normal B cells that they are derived from, a feature that is frequently used in their diagnosis. The role of microRNAs in mature B cells is largely unknown. Through concomitant microRNA and mRNA profiling, we demonstrate a potential regulatory role for microRNAs at every stage of the mature B-cell differentiation process. In addition, we have experimentally identified a direct role for the microRNA regulation of key transcription factors in B-cell differentiation: LMO2 and PRDM1 (Blimp1). We also profiled the microRNA of B-cell tumors derived from diffuse large B-cell lymphoma, Burkitt lymphoma, and chronic lymphocytic leukemia. We found that, in contrast to many other malignancies, common B-cell malignancies do not down-regulate microRNA expression. Although these tumors could be distinguished from each other with use of microRNA expression, each tumor type maintained the expression of the lineage-specific microRNAs. Expression of these lineage-specific microRNAs could correctly predict the lineage of B-cell malignancies in more than 95% of the cases. Thus, our data demonstrate that microRNAs may be important in maintaining the mature B-cell phenotype in normal and malignant B cells.

Authors
Zhang, J; Jima, DD; Jacobs, C; Fischer, R; Gottwein, E; Huang, G; Lugar, PL; Lagoo, AS; Rizzieri, DA; Friedman, DR; Weinberg, JB; Lipsky, PE; Dave, SS
MLA Citation
Zhang, J, Jima, DD, Jacobs, C, Fischer, R, Gottwein, E, Huang, G, Lugar, PL, Lagoo, AS, Rizzieri, DA, Friedman, DR, Weinberg, JB, Lipsky, PE, and Dave, SS. "Patterns of microRNA expression characterize stages of human B-cell differentiation." Blood 113.19 (May 7, 2009): 4586-4594.
PMID
19202128
Source
pubmed
Published In
Blood
Volume
113
Issue
19
Publish Date
2009
Start Page
4586
End Page
4594
DOI
10.1182/blood-2008-09-178186

Oligoclonal TRBV gene usage among CD8(+) T cells in monoclonal B lymphocytosis and CLL.

Authors
Lanasa, MC; Allgood, SD; Bond, KM; Gockerman, JP; Levesque, MC; Weinberg, JB
MLA Citation
Lanasa, MC, Allgood, SD, Bond, KM, Gockerman, JP, Levesque, MC, and Weinberg, JB. "Oligoclonal TRBV gene usage among CD8(+) T cells in monoclonal B lymphocytosis and CLL." Br J Haematol 145.4 (May 2009): 535-537.
PMID
19298246
Source
pubmed
Published In
British Journal of Haematology
Volume
145
Issue
4
Publish Date
2009
Start Page
535
End Page
537
DOI
10.1111/j.1365-2141.2009.07635.x

Intraprotein electron transfer in inducible nitric oxide synthase holoenzyme

Intraprotein electron transfer (IET) from flavin mononucleotide (FMN) to heme is essential in NO synthesis by NO synthase (NOS). Our previous laser flash photolysis studies provided a direct determination of the kinetics of the FMN-heme IET in a truncated two-domain construct (oxyFMN) of murine inducible NOS (iNOS), in which only the oxygenase and FMN domains along with the calmodulin (CaM) binding site are present (Feng et al. J. Am. Chem. Soc. 128, 3808-3811, 2006). Here we report the kinetics of the IET in a human iNOS oxyFMN construct, a human iNOS holoenzyme, and a murine iNOS holoenzyme, using CO photolysis in comparative studies on partially reduced NOS and a NOS oxygenase construct that lacks the FMN domain. The IET rate constants for the human and murine iNOS holoenzymes are 34 ± 5 and 35 ± 3 s-1, respectively, thereby providing a direct measurement of this IET between the catalytically significant redox couples of FMN and heme in the iNOS holoenzyme. These values are approximately an order of magnitude smaller than that in the corresponding iNOS oxyFMN construct, suggesting that in the holoenzyme the rate-limiting step in the IET is the conversion of the shielded electron-accepting (input) state to a new electron-donating (output) state. The fact that there is no rapid IET component in the kinetic traces obtained with the iNOS holoenzyme implies that the enzyme remains mainly in the input state. The IET rate constant value for the iNOS holoenzyme is similar to that obtained for a CaM-bound neuronal NOS holoenzyme, suggesting that CaM activation effectively removes the inhibitory effect of the unique autoregulatory insert in neuronal NOS. © 2008 SBIC.

Authors
Feng, C; Dupont, AL; Nahm, NJ; Spratt, DE; Hazzard, JT; Weinberg, JB; Guillemette, JG; Tollin, G; Ghosh, DK
MLA Citation
Feng, C, Dupont, AL, Nahm, NJ, Spratt, DE, Hazzard, JT, Weinberg, JB, Guillemette, JG, Tollin, G, and Ghosh, DK. "Intraprotein electron transfer in inducible nitric oxide synthase holoenzyme." Journal of Biological Inorganic Chemistry 14.1 (2009): 133-142.
PMID
18830722
Source
scival
Published In
JBIC Journal of Biological Inorganic Chemistry
Volume
14
Issue
1
Publish Date
2009
Start Page
133
End Page
142
DOI
10.1007/s00775-008-0431-2

Apolipoprotein E genotype as a determinant of survival in chronic lymphocytic leukemia.

Survival of chronic lymphocytic leukemia (CLL) cells requires sustained activation of the antiapoptotic PI-3-K/Akt pathway, and many therapies for CLL cause leukemia cell death by triggering apoptosis. Blood lipoprotein particles are either pro- or antiapoptotic. High-density lipoprotein particles are antiapoptotic through sphingosine-1-phosphate receptor 3-mediated activation of the PI-3-K/Akt pathway. Apolipoprotein E4 (apoE4)-very low density lipoproteins (VLDL) increase apoptosis, but the apoE2-VLDL and apoE3-VLDL isoforms do not. As increased B-cell apoptosis favors longer survival of CLL patients, we hypothesized that APOE4 genotype would beneficially influence the clinical course of CLL. We report here that women (but not men) with an APOE4 genotype had markedly longer survival than non-APOE4 patients. VLDL is metabolized to low-density lipoprotein through lipoprotein lipase. Higher levels of lipoprotein lipase mRNA in these CLL patients correlated with shorter survival. The beneficial effect of APOE4 in CLL survival is likely mediated through APOE4 allele-specific regulation of leukemia cell apoptosis. The APOE allele and genotype distribution in these CLL patients is the same as in unaffected control populations, suggesting that although APOE genotype influences CLL outcome and response to therapy, it does not alter susceptibility to developing this disease.

Authors
Weinberg, JB; Volkheimer, AD; Mihovilovic, M; Jiang, N; Chen, Y; Bond, K; Moore, JO; Gockerman, JP; Diehl, LF; de Castro, CM; Rizzieri, DA; Levesque, MC; Dekroon, R; Strittmatter, WJ
MLA Citation
Weinberg, JB, Volkheimer, AD, Mihovilovic, M, Jiang, N, Chen, Y, Bond, K, Moore, JO, Gockerman, JP, Diehl, LF, de Castro, CM, Rizzieri, DA, Levesque, MC, Dekroon, R, and Strittmatter, WJ. "Apolipoprotein E genotype as a determinant of survival in chronic lymphocytic leukemia." Leukemia 22.12 (December 2008): 2184-2192.
PMID
18784741
Source
pubmed
Published In
Leukemia
Volume
22
Issue
12
Publish Date
2008
Start Page
2184
End Page
2192
DOI
10.1038/leu.2008.241

INTRAVASCULAR HEMOLYSIS: A NEGLECTED MECHANISM OF NITRIC OXIDE QUENCHING, ENDOTHELIAL DYSFUNCTION AND IMPAIRED PERFUSION IN SEVERE FALCIPARUM MALARIA?

Authors
Yeo, TW; Lampah, D; Tjitra, E; Gitawati, R; Kenangalem, E; Piera, K; Lopansri, B; Granger, D; Weinberg, JB; Price, R; Celermajer, D; Duffull, S; Anstey, N
MLA Citation
Yeo, TW, Lampah, D, Tjitra, E, Gitawati, R, Kenangalem, E, Piera, K, Lopansri, B, Granger, D, Weinberg, JB, Price, R, Celermajer, D, Duffull, S, and Anstey, N. "INTRAVASCULAR HEMOLYSIS: A NEGLECTED MECHANISM OF NITRIC OXIDE QUENCHING, ENDOTHELIAL DYSFUNCTION AND IMPAIRED PERFUSION IN SEVERE FALCIPARUM MALARIA?." AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE 79.6 (December 2008): 351-351.
Source
wos-lite
Published In
American Journal of Tropical Medicine and Hygiene
Volume
79
Issue
6
Publish Date
2008
Start Page
351
End Page
351

Family-Associated Monoclonal B Lymphocytosis Is Commonly Oligoclonal and Expresses Markers Associated with Adverse Risk in CLL

Authors
Lanasa, MC; Allgood, SD; Slager, SL; Camp, N; Spector, L; Rassenti, L; Kay, NE; Gockerman, JP; Volkheimer, A; Goodman, BK; Strom, S; Call, T; Cerhan, J; Leis, JF; Goldin, L; Marti, G; Weinberg, JB; Caporaso, N; Levesque, MC
MLA Citation
Lanasa, MC, Allgood, SD, Slager, SL, Camp, N, Spector, L, Rassenti, L, Kay, NE, Gockerman, JP, Volkheimer, A, Goodman, BK, Strom, S, Call, T, Cerhan, J, Leis, JF, Goldin, L, Marti, G, Weinberg, JB, Caporaso, N, and Levesque, MC. "Family-Associated Monoclonal B Lymphocytosis Is Commonly Oligoclonal and Expresses Markers Associated with Adverse Risk in CLL." BLOOD 112.11 (November 16, 2008): 1078-1078.
Source
wos-lite
Published In
Blood
Volume
112
Issue
11
Publish Date
2008
Start Page
1078
End Page
1078

Identification of Therapeutic Targets for Chronic Lymphocytic Leukemia in the Relapsed and Refractory Setting

Authors
Friedman, D; Weinberg, JB; Bond, KM; Volkheimer, AD; Chen, Y; Nevins, JR
MLA Citation
Friedman, D, Weinberg, JB, Bond, KM, Volkheimer, AD, Chen, Y, and Nevins, JR. "Identification of Therapeutic Targets for Chronic Lymphocytic Leukemia in the Relapsed and Refractory Setting." BLOOD 112.11 (November 16, 2008): 720-720.
Source
wos-lite
Published In
Blood
Volume
112
Issue
11
Publish Date
2008
Start Page
720
End Page
720

Arginine, nitric oxide, carbon monoxide, and endothelial function in severe malaria.

PURPOSE OF REVIEW: Parasiticidal therapy of severe falciparum malaria improves outcome, but up to 30% of these patients die despite best therapy. Nitric oxide is protective against severe disease, and both nitric oxide and arginine (the substrate for nitric oxide synthase) are low in clinical malaria. Parasitized red blood cell interactions with endothelium are important in the pathophysiology of malaria. This review describes new information regarding nitric oxide, arginine, carbon monoxide, and endothelial function in malaria. RECENT FINDINGS: Low arginine, low nitric oxide production, and endothelial dysfunction are common in severe malaria. The degree of hypoargininemia and endothelial dysfunction (measured by reactive hyperemia-peripheral artery tonometry) is proportional to parasite burden and severity of illness. Plasma arginase (an enzyme that catabolizes arginine) is elevated in severe malaria. Administering arginine intravenously reverses hypoargininemia and endothelial dysfunction. The cause(s) of hypoargininemia in malaria is unknown. Carbon monoxide (which shares certain functional properties with nitric oxide) protects against cerebral malaria in mice. SUMMARY: Replenishment of arginine and restoration of nitric oxide production in clinical malaria should diminish parasitized red blood cells adherence to endothelium and reduce the sequelae of these interactions (e.g. cerebral malaria). Arginine therapy given in addition to conventional antimalaria treatment may prove to be beneficial in severe malaria.

Authors
Weinberg, JB; Lopansri, BK; Mwaikambo, E; Granger, DL
MLA Citation
Weinberg, JB, Lopansri, BK, Mwaikambo, E, and Granger, DL. "Arginine, nitric oxide, carbon monoxide, and endothelial function in severe malaria." Curr Opin Infect Dis 21.5 (October 2008): 468-475. (Review)
PMID
18725795
Source
pubmed
Published In
Current Opinion in Infectious Diseases
Volume
21
Issue
5
Publish Date
2008
Start Page
468
End Page
475
DOI
10.1097/QCO.0b013e32830ef5cf

Recovery of endothelial function in severe falciparum malaria: relationship with improvement in plasma L-arginine and blood lactate concentrations.

BACKGROUND: Severe malaria is characterized by microvascular obstruction, endothelial dysfunction, and reduced levels of L-arginine and nitric oxide (NO). L-Arginine infusion improves endothelial function in moderately severe malaria. Neither the longitudinal course of endothelial dysfunction nor factors associated with recovery have been characterized in severe malaria. METHODS: Endothelial function was measured longitudinally in adults with severe malaria (n = 49) or moderately severe malaria (n = 48) in Indonesia, using reactive hyperemia peripheral arterial tonometry (RH-PAT). In a mixed-effects model, changes in RH-PAT index values in patients with severe malaria were related to changes in parasitemia, lactate, acidosis, and plasma L-arginine concentrations. RESULTS: Among patients with severe malaria, the proportion with endothelial dysfunction fell from 94% (46/49 patients) to 14% (6/42 patients) before discharge or death (P < .001). In severe malaria, the median time to normal endothelial function was 49 h (interquartile range, 20-70 h) after the start of antimalarial therapy. The mean increase in L-arginine concentrations in patients with severe malaria was 11 micromol/L/24 h (95% confidence interval [CI], 9-13 micromol/L/24 h), from a baseline of 49 micromol/L (95% CI, 37-45 micromol/L). Improvement of endothelial function in patients with severe malaria correlated with increasing levels of L-arginine (r = 0.56; P = .008) and decreasing levels of lactate (r = -0.44; P = .001). CONCLUSIONS: Recovery of endothelial function in severe malaria is associated with recovery from hypoargininemia and lactic acidosis. Agents that can improve endothelial NO production and endothelial function, such as L-arginine, may have potential as adjunctive therapy early during the course of severe malaria.

Authors
Yeo, TW; Lampah, DA; Gitawati, R; Tjitra, E; Kenangalem, E; McNeil, YR; Darcy, CJ; Granger, DL; Weinberg, JB; Lopansri, BK; Price, RN; Duffull, SB; Celermajer, DS; Anstey, NM
MLA Citation
Yeo, TW, Lampah, DA, Gitawati, R, Tjitra, E, Kenangalem, E, McNeil, YR, Darcy, CJ, Granger, DL, Weinberg, JB, Lopansri, BK, Price, RN, Duffull, SB, Celermajer, DS, and Anstey, NM. "Recovery of endothelial function in severe falciparum malaria: relationship with improvement in plasma L-arginine and blood lactate concentrations." J Infect Dis 198.4 (August 15, 2008): 602-608.
PMID
18605903
Source
pubmed
Published In
Journal of Infectious Diseases
Volume
198
Issue
4
Publish Date
2008
Start Page
602
End Page
608
DOI
10.1086/590209

CLL cell apoptosis induced by nitric oxide synthase inhibitors: correlation with lipid solubility and NOS1 dissociation constant.

Nitric oxide synthase (NOS) inhibitors induce chronic lymphocytic leukemia (CLL) cell apoptosis and have potential as CLL therapeutics. We determined the half-maximal concentration (ED(50)) of 22 NOS inhibitors that induced CLL cell death in vitro. There was a direct correlation of the NOS1 (but not NOS2) dissociation constant (K(d)) and the hydrophobicity partitioning coefficient of each NOS inhibitor and its ED(50). NOS inhibitors that bound tightly to CLL cell NOS1 and were hydrophobic potently induced CLL cell death. CLL cell RNA and protein analyses confirmed CLL cell NOS1 expression. Our studies permit the rational selection of NOS inhibitors for testing as CLL therapeutics.

Authors
Levesque, MC; Ghosh, DK; Beasley, BE; Chen, Y; Volkheimer, AD; O'Loughlin, CW; Gockerman, JP; Moore, JO; Weinberg, JB
MLA Citation
Levesque, MC, Ghosh, DK, Beasley, BE, Chen, Y, Volkheimer, AD, O'Loughlin, CW, Gockerman, JP, Moore, JO, and Weinberg, JB. "CLL cell apoptosis induced by nitric oxide synthase inhibitors: correlation with lipid solubility and NOS1 dissociation constant." Leuk Res 32.7 (July 2008): 1061-1070.
PMID
18180035
Source
pubmed
Published In
Leukemia Research
Volume
32
Issue
7
Publish Date
2008
Start Page
1061
End Page
1070
DOI
10.1016/j.leukres.2007.11.026

Identification of genetic polymorphisms associated with risk for pulmonary hypertension in sickle cell disease.

Up to 30% of adult patients with sickle cell disease (SCD) will develop pulmonary hypertension (pHTN), a complication associated with significant morbidity and mortality. To identify genetic factors that contribute to risk for pHTN in SCD, we performed association analysis with 297 single nucleotide polymorphisms (SNPs) in 49 candidate genes in patients with sickle cell anemia (Hb SS) who had been screened for pHTN by echocardiography (n = 111). Evidence of association was primarily identified for genes in the TGFbeta superfamily, including activin A receptor, type II-like 1 (ACVRL1), bone morphogenetic protein receptor 2 (BMPR2), and bone morphogenetic protein 6 (BMP6). The association of pHTN with ACVRL1 and BMPR2 corroborates the previous association of these genes with primary pHTN. Moreover, genes in the TGFbeta pathway have been independently implicated in risk for several sickle cell complications, suggesting that this gene pathway is important in overall sickle cell pathophysiology. Genetic variation in the beta-1 adrenergic receptor (ADRB1) was also associated with pHTN in our dataset. A multiple regression model, which included age and baseline hemoglobin as covariates, retained SNPs in ACVRL1, BMP6, and ADRB1 as independently contributing to pHTN risk. These findings may offer new promise for identifying patients at risk for pHTN, developing new therapeutic targets, and reducing the occurrence of this life-threatening SCD complication.

Authors
Ashley-Koch, AE; Elliott, L; Kail, ME; De Castro, LM; Jonassaint, J; Jackson, TL; Price, J; Ataga, KI; Levesque, MC; Weinberg, JB; Orringer, EP; Collins, A; Vance, JM; Telen, MJ
MLA Citation
Ashley-Koch, AE, Elliott, L, Kail, ME, De Castro, LM, Jonassaint, J, Jackson, TL, Price, J, Ataga, KI, Levesque, MC, Weinberg, JB, Orringer, EP, Collins, A, Vance, JM, and Telen, MJ. "Identification of genetic polymorphisms associated with risk for pulmonary hypertension in sickle cell disease." Blood 111.12 (June 15, 2008): 5721-5726.
PMID
18187665
Source
pubmed
Published In
Blood
Volume
111
Issue
12
Publish Date
2008
Start Page
5721
End Page
5726
DOI
10.1182/blood-2007-02-074849

Safety profile of L-arginine infusion in moderately severe falciparum malaria.

BACKGROUND: L-arginine infusion improves endothelial function in malaria but its safety profile has not been described in detail. We assessed clinical symptoms, hemodynamic status and biochemical parameters before and after a single L-arginine infusion in adults with moderately severe malaria. METHODOLOGY AND FINDINGS: In an ascending dose study, adjunctive intravenous L-arginine hydrochloride was infused over 30 minutes in doses of 3 g, 6 g and 12 g to three separate groups of 10 adults hospitalized with moderately severe Plasmodium falciparum malaria in addition to standard quinine therapy. Symptoms, vital signs and selected biochemical measurements were assessed before, during, and for 24 hours after infusion. No new or worsening symptoms developed apart from mild discomfort at the intravenous cannula site in two patients. There was a dose-response relationship between increasing mg/kg dose and the maximum decrease in systolic (rho = 0.463; Spearman's, p = 0.02) and diastolic blood pressure (r = 0.42; Pearson's, p = 0.02), and with the maximum increment in blood potassium (r = 0.70, p<0.001) and maximum decrement in bicarbonate concentrations (r = 0.53, p = 0.003) and pH (r = 0.48, p = 0.007). At the highest dose (12 g), changes in blood pressure and electrolytes were not clinically significant, with a mean maximum decrease in mean arterial blood pressure of 6 mmHg (range: 0-11; p<0.001), mean maximal increase in potassium of 0.5 mmol/L (range 0.2-0.7 mmol/L; p<0.001), and mean maximal decrease in bicarbonate of 3 mEq/L (range 1-7; p<0.01) without a significant change in pH. There was no significant dose-response relationship with blood phosphate, lactate, anion gap and glucose concentrations. All patients had an uncomplicated clinical recovery. CONCLUSIONS/SIGNIFICANCE: Infusion of up to 12 g of intravenous L-arginine hydrochloride over 30 minutes is well tolerated in adults with moderately severe malaria, with no clinically important changes in hemodynamic or biochemical status. Trials of adjunctive L-arginine can be extended to phase 2 studies in severe malaria. TRIAL REGISTRATION: ClinicalTrials.gov NCT00147368.

Authors
Yeo, TW; Lampah, DA; Gitawati, R; Tjitra, E; Kenangalem, E; Granger, DL; Weinberg, JB; Lopansri, BK; Price, RN; Celermajer, DS; Duffull, SB; Anstey, NM
MLA Citation
Yeo, TW, Lampah, DA, Gitawati, R, Tjitra, E, Kenangalem, E, Granger, DL, Weinberg, JB, Lopansri, BK, Price, RN, Celermajer, DS, Duffull, SB, and Anstey, NM. "Safety profile of L-arginine infusion in moderately severe falciparum malaria. (Published online)" PLoS One 3.6 (June 11, 2008): e2347-.
Website
http://hdl.handle.net/10161/4494
PMID
18545693
Source
pubmed
Published In
PloS one
Volume
3
Issue
6
Publish Date
2008
Start Page
e2347
DOI
10.1371/journal.pone.0002347

Reactive nitrogen and oxygen species in interleukin-1-mediated DNA damage associated with osteoarthritis.

OBJECTIVE: Osteoarthritis (OA) is associated with increased levels of reactive nitrogen and oxygen species and pro-inflammatory cytokines, such as interleukin-1 (IL-1). Nitric oxide (NO) can mediate a number of the catabolic effects of IL-1 in articular cartilage. The aims of this study were to determine if OA cartilage shows evidence of DNA damage, and if IL-1 could induce DNA damage in non-OA cartilage by increasing NO or superoxide. METHODS: Articular chondrocytes were isolated from porcine femoral condyles and embedded in 1.2% alginate. The effects of 24h incubation with IL-1, the nitric oxide synthase 2 (NOS2)-selective inhibitor, the free radical scavenger superoxide dismutase (SOD), the NO donor NOC18, or the combined NO and peroxynitrite donor SIN-1 on DNA damage were tested, using the "comet" assay. NO production was measured using the Griess assay. The type of oxidative damage present was assessed using a modified comet assay. RESULTS: OA cartilage had significantly more DNA damage than non-OA cartilage (P<0.001). IL-1 caused an increase in DNA damage (P<0.01), which was associated with increased NO production (P<0.01). Both oxidative DNA strand breaks and base modifications of purines and pyrimidines were observed. IL-1-induced DNA damage was inhibited by an NOS2 inhibitor or by SOD (P<0.01). Furthermore, NOC18 or SIN-1 caused DNA damage (P<0.001). CONCLUSION: Our work shows chondrocytes in osteoarthritic cartilage exhibit DNA damage, and that IL-1 induces DNA damage and reactive oxygen and nitrogen species in non-OA chondrocytes in alginate.

Authors
Davies, CM; Guilak, F; Weinberg, JB; Fermor, B
MLA Citation
Davies, CM, Guilak, F, Weinberg, JB, and Fermor, B. "Reactive nitrogen and oxygen species in interleukin-1-mediated DNA damage associated with osteoarthritis." Osteoarthritis Cartilage 16.5 (May 2008): 624-630.
PMID
17945515
Source
pubmed
Published In
Osteoarthritis and Cartilage
Volume
16
Issue
5
Publish Date
2008
Start Page
624
End Page
630
DOI
10.1016/j.joca.2007.09.012

Inhibition of integrative repair of the meniscus following acute exposure to interleukin-1 in vitro.

Damage or loss of the meniscus is associated with progressive osteoarthritic degeneration of the knee joint. Injured and degenerative joints are characterized by elevated levels of the pro-inflammatory cytokine interleukin-1 (IL-1), which with prolonged exposure can induce catabolic and anti-anabolic activities that inhibit tissue repair. We used an in vitro model system to examine the hypotheses that acute exposure to IL-1 inhibits meniscal repair, and that an IL-1-mediated increase in matrix metalloproteinase (MMP) activity is associated with the inhibition of repair. Integrative tissue repair was studied between concentric explants of porcine medial menisci that were treated with IL-1alpha acutely (100 pg/mL for 1 or 3 days) or chronically (100 pg/mL for entire culture duration). After 14 and 28 days in culture, biomechanical testing, cell viability, and histology were performed to assess meniscal repair. Total specific MMP activity in the culture media was measured using a quenched fluorescent substrate. As little as 1 day of IL-1 exposure significantly reduced shear strength, cell accumulation, and tissue repair compared to controls. IL-1 exposure for 1 or 3 days significantly increased MMP activity that subsided by day 9. With chronic IL-1 exposure, MMP activity remained elevated for the duration of culture and was negatively correlated with repair strength. Our study shows that short-term exposure to physiologically relevant concentrations of IL-1 significantly reduces meniscal repair in vitro, and thus may potentially inhibit the intrinsic repair response in vivo. The suppression of IL-1 or MMP expression and/or activity warrant investigation as potential strategies for promoting meniscal repair.

Authors
Wilusz, RE; Weinberg, JB; Guilak, F; McNulty, AL
MLA Citation
Wilusz, RE, Weinberg, JB, Guilak, F, and McNulty, AL. "Inhibition of integrative repair of the meniscus following acute exposure to interleukin-1 in vitro." Journal of orthopaedic research : official publication of the Orthopaedic Research Society 26.4 (April 2008): 504-512.
PMID
18050309
Source
epmc
Published In
Journal of Orthopaedic Research
Volume
26
Issue
4
Publish Date
2008
Start Page
504
End Page
512
DOI
10.1002/jor.20538

Clinical and molecular predictors of disease severity and survival in chronic lymphocytic leukemia.

Several parameters may predict disease severity and overall survival in chronic lymphocytic leukemia (CLL). The purpose of our study of 190 CLL patients was to compare immunoglobulin heavy chain variable region (IgV(H)) mutation status, cytogenetic abnormalities, and leukemia cell CD38 and Zap-70 to older, traditional parameters. We also wanted to construct a simple, inexpensive prognosis score that would significantly predict TTT and survival in patients at the time of diagnosis and help practicing clinicians. In univariate analyses, patients with higher clinical stage, higher leukocyte count at diagnosis, shorter leukocyte doubling time, elevated serum lactate dehydrogenase (LDH), unmutated immunoglobulin heavy chain variable region (IgV(H)) genes, and higher CD38 had a shorter overall survival and time-to-treatment (TTT). CLL cell Zap-70 expression was higher in patients with unmutated IgV(H), and those with higher Zap-70 tended to have shorter survival. IgV(H)4-34 or IgV(H)1-69 was the most common IgV(H) genes used (16 and 12%, respectively). Of those with IgV(H)1-69, 86% had unmutated IgV(H) and had a significantly shorter TTT. A cytogenetic abnormality was noted in 71% of the patients tested. Patients with 11q22 del and 17p13 del or complex abnormalities were significantly more likely to have unmutated IgV(H). We found that a prognostic score constructed using modified Rai stage, cellular CD38, and serum LDH (parameters easily obtained clinically) significantly predicted TTT and survival in patients at the time of diagnosis and performed as well or better than models using the newer markers.

Authors
Weinberg, JB; Volkheimer, AD; Chen, Y; Beasley, BE; Jiang, N; Lanasa, MC; Friedman, D; Vaccaro, G; Rehder, CW; Decastro, CM; Rizzieri, DA; Diehl, LF; Gockerman, JP; Moore, JO; Goodman, BK; Levesque, MC
MLA Citation
Weinberg, JB, Volkheimer, AD, Chen, Y, Beasley, BE, Jiang, N, Lanasa, MC, Friedman, D, Vaccaro, G, Rehder, CW, Decastro, CM, Rizzieri, DA, Diehl, LF, Gockerman, JP, Moore, JO, Goodman, BK, and Levesque, MC. "Clinical and molecular predictors of disease severity and survival in chronic lymphocytic leukemia." Am J Hematol 82.12 (December 2007): 1063-1070.
PMID
17654680
Source
pubmed
Published In
American Journal of Hematology
Volume
82
Issue
12
Publish Date
2007
Start Page
1063
End Page
1070
DOI
10.1002/ajh.20987

A genomic strategy to refine prognosis and predict response to therapy in chronic lymphocytic leukemia.

Authors
Friedirian, DR; Weinberg, JB; Potti, A; Volkheimer, AD; Bond, KM; Chen, Y; Jiang, N; Moore, JO; Gockerman, JP; Diehl, LF; Decastro, CM; Nevins, JR
MLA Citation
Friedirian, DR, Weinberg, JB, Potti, A, Volkheimer, AD, Bond, KM, Chen, Y, Jiang, N, Moore, JO, Gockerman, JP, Diehl, LF, Decastro, CM, and Nevins, JR. "A genomic strategy to refine prognosis and predict response to therapy in chronic lymphocytic leukemia." November 16, 2007.
Source
wos-lite
Published In
Blood
Volume
110
Issue
11
Publish Date
2007
Start Page
911A
End Page
911A

Impaired nitric oxide bioavailability and L-arginine reversible endothelial dysfunction in adults with falciparum malaria.

Severe falciparum malaria (SM) is associated with tissue ischemia related to cytoadherence of parasitized erythrocytes to microvascular endothelium and reduced levels of NO and its precursor, l-arginine. Endothelial function has not been characterized in SM but can be improved by l-arginine in cardiovascular disease. In an observational study in Indonesia, we measured endothelial function using reactive hyperemia-peripheral arterial tonometry (RH-PAT) in 51 adults with SM, 48 patients with moderately severe falciparum malaria (MSM), and 48 controls. The mean RH-PAT index was lower in SM (1.41; 95% confidence interval [CI] = 1.33-1.47) than in MSM (1.82; 95% CI = 1.7-2.02) and controls (1.93; 95% CI = 1.8-2.06; P < 0.0001). Endothelial dysfunction was associated with elevated blood lactate and measures of hemolysis. Exhaled NO was also lower in SM relative to MSM and controls. In an ascending dose study of intravenous l-arginine in 30 more patients with MSM, l-arginine increased the RH-PAT index by 19% (95% CI = 6-34; P = 0.006) and exhaled NO by 55% (95% CI = 32-73; P < 0.0001) without important side effects. Hypoargininemia and hemolysis likely reduce NO bioavailability. Endothelial dysfunction in malaria is nearly universal in severe disease, is reversible with l-arginine, and likely contributes to its pathogenesis. Clinical trials in SM of adjunctive agents to improve endothelial NO bioavailability, including l-arginine, are warranted.

Authors
Yeo, TW; Lampah, DA; Gitawati, R; Tjitra, E; Kenangalem, E; McNeil, YR; Darcy, CJ; Granger, DL; Weinberg, JB; Lopansri, BK; Price, RN; Duffull, SB; Celermajer, DS; Anstey, NM
MLA Citation
Yeo, TW, Lampah, DA, Gitawati, R, Tjitra, E, Kenangalem, E, McNeil, YR, Darcy, CJ, Granger, DL, Weinberg, JB, Lopansri, BK, Price, RN, Duffull, SB, Celermajer, DS, and Anstey, NM. "Impaired nitric oxide bioavailability and L-arginine reversible endothelial dysfunction in adults with falciparum malaria." J Exp Med 204.11 (October 29, 2007): 2693-2704.
PMID
17954570
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
204
Issue
11
Publish Date
2007
Start Page
2693
End Page
2704
DOI
10.1084/jem.20070819

Enhanced integrative repair of the porcine meniscus in vitro by inhibition of interleukin-1 or tumor necrosis factor alpha.

To examine the hypotheses that increasing concentrations of interleukin-1 (IL-1) or tumor necrosis factor alpha (TNFalpha) inhibit the integrative repair of the knee meniscus in an in vitro model system, and that inhibitors of these cytokines will enhance repair.Explants (8 mm in diameter) were harvested from porcine medial menisci. To simulate a full-thickness defect, a 4-mm-diameter core was removed and reinserted. Explants were cultured for 14, 28, or 42 days in the presence of 0-1,000 pg/ml of IL-1 or TNFalpha. Explants were also cultured in the presence of IL-1 or TNFalpha with IL-1 receptor antagonist (IL-1Ra) or TNF monoclonal antibody (mAb). At the end of the culture period, biomechanical testing, cell viability, and histologic analyses were performed to quantify the extent of repair.Mechanical testing revealed increased repair strength, cell accumulation, and tissue formation at the interface over time under control conditions. Pathophysiologic concentrations of both IL-1 and TNFalpha significantly decreased repair strength, cell migration, and tissue formation at the interface. The addition of IL-1Ra or TNF mAb to explants prevented the effects of IL-1 or TNFalpha, respectively.Our findings document that physiologically relevant concentrations of IL-1 and TNFalpha inhibit meniscal repair in vitro and therefore may also inhibit meniscal repair during arthritis or following joint injury. The finding that IL-1Ra and TNF mAb promoted integrative meniscal repair in an inflammatory microenvironment suggests that intraarticular delivery of IL-1Ra and/or TNF mAb may be useful clinically to promote meniscal healing following injury.

Authors
McNulty, AL; Moutos, FT; Weinberg, JB; Guilak, F
MLA Citation
McNulty, AL, Moutos, FT, Weinberg, JB, and Guilak, F. "Enhanced integrative repair of the porcine meniscus in vitro by inhibition of interleukin-1 or tumor necrosis factor alpha." Arthritis and rheumatism 56.9 (September 2007): 3033-3042.
PMID
17729298
Source
epmc
Published In
Arthritis and Rheumatism
Volume
56
Issue
9
Publish Date
2007
Start Page
3033
End Page
3042
DOI
10.1002/art.22839

Interleukin-1 and tumor necrosis factor alpha inhibit repair of the porcine meniscus in vitro.

OBJECTIVE: Injury or removal of the knee meniscus leads to progressive joint degeneration, and current surgical therapies for meniscal tears seek to maximally preserve meniscal structure and function. However, the factors that influence intrinsic repair of the meniscus are not well understood. The goal of this study was to investigate the capacity of meniscus tissue to repair a simulated defect in vitro and to examine the effect of pro-inflammatory cytokines on this process. METHODS: Cylindrical explants were harvested from the outer one-third of medial porcine menisci. To simulate a full-thickness defect, a central core was removed and reinserted immediately into the defect. Explants were cultured for 2, 4, or 6 weeks in serum-containing media in the presence or absence of interleukin-1 (IL-1) or tumor necrosis factor alpha (TNF-alpha), and meniscal repair was investigated using mechanical testing and fluorescence confocal microscopy. RESULTS: Meniscal lesions in untreated samples showed a significant capacity for intrinsic repair in vitro, with increasing cell accumulation and repair strength over time in culture. In the presence of IL-1 or TNF-alpha, no repair was observed despite the presence of abundant viable cells. CONCLUSIONS: This study demonstrates that the meniscus exhibits an intrinsic repair response in vitro. However, the presence of pro-inflammatory cytokines completely inhibited repair. These findings suggest that increased levels of pro-inflammatory cytokines post-injury or under arthritic conditions may inhibit meniscal repair. Therefore, inhibition of these cytokines may provide a means of accelerating repair of damaged or injured menisci in vivo.

Authors
Hennerbichler, A; Moutos, FT; Hennerbichler, D; Weinberg, JB; Guilak, F
MLA Citation
Hennerbichler, A, Moutos, FT, Hennerbichler, D, Weinberg, JB, and Guilak, F. "Interleukin-1 and tumor necrosis factor alpha inhibit repair of the porcine meniscus in vitro." Osteoarthritis Cartilage 15.9 (September 2007): 1053-1060.
PMID
17448702
Source
pubmed
Published In
Osteoarthritis and Cartilage
Volume
15
Issue
9
Publish Date
2007
Start Page
1053
End Page
1060
DOI
10.1016/j.joca.2007.03.003

Regional differences in prostaglandin E2 and nitric oxide production in the knee meniscus in response to dynamic compression.

Injury or loss of the knee meniscus is associated with altered joint stresses that lead to progressive joint degeneration. The goal of this study was to determine if dynamic mechanical compression influences the production of inflammatory mediators by meniscal cells. Dynamic compression increased prostaglandin E2 (PGE(2)) and nitric oxide (NO) production over a range of stress magnitudes (0.0125-0.5 MPa) in a manner that depended on stress magnitude and zone of tissue origin. Inner zone explants showed greater increases in PGE(2) and NO production as compared to outer zone explants. Meniscal tissue expressed NOS2 and NOS3 protein, but not NOS1. Mechanically induced NO production was blocked by NOS inhibitors, and the non-selective NOS inhibitor L-NMMA augmented PGE(2) production in the outer zone only. These findings suggest that the meniscus may serve as an intra-articular source of pro-inflammatory mediators, and that alterations in the magnitude or distribution of joint loading could significantly influence the production of these mediators in vivo.

Authors
Hennerbichler, A; Fermor, B; Hennerbichler, D; Weinberg, JB; Guilak, F
MLA Citation
Hennerbichler, A, Fermor, B, Hennerbichler, D, Weinberg, JB, and Guilak, F. "Regional differences in prostaglandin E2 and nitric oxide production in the knee meniscus in response to dynamic compression." Biochem Biophys Res Commun 358.4 (July 13, 2007): 1047-1053.
PMID
17517372
Source
pubmed
Published In
Biochemical and Biophysical Research Communications
Volume
358
Issue
4
Publish Date
2007
Start Page
1047
End Page
1053
DOI
10.1016/j.bbrc.2007.05.026

A specific PDE-4 inhibitor as an inductor of apoptosis in B-CLL

Authors
Schulze, A; Daghish, M; Letschert, S; Mugridge, K; Herrmann, K; Weinberg, JB; DeAngelo, J
MLA Citation
Schulze, A, Daghish, M, Letschert, S, Mugridge, K, Herrmann, K, Weinberg, JB, and DeAngelo, J. "A specific PDE-4 inhibitor as an inductor of apoptosis in B-CLL." DRUGS OF THE FUTURE 32 (July 2007): 102-103.
Source
wos-lite
Published In
Drugs of the future
Volume
32
Publish Date
2007
Start Page
102
End Page
103

Higher production of peripheral blood macrophage migration inhibitory factor in healthy children with a history of mild malaria relative to children with a history of severe malaria.

Plasmodium falciparum malaria is one of the leading causes of childhood morbidity and mortality in sub-Saharan Africa. The host immune response to P. falciparum is a critical determinant of malarial pathogenesis and disease outcomes. Macrophage migration inhibitory factor (MIF) is a central regulator of innate immune responses to bacterial and parasitic infections. Our recent investigations demonstrated that peripheral blood MIF production was suppressed in children with severe malaria. Because examination of MIF production in children with active disease does not account for the inherent ability of the host to generate MIF, basal circulating MIF and peripheral blood mononuclear cell (PBMC) MIF transcript levels were determined in healthy children with a history of either mild or severe malaria. Children with prior mild malaria had higher plasma MIF levels and PBMC MIF transcripts than children with an identical number of previous episodes of severe malaria. These results suggest that increased basal MIF production may be important in generating immune responses that protect against the development of severe malaria.

Authors
Awandare, GA; Kremsner, PG; Hittner, JB; Keller, CC; Clark, IA; Weinberg, JB; Perkins, DJ
MLA Citation
Awandare, GA, Kremsner, PG, Hittner, JB, Keller, CC, Clark, IA, Weinberg, JB, and Perkins, DJ. "Higher production of peripheral blood macrophage migration inhibitory factor in healthy children with a history of mild malaria relative to children with a history of severe malaria." The American journal of tropical medicine and hygiene 76.6 (June 2007): 1033-1036. (Academic Article)
Source
manual
Published In
American Journal of Tropical Medicine and Hygiene
Volume
76
Issue
6
Publish Date
2007
Start Page
1033
End Page
1036

Repair response of the inner and outer regions of the porcine meniscus in vitro.

BACKGROUND: The menisci are essential intra-articular structures that contribute to knee function, and meniscal injury or loss is associated with joint degeneration. Tears of the outer vascularized zone have a greater potential for repair than do tears in the inner avascular region. OBJECTIVE AND HYPOTHESIS: Develop an in vitro explant model to examine the hypothesis that differences exist in the intrinsic repair response between the outer and inner region of the meniscus. STUDY DESIGN: Controlled laboratory study. METHODS: Cylindrical explants were harvested from the outer one third and inner two thirds of medial porcine menisci. To simulate a full-thickness defect, a central core was removed and reinserted immediately. Explants were cultured for 2, 4, or 6 weeks, and meniscal healing was investigated using mechanical testing, histologic analysis, and fluorescence confocal microscopy. RESULTS: Over the 6-week culture period, meniscal explants exhibited migration of cells into the repair site, followed by increased tissue formation that bridged the interface. The repair strength increased significantly over time, with no differences between the 2 regions. CONCLUSION: The findings show that explants from the avascular inner zone and vascular outer zone of the meniscus exhibit similar healing potential and repair strength in vitro. CLINICAL RELEVANCE: These findings support the hypothesis that the regional differences in meniscal repair observed clinically are owed to the additional vascular supply of the outer meniscus rather than intrinsic differences between the extracellular matrix and cells from these 2 areas.

Authors
Hennerbichler, A; Moutos, FT; Hennerbichler, D; Weinberg, JB; Guilak, F
MLA Citation
Hennerbichler, A, Moutos, FT, Hennerbichler, D, Weinberg, JB, and Guilak, F. "Repair response of the inner and outer regions of the porcine meniscus in vitro." Am J Sports Med 35.5 (May 2007): 754-762.
PMID
17261570
Source
pubmed
Published In
American Journal of Sports Medicine
Volume
35
Issue
5
Publish Date
2007
Start Page
754
End Page
762
DOI
10.1177/0363546506296416

Genetic polymorphisms associated with priapism in sickle cell disease.

Priapism occurs in 30-45% of male patients with sickle cell disease (SCD), but the possible influence of genetic risk factors on the incidence of priapism is not well understood. We examined genetic polymorphisms in 199 unrelated, adult (>18 years), male patients with Hb SS and Hb Sbeta(0)-thalassaemia, 83 (42%) of whom reported a history of priapism. Candidate genes for association with priapism were identified based on their involvement in adhesion, coagulation, inflammation and cell signalling. Additionally, we examined genes involved in nitric oxide biology (NOS2, NOS3, SLC4A1), as well as polymorphisms in the klotho (KL) gene, which has previously been associated with priapism. Strong evidence of association was found for single nucleotide polymorphisms in transforming growth factor-beta receptor, type III (TGFBR3) (rs7526590; P = 0.00058), aquaporin (AQP1) (rs10244884; P = 0.00068), integrin alphav (ITGAV) (rs3768780; P = 0.00090), and the A1 subunit of coagulation factor XIII (F13A1) (hcv1860621; P = 0.00156). Associations with TGFBR3, AQP1, and ITGAV remained significant after adjusting for multiple testing, using the Benjamini-Hochberg procedure. Our data suggest that genes involved in the TGFbeta pathway, coagulation, cell adhesion and cell hydration pathways may be important in risk for priapism.

Authors
Elliott, L; Ashley-Koch, AE; De Castro, L; Jonassaint, J; Price, J; Ataga, KI; Levesque, MC; Brice Weinberg, J; Eckman, JR; Orringer, EP; Vance, JM; Telen, MJ
MLA Citation
Elliott, L, Ashley-Koch, AE, De Castro, L, Jonassaint, J, Price, J, Ataga, KI, Levesque, MC, Brice Weinberg, J, Eckman, JR, Orringer, EP, Vance, JM, and Telen, MJ. "Genetic polymorphisms associated with priapism in sickle cell disease." Br J Haematol 137.3 (May 2007): 262-267.
PMID
17408468
Source
pubmed
Published In
British Journal of Haematology
Volume
137
Issue
3
Publish Date
2007
Start Page
262
End Page
267
DOI
10.1111/j.1365-2141.2007.06560.x

Oxygen, nitric oxide and articular cartilage.

Molecular oxygen is required for the production of nitric oxide (NO), a pro-inflammatory mediator that is associated with osteoarthritis and rheumatoid arthritis. To date there has been little consideration of the role of oxygen tension in the regulation of nitric oxide production associated with arthritis. Oxygen tension may be particularly relevant to articular cartilage since it is avascular and therefore exists at a reduced oxygen tension. The superficial zone exists at approximately 6% O2, while the deep zone exists at less than 1% O2. Furthermore, oxygen tension can alter matrix synthesis, and the material properties of articular cartilage in vitro. The increase in nitric oxide associated with arthritis can be caused by pro-inflammatory cytokines and mechanical stress. Oxygen tension significantly alters endogenous NO production in articular cartilage, as well as the stimulation of NO in response to both mechanical loading and pro-inflammatory cytokines. Mechanical loading and pro-inflammatory cytokines also increase the production of prostaglandin E2 (PGE2). There is a complex interaction between NO and PGE2, and oxygen tension can alter this interaction. These findings suggest that the relatively low levels of oxygen within the joint may have significant influences on the metabolic activity, and inflammatory response of cartilage as compared to ambient levels. A better understanding of the role of oxygen in the production of inflammatory mediators in response to mechanical loading, or pro-inflammatory cytokines, may aid in the development of strategies for therapeutic intervention in arthritis.

Authors
Fermor, B; Christensen, SE; Youn, I; Cernanec, JM; Davies, CM; Weinberg, JB
MLA Citation
Fermor, B, Christensen, SE, Youn, I, Cernanec, JM, Davies, CM, and Weinberg, JB. "Oxygen, nitric oxide and articular cartilage. (Published online)" Eur Cell Mater 13 (April 11, 2007): 56-65.
PMID
17427142
Source
pubmed
Published In
European cells & materials
Volume
13
Publish Date
2007
Start Page
56
End Page
65

Progressive immunoglobulin gene mutations in chronic lymphocytic leukemia: evidence for antigen-driven intraclonal diversification.

Somatic mutations of immunoglobulin genes characterize mature memory B cells, and intraclonal B-cell diversification is typically associated with expansion of B-cell clones with greater affinity for antigen (antigen drive). Evidence for a role of antigen in progression of intraclonal chronic lymphocytic leukemia (CLL) cell diversification in patients with mutated immunoglobulin genes has not been previously presented. We performed a single-cell analysis of immunoglobulin heavy and light chains in 6 patients with somatically mutated CLL-cell immunoglobulin genes and identified 2 patients with multiple related (oligoclonal) subgroups of CLL cells. We constructed genealogic trees of these oligoclonal CLL-cell subgroups and assessed the effects of immunoglobulin somatic mutations on the ratios of replacement and silent amino acid changes in the framework and antigen-binding regions (CDRs) of the immunoglobulin heavy and light chains from each oligoclonal CLL-cell population. In one subject, the amino acid changes were consistent with an antigen-driven progression of clonally related CLL-cell populations. In the other subject, intraclonal diversification was associated with immunoglobulin amino acid changes that would have likely lessened antigen affinity. Taken together, these studies support the hypothesis that in some CLL cases intraclonal diversification is dependent on antigen interactions with immunoglobulin receptors.

Authors
Volkheimer, AD; Weinberg, JB; Beasley, BE; Whitesides, JF; Gockerman, JP; Moore, JO; Kelsoe, G; Goodman, BK; Levesque, MC
MLA Citation
Volkheimer, AD, Weinberg, JB, Beasley, BE, Whitesides, JF, Gockerman, JP, Moore, JO, Kelsoe, G, Goodman, BK, and Levesque, MC. "Progressive immunoglobulin gene mutations in chronic lymphocytic leukemia: evidence for antigen-driven intraclonal diversification." Blood 109.4 (February 15, 2007): 1559-1567.
PMID
17082314
Source
pubmed
Published In
Blood
Volume
109
Issue
4
Publish Date
2007
Start Page
1559
End Page
1567
DOI
10.1182/blood-2006-05-020644

Influence of oxygen tension on interleukin 1-induced peroxynitrite formation and matrix turnover in articular cartilage.

OBJECTIVE: Osteoarthritis is characterized by the degradation of articular cartilage. The catabolic activity of chondrocytes is partly regulated by nitric oxide (NO), which with superoxide (O2-) leads to the formation of peroxynitrite (OONO-), a potentially damaging reactive species. Cartilage is avascular and functions at reduced oxygen tension. We investigated whether oxygen tension influences the effects of interleukin 1 (IL-1) on peroxynitrite formation and cartilage matrix metabolism. METHODS: Porcine cartilage explants were incubated at either 1% O2 or 20% O2 with either 1 ng/ml IL-1alpha, 25 microM MnTE-2-PyP5+ [Mn porphyrin-based catalytic antioxidant, Mn(III) tetrakis(N-ethylpyridinium-2-yl)porphyrin], or 1 ng/ml IL-1 + 25 microM MnTE-2-PyP5+ to decrease peroxynitrite formation. Nitrotyrosine, formed by nitration of tyrosine by peroxynitrite, was measured by immunoblot. Proteoglycan and collagen synthesis and proteoglycan degradation were also determined. RESULTS: IL-1-induced peroxynitrite formation was decreased in 1% O2 as compared to 20% O2. MnTE-2-PyP5+ inhibited IL-1-induced peroxynitrite formation in either 1% O2 or 20% O2. In 1% O2 (but not in 20% O2), Mn porphyrin significantly inhibited IL-1-induced proteoglycan degradation. IL-1 decreased both proteoglycan and collagen II synthesis in cartilage explants in 1% O2 or 20% O2, but MnTE-2-PyP5+ did not prevent these anti-anabolic effects. MnTE-2-PyP5+ alone caused a significant decrease in collagen synthesis at 20% O2 but not at 1% O2. CONCLUSION: Our findings show that oxygen tension alters IL-1-induced peroxynitrite formation, which can influence proteoglycan degradation. Oxygen tension may influence the effects of reactive oxygen and nitrogen species on matrix homeostasis.

Authors
Cernanec, JM; Weinberg, JB; Batinic-Haberle, I; Guilak, F; Fermor, B
MLA Citation
Cernanec, JM, Weinberg, JB, Batinic-Haberle, I, Guilak, F, and Fermor, B. "Influence of oxygen tension on interleukin 1-induced peroxynitrite formation and matrix turnover in articular cartilage." J Rheumatol 34.2 (February 2007): 401-407.
PMID
17295437
Source
pubmed
Published In
The Journal of rheumatology
Volume
34
Issue
2
Publish Date
2007
Start Page
401
End Page
407

Burkholderia glumae infection in an infant with chronic granulomatous disease.

An 8-month-old boy developed a necrotic lung mass from which Burkholderia glumae was recovered, leading to the diagnosis of chronic granulomatous disease (CGD). While other Burkholderia species have been identified as important pathogens in persons with CGD, B. glumae has not been previously reported to cause human infection.

Authors
Weinberg, JB; Alexander, BD; Majure, JM; Williams, LW; Kim, JY; Vandamme, P; LiPuma, JJ
MLA Citation
Weinberg, JB, Alexander, BD, Majure, JM, Williams, LW, Kim, JY, Vandamme, P, and LiPuma, JJ. "Burkholderia glumae infection in an infant with chronic granulomatous disease." J Clin Microbiol 45.2 (February 2007): 662-665.
PMID
17135434
Source
pubmed
Published In
Journal of clinical microbiology
Volume
45
Issue
2
Publish Date
2007
Start Page
662
End Page
665
DOI
10.1128/JCM.02058-06

Nitric oxide synthase and cyclooxygenase interactions in cartilage and meniscus: relationships to joint physiology, arthritis, and tissue repair.

Rheumatoid arthritis and osteoarthritis are painful and debilitating diseases with complex pathophysiology. There is growing evidence that pro-inflammatory cytokines (e.g., interleukin-1 and tumor necrosis factor alpha) and mediators (e.g., prostaglandins, leukotrienes, and nitric oxide) play critical roles in the development and perpetuation of tissue inflammation and damage in joint tissues such as articular cartilage and meniscus. While earlier studies have generally focused on cells of the synovium (especially macrophages), there is increasing evidence that chondrocytes and meniscal cells actively contribute to inflammatory processes. In particular, it is now apparent that mechanical forces engendered by joint loading are transduced to biological signals at the cellular level and that these signals modulate gene expression and biochemical processes. Here we give an overview of the interplay of cytokines and mechanical stress in the production of cyclooxygenases and prostaglandins; lipoxygenases and leukotrienes; and nitric oxide synthases and nitric oxide in arthritis, with particular focus on the interactions of these pathways in articular cartilage and meniscus.

Authors
Weinberg, JB; Fermor, B; Guilak, F
MLA Citation
Weinberg, JB, Fermor, B, and Guilak, F. "Nitric oxide synthase and cyclooxygenase interactions in cartilage and meniscus: relationships to joint physiology, arthritis, and tissue repair." Subcell Biochem 42 (2007): 31-62. (Review)
PMID
17612045
Source
pubmed
Published In
Sub-Cellular Biochemistry
Volume
42
Publish Date
2007
Start Page
31
End Page
62

Short report: Higher production of peripheral blood macrophage migration inhibitory factor in healthy children with a history of mild malaria relative to children with a history of severe malaria

Plasmodium falciparum malaria is one of the leading causes of childhood morbidity and mortality in sub-Saharan Africa. The host immune response to P. falciparum is a critical determinant of malarial pathogenesis and disease outcomes. Macrophage migration inhibitory factor (MIF) is a central regulator of innate immune responses to bacterial and parasitic infections. Our recent investigations demonstrated that peripheral blood MIF production was suppressed in children with severe malaria. Because examination of MIF production in children with active disease does not account for the inherent ability of the host to generate MIF, basal circulating MIF and peripheral blood mononuclear cell (PBMC) MIF transcript levels were determined in healthy children with a history of either mild or severe malaria. Children with prior mild malaria had higher plasma MIF levels and PBMC MIF transcripts than children with an identical number of previous episodes of severe malaria. These results suggest that increased basal MIF production may be important in generating immune responses that protect against the development of severe malaria. Copyright © 2007 by The American Society of Tropical Medicine and Hygiene.

Authors
Awandare, GA; Kremsner, PG; Hittner, JB; Keller, CC; Clark, IA; Weinberg, JB; Perkins, DJ
MLA Citation
Awandare, GA, Kremsner, PG, Hittner, JB, Keller, CC, Clark, IA, Weinberg, JB, and Perkins, DJ. "Short report: Higher production of peripheral blood macrophage migration inhibitory factor in healthy children with a history of mild malaria relative to children with a history of severe malaria." American Journal of Tropical Medicine and Hygiene 76.6 (2007): 1033-1036.
PMID
17556607
Source
scival
Published In
American Journal of Tropical Medicine and Hygiene
Volume
76
Issue
6
Publish Date
2007
Start Page
1033
End Page
1036

The effects of pro-inflammatory cytokines on functional repair of the meniscus

A study was performed to examine the hypotheses that increasing concentrations of the pro-inflammatory cytokines interleukin-1 (IL-1) or tumor necrosis factor-alpha (TNF) inhibit integrative repair of the knee meniscus in an in vitro model system and that inhibitors of these cytokines will enhance repair. Explants harvested from either the inner or outer zone of porcine medical menisci were cultured for 14, 28, or 42 days in the presence of 0-10 ng/mL of IL-1 or TNF. Explants were also cultured in the presence of IL-1 or TNF with IL-1 receptor antagonist (IL-1ra) or TNF monoclonal antibody (TNF mAb). At the end of the culture period, biomechanical testing, cell viability, and histological analyses were performed to quantify the extent of repair. It was found that physiologically relevant concentrations of IL-1 and TNF inhibit meniscal repair in vitro and thus may also inhibit meniscal repair during arthritis or following joint injury.

Authors
McNulty, AL; Moutos, FT; Wilusz, RE; Weinberg, JB; Guilak, F
MLA Citation
McNulty, AL, Moutos, FT, Wilusz, RE, Weinberg, JB, and Guilak, F. "The effects of pro-inflammatory cytokines on functional repair of the meniscus." MCB Molecular and Cellular Biomechanics 3.4 (December 1, 2006): 197-198.
Source
scopus
Published In
Molecular & cellular biomechanics : MCB
Volume
3
Issue
4
Publish Date
2006
Start Page
197
End Page
198

Genetic polymorphisms associated with priapism in sickle cell disease.

Authors
Elliott, L; Ashley-Koch, AE; Jonassaint, J; Price, J; Galloway, J; Ataga, KI; Levesque, MC; Weinberg, JB; Eckman, JR; Orringer, EP; Vance, JM; Telen, MJ
MLA Citation
Elliott, L, Ashley-Koch, AE, Jonassaint, J, Price, J, Galloway, J, Ataga, KI, Levesque, MC, Weinberg, JB, Eckman, JR, Orringer, EP, Vance, JM, and Telen, MJ. "Genetic polymorphisms associated with priapism in sickle cell disease." BLOOD 108.11 (November 16, 2006): 236A-237A.
Source
wos-lite
Published In
Blood
Volume
108
Issue
11
Publish Date
2006
Start Page
236A
End Page
237A

NO synthase 2 (NOS2) deletion promotes multiple pathologies in a mouse model of Alzheimer's disease.

Alzheimer's disease is characterized by two primary pathological features: amyloid plaques and neurofibrillary tangles. The interconnection between amyloid and tau aggregates is of intense interest, but mouse models have yet to reveal a direct interrelationship. We now show that NO may be a key factor that connects amyloid and tau pathologies. Genetic removal of NO synthase 2 in mice expressing mutated amyloid precursor protein results in pathological hyperphosphorylation of mouse tau, its redistribution to the somatodendritic compartment in cortical and hippocampal neurons, and aggregate formation. Lack of NO synthase 2 in the amyloid precursor protein Swedish mutant mouse increased insoluble beta-amyloid peptide levels, neuronal degeneration, caspase-3 activation, and tau cleavage, suggesting that NO acts at a junction point between beta-amyloid peptides, caspase activation, and tau aggregation.

Authors
Colton, CA; Vitek, MP; Wink, DA; Xu, Q; Cantillana, V; Previti, ML; Van Nostrand, WE; Weinberg, JB; Dawson, H
MLA Citation
Colton, CA, Vitek, MP, Wink, DA, Xu, Q, Cantillana, V, Previti, ML, Van Nostrand, WE, Weinberg, JB, and Dawson, H. "NO synthase 2 (NOS2) deletion promotes multiple pathologies in a mouse model of Alzheimer's disease." Proc Natl Acad Sci U S A 103.34 (August 22, 2006): 12867-12872.
PMID
16908860
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
103
Issue
34
Publish Date
2006
Start Page
12867
End Page
12872
DOI
10.1073/pnas.0601075103

Elevated plasma phenylalanine in severe malaria and implications for pathophysiology of neurological complications.

Cerebral malaria is associated with decreased production of nitric oxide and decreased levels of its precursor, l-arginine. Abnormal amino acid metabolism may thus be an important factor in malaria pathogenesis. We sought to determine if other amino acid abnormalities are associated with disease severity in falciparum malaria. Subjects were enrolled in Dar es Salaam, Tanzania (children) (n = 126), and Papua, Indonesia (adults) (n = 156), in two separate studies. Plasma samples were collected from subjects with WHO-defined cerebral malaria (children), all forms of severe malaria (adults), and uncomplicated malaria (children and adults). Healthy children and adults without fever or illness served as controls. Plasma amino acids were measured using reverse-phase high-performance liquid chromatography with fluorescence detection. Several plasma amino acids were significantly lower in the clinical malaria groups than in healthy controls. Despite the differences, phenylalanine was the only amino acid with mean levels outside the normal range (40 to 84 microM) and was markedly elevated in children with cerebral malaria (median [95% confidence interval], 163 [134 to 193] microM; P < 0.0001) and adults with all forms of severe malaria (median [95% confidence interval], 129 [111 to 155] microM; P < 0.0001). In adults who survived severe malaria, phenylalanine levels returned to normal, with clinical improvement (P = 0.0002). Maintenance of plasma phenylalanine homeostasis is disrupted in severe malaria, leading to significant hyperphenylalaninemia. This is likely a result of an acquired abnormality in the function of the liver enzyme phenylalanine hydroxylase. Determination of the mechanism of this abnormality may contribute to the understanding of neurological complications in malaria.

Authors
Lopansri, BK; Anstey, NM; Stoddard, GJ; Mwaikambo, ED; Boutlis, CS; Tjitra, E; Maniboey, H; Hobbs, MR; Levesque, MC; Weinberg, JB; Granger, DL
MLA Citation
Lopansri, BK, Anstey, NM, Stoddard, GJ, Mwaikambo, ED, Boutlis, CS, Tjitra, E, Maniboey, H, Hobbs, MR, Levesque, MC, Weinberg, JB, and Granger, DL. "Elevated plasma phenylalanine in severe malaria and implications for pathophysiology of neurological complications." Infect Immun 74.6 (June 2006): 3355-3359.
PMID
16714564
Source
pubmed
Published In
Infection and immunity
Volume
74
Issue
6
Publish Date
2006
Start Page
3355
End Page
3359
DOI
10.1128/IAI.02106-05

Towards a NOS output state: Design and properties of NOS oxygenase/FMN domain constructs

Authors
Salerno, JC; Holliday, M; Weinberg, JB; Nahm, N; Clayton, T; Smith, SME; Ghosh, DK
MLA Citation
Salerno, JC, Holliday, M, Weinberg, JB, Nahm, N, Clayton, T, Smith, SME, and Ghosh, DK. "Towards a NOS output state: Design and properties of NOS oxygenase/FMN domain constructs." June 2006.
Source
wos-lite
Published In
Nitric Oxide: Biology and Chemistry
Volume
14
Issue
4
Publish Date
2006
Start Page
A15
End Page
A15
DOI
10.1016/j.niox.2006.04.052

Nitric-oxide synthase output state. Design and properties of nitric-oxide synthase oxygenase/FMN domain constructs.

Mammalian nitric-oxide synthases are large modular enzymes that evolved from independently expressed ancestors. Calmodulin-controlled isoforms are signal generators; calmodulin activates electron transfer from NADPH through three reductase domains to an oxygenase domain. Structures of the reductase unit and its homologs show FMN and FAD in contact but too isolated from the protein surface to permit exit of reducing equivalents. To study states in which FMN/heme electron transfer is feasible, we designed and produced constructs including only oxygenase and FMN binding domains, eliminating strong internal reductase complex interactions. Constructs for all mammalian isoforms were expressed and purified as dimers. All synthesize NO with peroxide as the electron donor at rates comparable with corresponding oxygenase constructs. All bind cofactors nearly stoichiometrically and have native catalytic sites by spectroscopic criteria. Modest differences in electrochemistry versus independently expressed heme and FMN binding domains suggest interdomain interactions. These interactions can be convincingly demonstrated via calmodulin-induced shifts in high spin ferriheme EPR spectra and through mutual broadening of heme and FMNH. radical signals in inducible nitric-oxide synthase constructs. Blue neutral FMN semiquinone can be readily observed; potentials of one electron couple (in inducible nitric-oxide synthase oxygenase FMN, FMN oxidized/semiquinone couple = +70 mV, FMN semiquinone/hydroquinone couple = -180 mV, and heme = -180 mV) indicate that FMN is capable of serving as a one electron heme reductant. The construct will serve as the basis for future studies of the output state for NADPH derived reducing equivalents.

Authors
Ghosh, DK; Holliday, MA; Thomas, C; Weinberg, JB; Smith, SME; Salerno, JC
MLA Citation
Ghosh, DK, Holliday, MA, Thomas, C, Weinberg, JB, Smith, SME, and Salerno, JC. "Nitric-oxide synthase output state. Design and properties of nitric-oxide synthase oxygenase/FMN domain constructs." J Biol Chem 281.20 (May 19, 2006): 14173-14183.
PMID
16461329
Source
pubmed
Published In
The Journal of biological chemistry
Volume
281
Issue
20
Publish Date
2006
Start Page
14173
End Page
14183
DOI
10.1074/jbc.M509937200

Chronic lymphocytic leukemia cell CD38 expression and inducible nitric oxide synthase expression are associated with serum IL-4 levels.

B cell chronic lymphocytic leukemia (CLL) CD38 expression is variable and may predict outcome. Inducible nitric oxide synthase (NOS2) expression regulates CLL cell apoptosis. IL-4 and IFN-gamma regulate B cell CD38 expression and NOS2 expression. We compared IL-4 and IFN-gamma serum levels between CLL patients and normal individuals, and determined whether serum IL-4 and IFN-gamma levels correlated with CLL cell CD38 expression and NOS enzyme activity. IL-4 levels, but not IFN-gamma levels, differed between normal individuals and CLL patients. Furthermore, there was an association of IL-4 levels, but not IFN-gamma levels, with CD38 and NOS2 expression in CLL patients.

Authors
Levesque, MC; Chen, Y; Beasley, BE; O'Loughlin, CW; Gockerman, JP; Moore, JO; Weinberg, JB
MLA Citation
Levesque, MC, Chen, Y, Beasley, BE, O'Loughlin, CW, Gockerman, JP, Moore, JO, and Weinberg, JB. "Chronic lymphocytic leukemia cell CD38 expression and inducible nitric oxide synthase expression are associated with serum IL-4 levels." Leuk Res 30.1 (January 2006): 24-28.
PMID
16039714
Source
pubmed
Published In
Leukemia Research
Volume
30
Issue
1
Publish Date
2006
Start Page
24
End Page
28
DOI
10.1016/j.leukres.2005.05.022

Decreased circulating macrophage migration inhibitory factor (MIF) protein and blood mononuclear cell MIF transcripts in children with Plasmodium falciparum malaria

Plasmodium falciparum malaria remains one of the most frequently lethal diseases affecting children in sub-Saharan Africa, yet the immune mediators that regulate pathogenesis are only partially defined. Since macrophage migration inhibitory factor (MIF) is important for regulating innate immunity in bacterial and parasitic infections, circulating MIF and peripheral blood mononuclear cell (PBMC) MIF transcripts were investigated in children with acute falciparum malaria. Peripheral blood levels of MIF-regulatory cytokines and effector molecules, including interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-12, IL-10, transforming growth factor (TGF)-β1, bicyclo-prostaglandin (PG) E2, and nitric oxide synthase activity were also determined. Circulating MIF and PBMC MIF mRNA were significantly lower in children with acute malaria relative to healthy, malaria-exposed children. Peripheral blood MIF levels showed no association with either parasitemia or hemoglobin concentrations. Circulating MIF was, however, significantly associated with IL-12 and TGF-β1. Multiple regression analyses revealed that IFN-γ was the most significant predictor of peripheral blood MIF concentrations. These findings suggest that reduced MIF production may promote enhanced disease severity in children with falciparum malaria. © 2006 Elsevier Inc. All rights reserved.

Authors
Awandare, GA; Hittner, JB; Kremsner, PG; Ochiel, DO; Keller, CC; Weinberg, JB; Clark, IA; Perkins, DJ
MLA Citation
Awandare, GA, Hittner, JB, Kremsner, PG, Ochiel, DO, Keller, CC, Weinberg, JB, Clark, IA, and Perkins, DJ. "Decreased circulating macrophage migration inhibitory factor (MIF) protein and blood mononuclear cell MIF transcripts in children with Plasmodium falciparum malaria." Clinical Immunology 119.2 (2006): 219-225.
PMID
16461006
Source
scival
Published In
Clinical Immunology
Volume
119
Issue
2
Publish Date
2006
Start Page
219
End Page
225
DOI
10.1016/j.clim.2005.12.003

Suppression of prostaglandin E2 by malaria parasite products and antipyretics promotes overproduction of tumor necrosis factor-α: Association with the pathogenesis of childhood malarial anemia

Cytokines and effector molecules are important immunoregulatory molecules in human malaria. Tumor necrosis factor (TNF)-α limits malaria parasitemia but also promotes pathogenesis at high concentrations, whereas prostaglandin E2 (PGE2) inhibits TNF-α production and is reduced in childhood malaria, at least in part, through suppression of cyclooxygenase (COX)-2 following the ingestion of Plasmodium falciparum hemozoin (pfHz; malarial pigment) by peripheral blood mononuclear cells (PBMCs). Although molecular interactions between TNF-α and PGE2 are largely unexplored in human malaria, results presented here show that pfHz-induced suppression of PBMC COX-2 gene products induces overproduction of TNF-α. Moreover, addition of exogenous PGE2 to pfHz-treated PBMCs dose-dependently decreased TNF-α production, whereas experimental COX inhibitors and antipyretics used during human malaria generated increased TNF-α production. Healthy, malaria-exposed children had elevated levels of circulating bicyclo-PGE2/TNF-α, compared with children with malarial anemia (P < .01), with systemic bicyclo-PGE2 and TNF-α significantly associated with hemoglobin concentrations (r = 0.745; P < .01). The results of the present study illustrate that pfHz-induced suppression of PGE2 promotes overproduction of TNF-α, which is associated with enhanced malarial anemia. © 2006 by the Infectious Diseases Society of America. All rights reserved.

Authors
Keller, CC; Davenport, GC; Dickman, KR; Hittner, JB; Kaplan, SS; Weinberg, JB; Kremsner, PG; Perkins, DJ
MLA Citation
Keller, CC, Davenport, GC, Dickman, KR, Hittner, JB, Kaplan, SS, Weinberg, JB, Kremsner, PG, and Perkins, DJ. "Suppression of prostaglandin E2 by malaria parasite products and antipyretics promotes overproduction of tumor necrosis factor-α: Association with the pathogenesis of childhood malarial anemia." Journal of Infectious Diseases 193.10 (2006): 1384-1393.
PMID
16619186
Source
scival
Published In
Journal of Infectious Diseases
Volume
193
Issue
10
Publish Date
2006
Start Page
1384
End Page
1393
DOI
10.1086/503047

Biaxial strain effects on cells from the inner and outer regions of the meniscus.

During knee joint loading, the fibrocartilaginous menisci experience significant spatial variations in mechanical stimuli. Meniscus cells also exhibit significant variations in biosynthesis and gene expression depending on their location within the tissue. These metabolic patterns are consistent with a more chondrocytic phenotype for cells located within the avascular inner two-thirds compared with a more fibroblastic phenotype for cells within the vascularized outer periphery. The spatial distribution of cell biosynthesis and gene expression patterns within the meniscus suggest that cells may exhibit intrinsically different responses to mechanical stimuli. The objective of our study was to test for intrinsic differences in the responsiveness of these meniscus cell populations to an equivalent mechanical stimulus. Cellular biosynthesis and gene expression for extracellular matrix proteins in isolated inner and outer meniscus cells in monolayer were quantified following cyclic biaxial stretch. The results demonstrate that inner and outer meniscus cells exhibit significant differences in matrix biosynthesis and gene expression regardless of stretching condition. Both inner and outer meniscus cells responded to stretch with increased nitric oxide production and total protein synthesis. The results suggest that inner and outer meniscus cells may respond similarly to biaxial stretch in vitro with measures of biosynthesis and gene expression.

Authors
Upton, ML; Hennerbichler, A; Fermor, B; Guilak, F; Weinberg, JB; Setton, LA
MLA Citation
Upton, ML, Hennerbichler, A, Fermor, B, Guilak, F, Weinberg, JB, and Setton, LA. "Biaxial strain effects on cells from the inner and outer regions of the meniscus." Connect Tissue Res 47.4 (2006): 207-214.
PMID
16987752
Source
pubmed
Published In
Connective Tissue Research (Informa)
Volume
47
Issue
4
Publish Date
2006
Start Page
207
End Page
214
DOI
10.1080/03008200600846663

Serum, urinary, and salivary nitric oxide in rheumatoid arthritis: complexities of interpreting nitric oxide measures.

Nitric oxide (NO) may play important roles in rheumatoid arthritis (RA). RA is an inflammatory disease involving joints and other systems including salivary glands. To assess NO production in RA patients, we compared levels of serum, urine, and salivary nitrite and nitrate (NOx) in patients with RA and normal subjects, and we examined the relationships of these measures to disease activity. Serum, urine, and NOx levels as well as renal creatinine, NOx clearance and fractional excretion rates were compared in 25 RA patients and 20 age- and gender-matched healthy controls. Subjects were hospitalized for 3 days and placed on a NOx restricted diet. NOx was assayed using nitrate reductase and the Griess reagent. RA activity was assessed using standard clinical and laboratory measures. While consuming a restricted diet for 3 days to eliminate the effects of oral intake of NOx, 24 hour urinary NOx excretion decreased in both RA patients and healthy controls. Urine NOx levels at all time points were not significantly different between RA patients and normal subjects. Serum NOx levels also decreased during the 3 days of NOx restriction, but RA patients had higher serum NOx levels at all time points compared with the control group. Likewise, serum NOx/creatinine ratios were higher in RA patients than in controls. Although basal salivary flow rate and tear flow were lower in RA patients, salivary NOx levels did not differ between normal and RA subjects. While renal creatinine clearance was not different between the two groups, we found that RA patients had lower renal NOx clearance and lower renal NOx fractional excretion. After correction of p values for multiple comparisons, there were no significant relationships for the RA group between measures of disease activity and the urinary NOx, serum NOx, or urinary NOx clearance. Despite interest in the use of NO as a marker of disease activity, alterations in renal NOx clearance and fractional excretion in RA make it difficult to assess in vivo NO production even with strict dietary restriction of NOx intake.

Authors
Weinberg, JB; Lang, T; Wilkinson, WE; Pisetsky, DS; St Clair, EW
MLA Citation
Weinberg, JB, Lang, T, Wilkinson, WE, Pisetsky, DS, and St Clair, EW. "Serum, urinary, and salivary nitric oxide in rheumatoid arthritis: complexities of interpreting nitric oxide measures." Arthritis Res Ther 8.5 (2006): R140-.
PMID
16907988
Source
pubmed
Published In
Arthritis Research and Therapy
Volume
8
Issue
5
Publish Date
2006
Start Page
R140
DOI
10.1186/ar2030

Erratum: NO synthase 2 (NOS2) deletion promotes multiple pathologies in a mouse model of Alzheimer's disease (Proceedings of the National Academy of Sciences of the United States of America (August 22, 2006) 103, 34 (12867-1872) DOI: 10.1073/pnas.0601075103)

Authors
Colton, CA; Vitek, MP; Wink, DA; Xu, Q; Cantillana, V; Previti, ML; Nostrand, WEV; Weinberg, JB; Dawson, H
MLA Citation
Colton, CA, Vitek, MP, Wink, DA, Xu, Q, Cantillana, V, Previti, ML, Nostrand, WEV, Weinberg, JB, and Dawson, H. "Erratum: NO synthase 2 (NOS2) deletion promotes multiple pathologies in a mouse model of Alzheimer's disease (Proceedings of the National Academy of Sciences of the United States of America (August 22, 2006) 103, 34 (12867-1872) DOI: 10.1073/pnas.0601075103)." Proceedings of the National Academy of Sciences of the United States of America 103.41 (2006): 15273--.
Source
scival
Published In
Proceedings of the National Academy of Sciences of USA
Volume
103
Issue
41
Publish Date
2006
Start Page
15273-
DOI
10.1073/pnas.0607808103

Oxygen, nitric oxide, and osteoarthritis

Authors
Fermor, B; Cernanec, JM; Davies, CM; Guilak, F; Weinberg, JB
MLA Citation
Fermor, B, Cernanec, JM, Davies, CM, Guilak, F, and Weinberg, JB. "Oxygen, nitric oxide, and osteoarthritis." European Cells and Materials 12.SUPPL.1 (2006): 22--.
Source
scival
Published In
European cells & materials
Volume
12
Issue
SUPPL.1
Publish Date
2006
Start Page
22-

Interleukin-1 induction of DNA damage in articular cartilage: Roles of nitric oxide and superoxide

Authors
Davies, CM; Guilak, F; Weinberg, JB; Fermor, B
MLA Citation
Davies, CM, Guilak, F, Weinberg, JB, and Fermor, B. "Interleukin-1 induction of DNA damage in articular cartilage: Roles of nitric oxide and superoxide." European Cells and Materials 12.SUPPL.1 (2006): 23--.
Source
scival
Published In
European cells & materials
Volume
12
Issue
SUPPL.1
Publish Date
2006
Start Page
23-

Patterns of gene expression that characterize outcomes of Plasmodium falciparum infection

Authors
Boutlis, CS; Dressman, HK; Tjitra, E; Maniboey, H; Nevins, JR; Weinberg, JB; Anstey, NM
MLA Citation
Boutlis, CS, Dressman, HK, Tjitra, E, Maniboey, H, Nevins, JR, Weinberg, JB, and Anstey, NM. "Patterns of gene expression that characterize outcomes of Plasmodium falciparum infection." AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE 73.6 (December 2005): 225-225.
Source
wos-lite
Published In
American Journal of Tropical Medicine and Hygiene
Volume
73
Issue
6
Publish Date
2005
Start Page
225
End Page
225

The influence of oxygen tension on the induction of nitric oxide and prostaglandin E2 by mechanical stress in articular cartilage.

OBJECTIVES: Articular cartilage is an avascular tissue that exists at low oxygen tension. Oxygen tension can influence the production of the pro-inflammatory mediators nitric oxide (NO) and prostaglandin E2 (PGE(2)) in cartilage, which are increased in osteoarthritis (OA). The synthesis of these molecules can be stimulated by mechanical stress, which is an important risk factor for OA. The objective of this study was to determine the influence of oxygen tension on the induction of NO and PGE(2) production in articular cartilage in response to mechanical stress. DESIGN: Intermittent mechanical compression (0.05MPa, 0.5Hz for 24h) was applied to full thickness skeletally mature porcine articular cartilage explants at either 20%, 5%, or 1% O(2). NO, PGE(2) and peroxynitrite formation were measured, and the effect of the selective nitric oxide synthase 2 inhibitor 1400W was tested. RESULTS: Incubating articular cartilage at 5% O(2) significantly increased (P<0.001) baseline NO production, as compared with 1% or 20% O(2). Peroxynitrite formation was lower at reduced oxygen tension. Mechanical compression significantly increased (P<0.001) NO production at 20% O(2) but not at 5% or 1% O(2), and significantly increased (P<0.001) PGE(2) production at 20% O(2) (50 fold) and 5% O(2) (4 fold) but not at 1% O(2). 1400W blocked mechanically induced NO production and further increased PGE(2) production at 5% O(2) (P<0.05). CONCLUSIONS: Oxygen tension influences the endogenous production of NO and PGE(2) in cartilage and can have a significant effect on the induction of these inflammatory mediators in response to mechanical compression.

Authors
Fermor, B; Weinberg, JB; Pisetsky, DS; Guilak, F
MLA Citation
Fermor, B, Weinberg, JB, Pisetsky, DS, and Guilak, F. "The influence of oxygen tension on the induction of nitric oxide and prostaglandin E2 by mechanical stress in articular cartilage." Osteoarthritis Cartilage 13.10 (October 2005): 935-941.
PMID
15975834
Source
pubmed
Published In
Osteoarthritis and Cartilage
Volume
13
Issue
10
Publish Date
2005
Start Page
935
End Page
941
DOI
10.1016/j.joca.2005.05.001

p47 GTPases regulate Toxoplasma gondii survival in activated macrophages.

The cytokine gamma interferon (IFN-gamma) is critical for resistance to Toxoplasma gondii. IFN-gamma strongly activates macrophages and nonphagocytic host cells to limit intracellular growth of T. gondii; however, the cellular factors that are required for this effect are largely unknown. We have shown previously that IGTP and LRG-47, members of the IFN-gamma-regulated family of p47 GTPases, are required for resistance to acute T. gondii infections in vivo. In contrast, IRG-47, another member of this family, is not required. In the present work, we addressed whether these GTPases are required for IFN-gamma-induced suppression of T. gondii growth in macrophages in vitro. Bone marrow macrophages that lacked IGTP or LRG-47 displayed greatly attenuated IFN-gamma-induced inhibition of T. gondii growth, while macrophages that lacked IRG-47 displayed normal inhibition. Thus, the ability of the p47 GTPases to limit acute infection in vivo correlated with their ability to suppress intracellular growth in macrophages in vitro. Using confocal microscopy and sucrose density fractionation, we demonstrated that IGTP largely colocalizes with endoplasmic reticulum markers, while LRG-47 was mainly restricted to the Golgi. Although both IGTP and LRG-47 localized to vacuoles containing latex beads, neither protein localized to vacuoles containing live T. gondii. These results suggest that IGTP and LRG-47 are able to regulate host resistance to acute T. gondii infections through their ability to inhibit parasite growth within the macrophage.

Authors
Butcher, BA; Greene, RI; Henry, SC; Annecharico, KL; Weinberg, JB; Denkers, EY; Sher, A; Taylor, GA
MLA Citation
Butcher, BA, Greene, RI, Henry, SC, Annecharico, KL, Weinberg, JB, Denkers, EY, Sher, A, and Taylor, GA. "p47 GTPases regulate Toxoplasma gondii survival in activated macrophages." Infect Immun 73.6 (June 2005): 3278-3286.
PMID
15908352
Source
pubmed
Published In
Infection and immunity
Volume
73
Issue
6
Publish Date
2005
Start Page
3278
End Page
3286
DOI
10.1128/IAI.73.6.3278-3286.2005

Persistent nuclear factor-kappa B activation in Ucp2-/- mice leads to enhanced nitric oxide and inflammatory cytokine production.

One of the phenotypes of mice with targeted disruption of the uncoupling protein-2 gene (Ucp2-/-) is greater macrophage phagocytic activity and free radical production, resulting in a striking resistance to infectious microorganisms. In this study, the molecular mechanisms of this enhanced immune response were investigated. We found that levels of nitric oxide measured in either plasma or isolated macrophages from Ucp2-/- mice are significantly elevated in response to bacterial lipopolysaccharide challenge compared with similarly treated Ucp2+/+ mice. Likewise, expression of inducible nitric-oxide synthase and inflammatory cytokines is higher in Ucp2-/- mice in vivo and in vitro. Key steps in the activation cascade of nuclear factor (NF)-kappa B, including I kappa B kinase and nuclear translocation of NF-kappa B subunits, are all remarkably enhanced in Ucp2-/- mice, most notably even under basal conditions. The elevated basal activity of I kappa B kinase in macrophages from Ucp2-/- mice can be blocked by cell-permeable inhibitors of superoxide and hydrogen peroxide generation, but not by a specific inhibitor for inducible nitric-oxide synthase. Isolated mitochondria from Ucp2-/- cells produced more superoxide/hydrogen peroxide. We conclude that mitochrondrially derived reactive oxygen from Ucp2-/- cells constitutively activates NF-kappa B, resulting in a "primed" state to both potentiate and amplify the inflammatory response upon subsequent stimulation.

Authors
Bai, Y; Onuma, H; Bai, X; Medvedev, AV; Misukonis, M; Weinberg, JB; Cao, W; Robidoux, J; Floering, LM; Daniel, KW; Collins, S
MLA Citation
Bai, Y, Onuma, H, Bai, X, Medvedev, AV, Misukonis, M, Weinberg, JB, Cao, W, Robidoux, J, Floering, LM, Daniel, KW, and Collins, S. "Persistent nuclear factor-kappa B activation in Ucp2-/- mice leads to enhanced nitric oxide and inflammatory cytokine production." J Biol Chem 280.19 (May 13, 2005): 19062-19069.
PMID
15757894
Source
pubmed
Published In
The Journal of biological chemistry
Volume
280
Issue
19
Publish Date
2005
Start Page
19062
End Page
19069
DOI
10.1074/jbc.M500566200

Impaired systemic production of prostaglandin E2 in children with cerebral malaria.

Prostaglandins (PGs) are important mediators of macrophage activity, vascular permeability, fever, erythropoiesis, and proinflammatory responses to infection. Our recent studies have shown that plasma levels of bicyclo-PGE2 (a stable end product of PGE2 metabolism) and leukocyte cyclooxygenase (COX)-2 gene expression are suppressed in children with malarial anemia. Since the role of PGs as immunomodulators of human cerebral malaria (CM) has not been examined, we investigated urinary levels of bicyclo-PGE2/creatinine in children with varying clinical outcomes of CM. Among parasitemic children, those with asymptomatic parasitemia had the highest levels of bicyclo-PGE2/creatinine, whereas those with CM had significantly lower levels of bicyclo-PGE2. Systemic levels of bicyclo-PGE2/creatinine were not significantly associated with parasitemia, hemoglobin levels, or levels of the PG-regulatory cytokine tumor necrosis factor- alpha but were positively correlated with levels of interleukin-10. The results presented here show that impaired systemic production of PGE2 is associated with adverse outcomes of CM, whereas elevated levels of PGE2 in asymptomatic parasitemia suggest a potential role for PGs in protective immunity.

Authors
Perkins, DJ; Hittner, JB; Mwaikambo, ED; Granger, DL; Weinberg, JB; Anstey, NM
MLA Citation
Perkins, DJ, Hittner, JB, Mwaikambo, ED, Granger, DL, Weinberg, JB, and Anstey, NM. "Impaired systemic production of prostaglandin E2 in children with cerebral malaria." J Infect Dis 191.9 (May 1, 2005): 1548-1557.
PMID
15809915
Source
pubmed
Published In
Journal of Infectious Diseases
Volume
191
Issue
9
Publish Date
2005
Start Page
1548
End Page
1557
DOI
10.1086/429332

Differential regulation of β-chemokines in children with Plasmodium falciparum malaria

Chemokines regulate the host immune response to a variety of infectious pathogens. Since the role of chemokines in regulating host immunity in children with Plasmodium falciparum malaria has not previously been reported, circulating levels of β-chemokines (MIP-1α, MIP-1β, and RANTES) and their respective transcriptional profiles in ex vivo peripheral blood mononuclear cells (PBMCs) were investigated. Peripheral blood MIP-1α and MIP-1β levels were significantly elevated in mild and severe malaria, while RANTES levels decreased with increasing disease severity. β-Chemokine gene expression profiles in blood mononuclear cells closely matched those of circulating β-chemokines, illustrating that PBMCs are a primary source for the observed pattern of β-chemokine production during acute malaria. Statistical modeling revealed that none of the chemokines was significantly associated with either parasitemia or anemia. Additional investigations in healthy children with a known history of malaria showed that children with prior severe malaria had significantly lower baseline RANTES production than children with a history of mild malaria, suggesting inherent differences in the ability to produce RANTES in these two groups. Baseline MIP-1α and MIP-1β did not significantly differ between children with prior severe malaria and those with mild malaria. Additional in vitro experiments in PBMCs from healthy, malaria-naïve donors revealed that P. falciparum-derived hemozoin (Hz; malarial pigment) and synthetic Hz (β-hematin) promote a similar pattern of β-chemokine gene expression. Taken together, the results presented here demonstrate that children with severe malaria have a distinct profile of β-chemokines characterized by increased circulating levels of MIP-1α and MIP-1β and decreased RANTES. Altered patterns of circulating β-chemokines result, at least in part, from Hz-induced changes in β-chemokine gene expression in blood mononuclear cells. Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Authors
Ochiel, DO; Awandare, GA; Keller, CC; Hittner, JB; Kremsner, PG; Weinberg, JB; Perkins, DJ
MLA Citation
Ochiel, DO, Awandare, GA, Keller, CC, Hittner, JB, Kremsner, PG, Weinberg, JB, and Perkins, DJ. "Differential regulation of β-chemokines in children with Plasmodium falciparum malaria." Infection and Immunity 73.7 (2005): 4190-4197.
PMID
15972509
Source
scival
Published In
Infection and Immunity
Volume
73
Issue
7
Publish Date
2005
Start Page
4190
End Page
4197
DOI
10.1128/IAI.73.7.4190-4197.2005

Nitric oxide production and nitric oxide synthase activity in malaria-exposed Papua New Guinean children and adults show longitudinal stability and no association with parasitemia.

Individuals in areas of intense malaria transmission exhibit resistance (or tolerance) to levels of parasitemia in their blood that would normally be associated with febrile illness in malaria-naive subjects. The resulting level of parasitemia associated with illness (the pyrogenic threshold) is highest in childhood and lowest in adulthood. Clinical parallels between malarial and bacterial endotoxin tolerance have led to the supposition that both share common physiological processes, with nitric oxide (NO) proposed as a candidate mediator. The hypotheses that NO mediates tolerance and blood stage parasite killing in vivo were tested by determining its relationship to age and parasitemia cross-sectionally and longitudinally in a population of 195 children and adults from Papua New Guinea encountering intense malaria exposure. Despite pharmacological clearance of asymptomatic parasitemia, NO production and mononuclear cell NO synthase (NOS) activity were remarkably stable within individuals over time, were not influenced by parasitemia, and varied little with age. These results contrast with previous smaller cross-sectional studies. Baseline NO production and NOS activity did not protect against recurrent parasitemia, consistent with previous data suggesting that NO does not have antiparasitic effects against blood stage infection in vivo. The NO indices studied were markedly higher in specimens from study subjects than in samples from Australian controls, and NOS activity was significantly associated with plasma immunoglobulin E levels, consistent with induction of NO by chronic exposure to other infections and/or host genetic factors. These results suggest that NO is unlikely to mediate killing of blood stage parasites in this setting and is unlikely to be the primary mediator in the acquisition or maintenance of malarial tolerance.

Authors
Boutlis, CS; Weinberg, JB; Baker, J; Bockarie, MJ; Mgone, CS; Cheng, Q; Anstey, NM
MLA Citation
Boutlis, CS, Weinberg, JB, Baker, J, Bockarie, MJ, Mgone, CS, Cheng, Q, and Anstey, NM. "Nitric oxide production and nitric oxide synthase activity in malaria-exposed Papua New Guinean children and adults show longitudinal stability and no association with parasitemia." Infect Immun 72.12 (December 2004): 6932-6938.
PMID
15557614
Source
pubmed
Published In
Infection and immunity
Volume
72
Issue
12
Publish Date
2004
Start Page
6932
End Page
6938
DOI
10.1128/IAI.72.12.6932-6938.2004

The effects of cyclic mechanical strain and tumor necrosis factor alpha on the response of cells of the meniscus.

OBJECTIVES: Cells of the knee meniscus respond to changes in their biochemical and biomechanical environments with alterations in the biosynthesis of matrix constituents and inflammatory mediators. Tumor necrosis factor alpha (TNF-alpha) is a pro-inflammatory cytokine that is involved in the pathogenesis of both osteoarthritis and rheumatoid arthritis, but its influence on meniscal physiology or mechanobiology is not fully understood. The objectives of this study were to examine the hypothesis that cyclic mechanical strain of meniscal cells modulates the biosynthesis of matrix macromolecules and pro-inflammatory mediators, and to determine if this response is altered by TNF-alpha. METHODS: Cells were isolated from the inner two-thirds of porcine medial menisci and subjected to biaxial tensile strain of 5-15% at a frequency of 0.5Hz. The synthesis of proteoglycan, protein, nitric oxide (NO), and prostaglandin E(2) were determined. RESULTS: Cyclic tensile strain increased the production of nitric oxide through the upregulation of nitric oxide synthase 2 (NOS2) and also increased synthesis rates of prostaglandin E(2), proteoglycan, and total protein in a manner that depended on strain magnitude. TNF-alpha increased the production of NO and total protein, but inhibited proteoglycan synthesis rates. TNF-alpha prevented the mechanical stimulation of proteoglycan synthesis, and this effect was not dependent on NOS2. CONCLUSIONS: These findings indicate that pro-inflammatory cytokines can modulate the responses of meniscal cells to mechanical signals, suggesting that both biomechanical and inflammatory factors could contribute to the progression of joint disease as a consequence of altered loading of the meniscus.

Authors
Fermor, B; Jeffcoat, D; Hennerbichler, A; Pisetsky, DS; Weinberg, JB; Guilak, F
MLA Citation
Fermor, B, Jeffcoat, D, Hennerbichler, A, Pisetsky, DS, Weinberg, JB, and Guilak, F. "The effects of cyclic mechanical strain and tumor necrosis factor alpha on the response of cells of the meniscus." Osteoarthritis Cartilage 12.12 (December 2004): 956-962.
PMID
15564062
Source
pubmed
Published In
Osteoarthritis and Cartilage
Volume
12
Issue
12
Publish Date
2004
Start Page
956
End Page
962
DOI
10.1016/j.joca.2004.08.007

The dichotomous role of nitric oxide in the pathogenesis of accelerated atherosclerosis associated with systemic lupus erythematosus.

Atherosclerosis is an inflammatory disorder, and the inflammation associated with systemic lupus erythematosus (SLE) accelerates the development of atherosclerosis. Nitric oxide (NO) is an important mediator of inflammation including the inflammation associated with atherosclerosis and SLE. Endothelial nitric oxide synthase (NOS3)-mediated constitutive expression of NO promotes endothelial integrity and normal vascular function. In contrast, inducible nitric oxide synthase- (NOS2) mediated expression of NO promotes endothelial dysfunction and atherogenesis. Statins appear to have anti-inflammatory properties and reverse many of the deleterious effects associated with NO metabolism in atherosclerosis. Statins augment NOS3 expression and inhibit the induction of NOS2. Therefore, the balance between normal vascular function and atherogenesis may be mediated by differences in the quantity, location, and timing of NO production within vessel walls.

Authors
Levesque, MC; Weinberg, JB
MLA Citation
Levesque, MC, and Weinberg, JB. "The dichotomous role of nitric oxide in the pathogenesis of accelerated atherosclerosis associated with systemic lupus erythematosus." Curr Mol Med 4.7 (November 2004): 777-786. (Review)
PMID
15579024
Source
pubmed
Published In
Current molecular medicine
Volume
4
Issue
7
Publish Date
2004
Start Page
777
End Page
786

The role of biomechanics and inflammation in cartilage injury and repair.

Osteoarthritis is a painful and debilitating disease characterized by progressive degenerative changes in the articular cartilage and other joint tissues. Biomechanical factors play a critical role in the initiation and progression of this disease, as evidenced by clinical and animal studies of alterations in the mechanical environment of the joint caused by trauma, joint instability, disuse, or obesity. The onset of these changes after joint injury generally has been termed posttraumatic arthritis and can be accelerated by factors such as a displaced articular fracture. Within this context, there is considerable evidence that interactions between biomechanical factors and proinflammatory mediators are involved in the progression of cartilage degeneration in posttraumatic arthritis. In vivo studies have shown increased concentrations of inflammatory cytokines and mediators in the joint in mechanically induced models of osteoarthritis. In vitro explant studies confirm that mechanical load is a potent regulator of matrix metabolism, cell viability, and the production of proinflammatory mediators such as nitric oxide and prostaglandin E2. Knowledge of the interaction of inflammatory and biomechanical factors in regulating cartilage metabolism would be beneficial to an understanding of the etiopathogenesis of posttraumatic osteoarthritis and in the improvement of therapies for joint injury.

Authors
Guilak, F; Fermor, B; Keefe, FJ; Kraus, VB; Olson, SA; Pisetsky, DS; Setton, LA; Weinberg, JB
MLA Citation
Guilak, F, Fermor, B, Keefe, FJ, Kraus, VB, Olson, SA, Pisetsky, DS, Setton, LA, and Weinberg, JB. "The role of biomechanics and inflammation in cartilage injury and repair." Clin Orthop Relat Res 423 (June 2004): 17-26. (Review)
PMID
15232421
Source
pubmed
Published In
Clinical Orthopaedics and Related Research ®
Issue
423
Publish Date
2004
Start Page
17
End Page
26

Mouse strain differences in the chemokine response to acute lung infection with a murine gammaherpesvirus.

Numerous mouse strain-based differences in the immune response and in susceptibility to numerous pathogens have been described, but it is not known if these differences extend to chemokine responses to viral infection of the lungs. To define mouse strain-based differences in the host chemokine response and susceptibility to infection with murine gammaherpesvirus-68 (MHV-68), we compared the induced chemokine response to MHV-68 infection in the lungs of BALB/c and C57BL/6 mice at 1-15 days post-infection. CC and CXC chemokines were induced in both BALB/c and C57BL/6 following infection but the level of chemokine induction was significantly higher in the BALB/c mice for all chemokines measured. In addition, interferon-gamma (IFN-gamma) was also induced to a significantly higher level in the lungs of BALB/c infected mice compared to C57BL/6 mice. Interestingly, viral gene expression was lower in the lungs of C57BL/6 mice during the acute phase of replication. Titers of infectious virus were also greater in BALB/c lungs, although they did not achieve statistical significance. In contrast, latent viral load in the spleen, as measured by quantitative real-time PCR, did not significantly differ between mouse strains, suggesting that the establishment of latency is not affected by the amount of virus present during acute infection. This data suggests that robust chemokine response and expression of IFN-gamma in the lungs of infected BALB/c mice does not correlate with increased resistance to infection. In addition, the significant differences in chemokine responses observed will be important factors to consider in future studies of viral pathogenesis using mouse models.

Authors
Weinberg, JB; Lutzke, ML; Alfinito, R; Rochford, R
MLA Citation
Weinberg, JB, Lutzke, ML, Alfinito, R, and Rochford, R. "Mouse strain differences in the chemokine response to acute lung infection with a murine gammaherpesvirus." Viral immunology 17.1 (2004): 69-77. (Academic Article)
Source
manual
Published In
Viral Immunology
Volume
17
Issue
1
Publish Date
2004
Start Page
69
End Page
77

Thermodynamics of Oxidation-Reduction Reactions in Mammalian Nitric-oxide Synthase Isoforms

The three mammalian nitric-oxide synthases produce NO from arginine in a reaction requiring 3 electrons per NO, which are supplied to the catalytic center from NADPH through reductase domains incorporating FAD and FMN cofactors. The isoforms share a common reaction mechanism and requirements for reducing equivalents but differ in regulation; the endothelial and neuronal isoforms are controlled by calcium/calmodulin modulation of the electron transfer system, while the inducible isoform binds calmodulin at all physiological Ca 2+ concentrations and is always on. The thermodynamics of electron transfer through the flavin domains in all three isoforms are basically similar. The major flavin states are FMN, FMNH., FMNH2, FAD, FADH., and FADH2. The FMN/FMNH. couple is high potential (∼100 mV) in all three isoforms and is unlikely to be catalytically competent; the other three flavin couples form a nearly isopotential group clustered around -250 mV. Reduction of the flavins by the pyridine nucleotide couple at -325 mV is thus moderately thermodynamically favorable. The ferri/ferroheme couple in all three isoforms is ∼270 mV in the presence of saturating arginine. Ca2+/calmodulin has no effect on the potentials of any of the couples in endothelial nitric-oxide synthase (eNOS) or neuronal nitric-oxide synthase (nNOS). The pH dependence of the flavin couples suggests the presence of ionizable groups coupled to the flavin redox/protonation states.

Authors
Gao, YT; Smith, SME; Weinberg, JB; Montgomery, HJ; Newman, E; Guillemette, JG; Ghosh, DK; Roman, LJ; Martasek, P; Salerno, JC
MLA Citation
Gao, YT, Smith, SME, Weinberg, JB, Montgomery, HJ, Newman, E, Guillemette, JG, Ghosh, DK, Roman, LJ, Martasek, P, and Salerno, JC. "Thermodynamics of Oxidation-Reduction Reactions in Mammalian Nitric-oxide Synthase Isoforms." Journal of Biological Chemistry 279.18 (2004): 18759-18766.
PMID
14715665
Source
scival
Published In
Journal of Biological Chemistry
Volume
279
Issue
18
Publish Date
2004
Start Page
18759
End Page
18766
DOI
10.1074/jbc.M308936200

Differential activation of nitric-oxide synthase isozymes by calmodulin-troponin C chimeras

The interactions of neuronal nitric-oxide synthase (nNOS) with calmodulin (CaM) and mutant forms of CaM, including CaM-troponin C chimeras, have been previously reported, but there has been no comparable investigation of CaM interactions with the other constitutively expressed NOS (cNOS), endothelial NOS (eNOS), or the inducible isoform (iNOS). The present study was designed to evaluate the role of the four CaM EF hands in the activation of eNOS and iNOS. To assess the role of CaM regions on aspects of enzymatic function, three distinct activities associated with NOS were measured: NADPH oxidation, cytochrome c reduction, and nitric oxide (.NO) generation as assessed by the oxyhemoglobin capture assay. CaM activates the cNOS enzymes by a mechanism other than stimulating electron transfer into the oxygenase domain. Interactions with the reductase moiety are dominant in cNOS activation, and EF hand 1 is critical for activation of both nNOS and eNOS. Although the activation patterns for nNOS and eNOS are clearly related, effects of the chimeras on all the reactions are not equivalent. We propose that cytochrome c reduction is a measure of the release of the FMN domain from the reductase complex. In contrast, cytochrome c reduction by iNOS is readily activated by each of the chimeras examined here and may be constitutive. Each of the chimeras were coexpressed with the human iNOS enzyme in Escherichia coli and subsequently purified. Domains 2 and 3 of CaM contain important elements required for the Ca2+/cam independence of .NO production by the iNOS enzyme. The disparity between cytochrome c reduction and .NO production at low calcium can be attributed to poor association of heme and FMN domains when the bound CaM constructs are depleted of Ca2+. In general cNOSs are much more difficult to activate than iNOS, which can be attributed to their extra sequence elements, which are adjacent to the CaM-binding site and associated with CaM control.

Authors
Newman, E; Spratt, DE; Mosher, J; Cheyne, B; Montgomery, HJ; Wilson, DL; Weinberg, JB; Smith, SME; Salerno, JC; Ghosh, DK; Guillemette, JG
MLA Citation
Newman, E, Spratt, DE, Mosher, J, Cheyne, B, Montgomery, HJ, Wilson, DL, Weinberg, JB, Smith, SME, Salerno, JC, Ghosh, DK, and Guillemette, JG. "Differential activation of nitric-oxide synthase isozymes by calmodulin-troponin C chimeras." Journal of Biological Chemistry 279.32 (2004): 33547-33557.
PMID
15138276
Source
scival
Published In
Journal of Biological Chemistry
Volume
279
Issue
32
Publish Date
2004
Start Page
33547
End Page
33557
DOI
10.1074/jbc.M403892200

Elevated nitric oxide production in children with malarial anemia: Hemozoin-induced nitric oxide synthase type 2 transcripts and nitric oxide in blood mononuclear cells

Experiments outlined here investigate the role of nitric oxide (NO) in the pathogenesis of Plasmodium falciparum-induced malarial anemia (MA). The results show that ex vivo and in vitro NO synthase (NOS) activity in peripheral blood mononuclear cells (PBMCs) is significantly elevated in children with MA and inversely associated with hemoglobin levels. Additional experiments using PBMCs from non-malaria-exposed donors demonstrate that physiologic amounts of P. falciparum-derived hemozoin augment NOS type 2 (NOS2) transcripts and NO production. Results of these experiments illustrate that elevated NO production in children with MA is associated with decreased hemoglobin concentrations and that hemozoin can induce NOS2-derived NO formation in cultured blood mononuclear cells.

Authors
Keller, CC; Kremsner, PG; Hittner, JB; Misukonis, MA; Weinberg, JB; Perkins, DJ
MLA Citation
Keller, CC, Kremsner, PG, Hittner, JB, Misukonis, MA, Weinberg, JB, and Perkins, DJ. "Elevated nitric oxide production in children with malarial anemia: Hemozoin-induced nitric oxide synthase type 2 transcripts and nitric oxide in blood mononuclear cells." Infection and Immunity 72.8 (2004): 4868-4873.
PMID
15271950
Source
scival
Published In
Infection and Immunity
Volume
72
Issue
8
Publish Date
2004
Start Page
4868
End Page
4873
DOI
10.1128/IAI.72.8.4868-4873.2004

Reduced peripheral PGE2 biosynthesis in Plasmodium falciparum malaria occurs through hemozoin-induced suppression of blood mononuclear cell cyclooxygenase-2 gene expression via an interleukin-10-independent mechanism

Molecular immunologic determinants of disease severity during Plasmodium falciparum malaria are largely undetermined. Our recent investigations showed that peripheral blood mononuclear cell (PBMC) cyclooxygenase-2 (COX-2) gene expression and plasma prostaglandin E2 (PGE2) production are suppressed in children with falciparum malaria relative to healthy, malaria-exposed children with partial immunity. Furthermore, decreased COX-2/PGE2 levels were significantly associated with increased plasma interleukin-10 (IL-10), an anti-inflammatory cytokine that inhibits the expression of COX-2 gene products. To determine the mechanism(s) responsible for COX-2-derived PGE2 suppression, PBMCs were cultured from children with falciparum malaria. PGE2 production was suppressed under baseline and COX-2-promoting conditions (stimulation with lipopolysaccharide [LPS] and interferon [IFN]-γ) over prolonged periods, suggesting that an in vivo-derived product(s) was responsible for reduced PGE2 biosynthesis. Ingestion of hemozoin (malarial pigment) by PBMC was investigated as a source of COX-2/PGE2 suppression in PBMCs from healthy, malaria-naive adults. In addition, synthetically prepared hemozoin, β-hematin, was used to investigate the effects of the core iron component of hemozoin, ferriprotoporphyrin-IX (FPIX). Physiologic concentrations of hemozoin or β-hematin suppressed LPS- and IFN-γ-incluced COX-2 mRNA in a time- and dose-dependent manner, resulting in decreased COX-2 protein and PGE2 production. Suppression of COX-2/PGE2 by hemozoin was not due to decreased cell viability as evidenced by examination of mitochondrial bioactivity. These data illustrate that ingestion of FPIX by blood mononuclear cells is responsible for suppression of COX-2/PGE2. Although hemozoin induced over-production of IL-10, neutralizing IL-10 antibodies failed to restore PGE2 production. Thus, acquisition of hemozoin by blood mononuclear cells is responsible for suppression of PGE 2 in malaria through inhibition of de novo COX-2 transcripts via molecular mechanisms independent of increased IL-10 production.

Authors
Keller, CC; Hittner, JB; Nti, BK; Weinberg, JB; Kremsner, PG; Perkins, DJ
MLA Citation
Keller, CC, Hittner, JB, Nti, BK, Weinberg, JB, Kremsner, PG, and Perkins, DJ. "Reduced peripheral PGE2 biosynthesis in Plasmodium falciparum malaria occurs through hemozoin-induced suppression of blood mononuclear cell cyclooxygenase-2 gene expression via an interleukin-10-independent mechanism." Molecular Medicine 10.1-6 (2004): 45-54.
PMID
15502882
Source
scival
Published In
Molecular Medicine
Volume
10
Issue
1-6
Publish Date
2004
Start Page
45
End Page
54

Inducible nitric oxide synthase (NOS2) promoter CCTTT repeat polymorphism: relationship to in vivo nitric oxide production/NOS activity in an asymptomatic malaria-endemic population.

Polymorphisms in the inducible nitric oxide synthase gene (NOS2) promoter have been associated with clinical outcome from malaria. These include a CCTTT repeat (CCTTTn) 2.5 kilobases upstream from the NOS2 transcription start site, and two single nucleotide substitutions: G-->C at position -954 (G-954C), and C-->T at position -1173 (C-1173T). Although hypothesized to influence NO production in vivo, the functional relevance of (CCTTT)n and G-954C is uncertain because disease association studies have yielded inconsistent results. This study found no association between CCTTT repeat number and levels of plasma NO metabolites or peripheral blood mononuclear cell NOS activity in a cohort of asymptomatic malaria-exposed coastal Papua New Guineans 1-60 years old. This suggests that (CCTTT)n does not independently influence NOS2 transcription in vivo. Neither the G-954C nor the C-1173T polymorphisms were identified in this population, indicating the variability and complexity of selection for NOS2 promoter polymorphisms in different malaria-endemic populations.

Authors
Boutlis, CS; Hobbs, MR; Marsh, RL; Misukonis, MA; Tkachuk, AN; Lagog, M; Booth, J; Granger, DL; Bockarie, MJ; Mgone, CS; Levesque, MC; Weinberg, JB; Anstey, NM
MLA Citation
Boutlis, CS, Hobbs, MR, Marsh, RL, Misukonis, MA, Tkachuk, AN, Lagog, M, Booth, J, Granger, DL, Bockarie, MJ, Mgone, CS, Levesque, MC, Weinberg, JB, and Anstey, NM. "Inducible nitric oxide synthase (NOS2) promoter CCTTT repeat polymorphism: relationship to in vivo nitric oxide production/NOS activity in an asymptomatic malaria-endemic population." Am J Trop Med Hyg 69.6 (December 2003): 569-573.
PMID
14740870
Source
pubmed
Published In
American Journal of Tropical Medicine and Hygiene
Volume
69
Issue
6
Publish Date
2003
Start Page
569
End Page
573

Plasma interleukin-12 in malaria-tolerant papua new guineans: inverse correlation with Plasmodium falciparum parasitemia and peripheral blood mononuclear cell nitric oxide synthase activity.

Interleukin-12 (IL-12) has been inversely associated with disease severity in human and murine malaria, and a polymorphism in the IL-12 p40 subunit gene (IL12B) has been associated with susceptibility to human cerebral malaria and reduced nitric oxide (NO) production. To better define the relationships between IL-12, NO, malaria parasitemia, and IL12B polymorphisms during malarial tolerance, plasma IL-12 levels and peripheral blood mononuclear cell NO synthase (NOS) activity were measured in asymptomatic Papua New Guineans exposed to intense malaria transmission. The IL-12 level was strongly inversely correlated with the density of Plasmodium falciparum parasitemia (rho = -0.45; P < 0.001) and was predicted to decrease by 19% (95% confidence interval [CI], 10 to 27%) for each twofold increase in P. falciparum parasitemia. This is consistent with a suppressive effect of parasitemia on IL-12 production, an effect previously shown in vitro and in rodent models of disease. The IL-12 level was inversely correlated with NOS activity (r = -0.22; P = 0.007), with each twofold increase in NOS activity being predictive of a 25% (95% CI, 7 to 38%) decrease in plasma IL-12 levels. This probably reflects additional down-regulation of IL-12 by the high basal NO production and monocyte NOS expression found in the malaria-tolerant state. Neither the IL-12 level nor NOS activity was associated with either of two IL12B polymorphisms, reflecting the diversity of genetic control over immune responses in different populations.

Authors
Boutlis, CS; Lagog, M; Chaisavaneeyakorn, S; Misukonis, MA; Bockarie, MJ; Mgone, CS; Wang, Z; Morahan, G; Weinberg, JB; Udhayakumar, V; Anstey, NM
MLA Citation
Boutlis, CS, Lagog, M, Chaisavaneeyakorn, S, Misukonis, MA, Bockarie, MJ, Mgone, CS, Wang, Z, Morahan, G, Weinberg, JB, Udhayakumar, V, and Anstey, NM. "Plasma interleukin-12 in malaria-tolerant papua new guineans: inverse correlation with Plasmodium falciparum parasitemia and peripheral blood mononuclear cell nitric oxide synthase activity." Infect Immun 71.11 (November 2003): 6354-6357.
PMID
14573655
Source
pubmed
Published In
Infection and immunity
Volume
71
Issue
11
Publish Date
2003
Start Page
6354
End Page
6357

Nitric oxide production and mononuclear cell nitric oxide synthase activity in malaria-tolerant Papuan adults.

Individuals living in regions of intense malaria transmission exhibit natural immunity that allows them to be without fever and other symptoms for most of the time despite frequent parasitization. Although this tolerance of parasitemia appears to be more effective in children than in adults (as evidenced by lower parasitemia fever thresholds with age), adults do exhibit a degree of tolerance but the mechanism(s) underlying this are unclear. Asymptomatic malaria-exposed children have higher levels of nitric oxide (NO) than children with severe disease, and NO has been proposed as a mediator of malarial tolerance. However, the ability of highly malaria-exposed asymptomatic adults to generate high-level basal NO is unknown, as is the relationship between NO and malaria tolerance in adults. The relationship between NO and malaria parasitemia was therefore determined in asymptomatic adults from Papua, Indonesia. Adults with Plasmodium falciparum parasitemia had markedly increased basal systemic NO production relative to aparasitemic Papuan controls, who in turn produced more NO than healthy controls from a region without malaria. Immunoglobulin E levels were universally elevated in malaria-exposed Papuan subjects, suggesting that the prevalence of intestinal parasitosis may be high and that nonmalarial infection may also contribute to high basal NO production. Basal peripheral blood mononuclear cell (PBMC) NO synthase activity was elevated in Papuans but poorly correlated with systemic NO production, suggesting that NO production in this setting arises not only from PBMCs but also from other tissue and cellular sources. NO production was associated with and may contribute to malaria tolerance in Papuan adults.

Authors
Boutlis, CS; Tjitra, E; Maniboey, H; Misukonis, MA; Saunders, JR; Suprianto, S; Weinberg, JB; Anstey, NM
MLA Citation
Boutlis, CS, Tjitra, E, Maniboey, H, Misukonis, MA, Saunders, JR, Suprianto, S, Weinberg, JB, and Anstey, NM. "Nitric oxide production and mononuclear cell nitric oxide synthase activity in malaria-tolerant Papuan adults." Infect Immun 71.7 (July 2003): 3682-3689.
PMID
12819048
Source
pubmed
Published In
Infection and immunity
Volume
71
Issue
7
Publish Date
2003
Start Page
3682
End Page
3689

Regulation of matrix turnover in meniscal explants: role of mechanical stress, interleukin-1, and nitric oxide.

The meniscus is an intra-articular fibrocartilaginous structure that serves essential biomechanical roles in the knee. With injury or arthritis, the meniscus may be exposed to significant changes in its biochemical and biomechanical environments that likely contribute to the progression of joint disease. The goal of this study was to examine the influence of mechanical stress on matrix turnover in the meniscus in the presence of interleukin-1 (IL-1) and to determine the role of nitric oxide (NO) in these processes. Explants of porcine menisci were subjected to dynamic compressive stresses at 0.1 MPa for 24 h at 0.5 Hz with 1 ng/ml IL-1, and the synthesis of total protein, proteoglycan, and NO was measured. The effects of a nitric oxide synthase 2 (NOS2) inhibitor were determined. Dynamic compression significantly increased protein and proteoglycan synthesis by 68 and 58%, respectively, compared with uncompressed explants. This stimulatory effect of mechanical stress was prevented by the presence of IL-1 but was restored by specifically inhibiting NOS2. Release of proteoglycans into the medium was increased by IL-1 or mechanical compression and further enhanced by IL-1 and compression together. Stimulation of proteoglycan release in response to compression was dependent on NOS2 regardless of the presence of IL-1. These finding suggest that IL-1 may modulate the effects of mechanical stress on extracellular matrix turnover through a pathway that is dependent on NO.

Authors
Shin, S-J; Fermor, B; Weinberg, JB; Pisetsky, DS; Guilak, F
MLA Citation
Shin, S-J, Fermor, B, Weinberg, JB, Pisetsky, DS, and Guilak, F. "Regulation of matrix turnover in meniscal explants: role of mechanical stress, interleukin-1, and nitric oxide." J Appl Physiol (1985) 95.1 (July 2003): 308-313.
PMID
12665533
Source
pubmed
Published In
Journal of applied physiology (Bethesda, Md. : 1985)
Volume
95
Issue
1
Publish Date
2003
Start Page
308
End Page
313
DOI
10.1152/japplphysiol.00131.2003

Low plasma arginine concentrations in children with cerebral malaria and decreased nitric oxide production.

Nitric oxide (NO) production and mononuclear cell NO synthase 2 (NOS2) expression are high in healthy Tanzanian children but low in those with cerebral malaria. Factors that downregulate NOS2 also diminish factors involved in cellular uptake and biosynthesis of L-arginine, the substrate for NO synthesis. We therefore postulated that L-arginine concentrations would be low in individuals with cerebral malaria. We measured concentrations of L-arginine in cryopreserved plasma samples from Tanzanian children with and without malaria. L-arginine concentrations were low in individuals with cerebral malaria (mean 46 micromol/L, SD 14), intermediate in those with uncomplicated malaria (70 micromol/L, 20), and within the normal range in healthy controls (122 micromol/L, 22; p<0.0001). Analysis by logistic regression showed that hypoargininaemia was significantly associated with cerebral malaria case-fatality. Hypoargininaemia may contribute to limited NO production in children with cerebral malaria and to severe disease.

Authors
Lopansri, BK; Anstey, NM; Weinberg, JB; Stoddard, GJ; Hobbs, MR; Levesque, MC; Mwaikambo, ED; Granger, DL
MLA Citation
Lopansri, BK, Anstey, NM, Weinberg, JB, Stoddard, GJ, Hobbs, MR, Levesque, MC, Mwaikambo, ED, and Granger, DL. "Low plasma arginine concentrations in children with cerebral malaria and decreased nitric oxide production." Lancet 361.9358 (February 22, 2003): 676-678.
PMID
12606182
Source
pubmed
Published In
The Lancet
Volume
361
Issue
9358
Publish Date
2003
Start Page
676
End Page
678
DOI
10.1016/S0140-6736(03)12564-0

Increased nitric oxide production and protection from malaria - Reply

Authors
Hobbs, MR; Levesque, MC; Anstey, NM; Granger, DL; Weinberg, JB
MLA Citation
Hobbs, MR, Levesque, MC, Anstey, NM, Granger, DL, and Weinberg, JB. "Increased nitric oxide production and protection from malaria - Reply." LANCET 361.9357 (February 15, 2003): 610-611.
Source
wos-lite
Published In
The Lancet
Volume
361
Issue
9357
Publish Date
2003
Start Page
610
End Page
611
DOI
10.1016/S0140-6736(03)12530-5

IL-4 and interferon gamma regulate expression of inducible nitric oxide synthase in chronic lymphocytic leukemia cells.

Chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of long-lived non-dividing CD5(+) B cells. Nitric oxide (NO) is an important regulator of apoptosis, and the viability of cultured B-CLL cells may be dependent on the autocrine production of nitric oxide by inducible nitric oxide synthase (NOS2). We performed this study to determine whether cytokine factors that prevent spontaneous in vitroapoptosis of B-CLL cells induce B-CLL cell NOS2 enzyme activity. B-CLL cells expressed NOS enzyme activity and NOS2 protein and mRNA. IL-4 and IFN-gamma increased B-CLL cell NOS2 enzyme activity and protein expression during in vitro culture. IFN-gamma, but not IL-4, increased NOS2 mRNA expression in cultured B-CLL cells suggesting that IL-4-mediated changes of NOS2 protein expression occurred at the post-transcriptional level. We were unable to detect increased concentrations of nitrite or nitrate (NO(x)) as surrogate markers of NO production in B-CLL cell cultures treated with IL-4 or IFN-gamma. IL-4 and IFN-gamma diminished NOS inhibitor-induced B-CLL cell death. In summary, we found that B-CLL cells expressed NOS2 and that IL-4 and IFN-gamma increased B-CLL NOS2 expression. Cytokine-mediated expression of NOS2 by B-CLL cells may promote their survival, and therapeutic strategies that target NOS2 or quench NO may be beneficial in patients with B-CLL.

Authors
Levesque, MC; Misukonis, MA; O'Loughlin, CW; Chen, Y; Beasley, BE; Wilson, DL; Adams, DJ; Silber, R; Weinberg, JB
MLA Citation
Levesque, MC, Misukonis, MA, O'Loughlin, CW, Chen, Y, Beasley, BE, Wilson, DL, Adams, DJ, Silber, R, and Weinberg, JB. "IL-4 and interferon gamma regulate expression of inducible nitric oxide synthase in chronic lymphocytic leukemia cells." Leukemia 17.2 (February 2003): 442-450.
PMID
12592345
Source
pubmed
Published In
Leukemia
Volume
17
Issue
2
Publish Date
2003
Start Page
442
End Page
450
DOI
10.1038/sj.leu.2402783

Case report of Staphylococcus aureus endocarditis after navel piercing.

A 13-year-old girl with surgically corrected congenital heart disease presented with a 3-day history of fever 1 month after piercing her navel. An echocardiogram demonstrated a vegetation within her right ventricle to pulmonary artery conduit, and several blood cultures were repeatedly positive for Staphylococcus aureus. Surgical replacement of the conduit in conjunction with intravenous antibiotic therapy was curative.

Authors
Weinberg, JB; Blackwood, RA
MLA Citation
Weinberg, JB, and Blackwood, RA. "Case report of Staphylococcus aureus endocarditis after navel piercing." The Pediatric infectious disease journal 22.1 (January 2003): 94-96. (Academic Article)
Source
manual
Published In
Pediatric Infectious Disease Journal
Volume
22
Issue
1
Publish Date
2003
Start Page
94
End Page
96

Nitric oxide synthase 2 promoter polymorphisms and systemic lupus erythematosus in african-americans.

OBJECTIVE: Systemic lupus erythematosus (SLE) is an autoimmune disease in which morbidity and mortality are higher in African-Americans. The etiology of this racial disparity is unknown. A genetic predisposition to enhanced nitric oxide (NO) production may predispose African-Americans to develop SLE and may increase disease severity. We have demonstrated a correlation between NO production and disease activity in SLE. Two polymorphisms in the inducible NO synthase (NOS2) promoter region (G-954C and CCTTT microsatellite repeat polymorphisms) are associated with improved outcome in some African patients with malaria. This study was designed to determine if these polymorphisms are associated with SLE. METHODS: We assessed the frequency of both the G-954C and CCTTT microsatellite repeat NOS2 promoter polymorphisms in a cohort of patients with SLE and age, sex, and race matched controls in North Carolina and South Carolina. RESULTS: Both polymorphisms were more frequent among African-American female SLE patients when compared with controls (p = 0.04 for the G-954C polymorphism and p = 0.03 for the CCTTT-8 repeat polymorphism). Further, the G-954C and CCTTT-8 repeat polymorphisms were in linkage disequilibrium (D cent = 0.89, p = 0.0001) among African-American female SLE patients. CONCLUSION: Altered genetic control of NOS2 transcription may be a risk factor for SLE among African-American females. The extent of linkage disequilibrium between the G-954C and CCTTT-8 repeat NOS2 promoter polymorphisms suggests that they were co-inherited.

Authors
Oates, JC; Levesque, MC; Hobbs, MR; Smith, EG; Molano, ID; Page, GP; Hill, BS; Weinberg, JB; Cooper, GS; Gilkeson, GS
MLA Citation
Oates, JC, Levesque, MC, Hobbs, MR, Smith, EG, Molano, ID, Page, GP, Hill, BS, Weinberg, JB, Cooper, GS, and Gilkeson, GS. "Nitric oxide synthase 2 promoter polymorphisms and systemic lupus erythematosus in african-americans." J Rheumatol 30.1 (January 2003): 60-67.
PMID
12508391
Source
pubmed
Published In
The Journal of rheumatology
Volume
30
Issue
1
Publish Date
2003
Start Page
60
End Page
67

Increased nitric oxide production and protection from malaria [2] (multiple letters)

Authors
Heales, S; Wang, WYS; Adams, DJ; Hobbs, MR; Levesque, MC; Anstey, NM; Granger, DL; Weinberg, JB
MLA Citation
Heales, S, Wang, WYS, Adams, DJ, Hobbs, MR, Levesque, MC, Anstey, NM, Granger, DL, and Weinberg, JB. "Increased nitric oxide production and protection from malaria [2] (multiple letters)." Lancet 361.9357 (2003): 609-611.
PMID
12598161
Source
scival
Published In
Lancet
Volume
361
Issue
9357
Publish Date
2003
Start Page
609
End Page
611
DOI
10.1016/S0140-6736(03)12529-9

A new NOS2 promoter polymorphism associated with increased nitric oxide production and protection from severe malaria in Tanzanian and Kenyan children.

BACKGROUND: Nitric oxide (NO) is a mediator of immunity to malaria, and genetic polymorphisms in the promoter of the inducible NO synthase gene (NOS2) could modulate production of NO. We postulated that NOS2 promoter polymorphisms would affect resistance to severe malaria. METHODS: We assessed genomic DNA from healthy children and from those diagnosed with malaria from Tanzania (n=47 and n=138, respectively) and Kenya (n=1106) for polymorphisms by single-stranded conformational polymorphism (SSCP) analysis and sequencing. We also measured in-vivo NO production in Tanzanian children. FINDINGS: We identified a novel single nucleotide polymorphism, -1173 C-->T, in the NOS2 promoter that was significantly associated with protection from symptomatic malaria (odds ratio 0.12, 95% CI 0.03-0.48, p=0.0006) in 179 Tanzanian children, and significantly associated with protection from severe malarial anaemia (adjusted relative risk 0.25, 95% CI 0.09-0.66, p=0.0005) in 1106 Kenyan children studied over 5 years. The risk of parasitaemia was not significantly different in wild-type or -1173 C-->T individuals. -1173 C-->T protection in Tanzanians was independent of the previously recognised NOS2-954 G-->C polymorphism. The (CCTTT)(n) NOS2 polymorphism (Tanzania and Kenya) was not associated with severe malaria outcomes. -1173 C-->T was associated with increased fasting urine and plasma NO metabolite concentrations in Tanzanian children, suggesting that the polymorphism was functional in vivo. Interpretation The NOS2 promoter -1173 C-->T single nucleotide polymorphism is associated with protection against cerebral malaria and severe malarial anaemia. Increased NO production in individuals with the -1173 C-->T polymorphism lends support to a protective role for NO against these syndromes. Targeted interventions to increase NO delivery or production could provide novel preventive and therapeutic strategies against these major causes of mortality in African children.

Authors
Hobbs, MR; Udhayakumar, V; Levesque, MC; Booth, J; Roberts, JM; Tkachuk, AN; Pole, A; Coon, H; Kariuki, S; Nahlen, BL; Mwaikambo, ED; Lal, AL; Granger, DL; Anstey, NM; Weinberg, JB
MLA Citation
Hobbs, MR, Udhayakumar, V, Levesque, MC, Booth, J, Roberts, JM, Tkachuk, AN, Pole, A, Coon, H, Kariuki, S, Nahlen, BL, Mwaikambo, ED, Lal, AL, Granger, DL, Anstey, NM, and Weinberg, JB. "A new NOS2 promoter polymorphism associated with increased nitric oxide production and protection from severe malaria in Tanzanian and Kenyan children." Lancet 360.9344 (November 9, 2002): 1468-1475.
PMID
12433515
Source
pubmed
Published In
The Lancet
Volume
360
Issue
9344
Publish Date
2002
Start Page
1468
End Page
1475
DOI
10.1016/S0140-6736(02)11474-7

A promoter polymorphism in the gene encoding interleukin-12 p40 (IL12B) is associated with mortality from cerebral malaria and with reduced nitric oxide production.

Interleukin-12 (IL-12) is an important regulatory cytokine in infection and immunity. Administration of IL-12 may reduce complications of severe malaria in rodents. Polymorphisms in IL12B, the gene encoding the IL-12 p40 subunit, influence the secretion of IL-12 and susceptibility to Type 1 diabetes. We therefore investigated whether IL12B polymorphisms may affect the outcome of severe malaria. Homozygosity for a polymorphism in the IL12B promoter was associated with increased mortality in Tanzanian children having cerebral malaria but not in Kenyan children with severe malaria. Furthermore, homozygotes for the IL12B promotor polymorphism had decreased production of nitric oxide, which is in part regulated by IL-12 activity. These studies suggest that IL12B polymorphisms, via regulation of IL-12 production, may influence the outcome of malaria infection in at least one African population.

Authors
Morahan, G; Boutlis, CS; Huang, D; Pain, A; Saunders, JR; Hobbs, MR; Granger, DL; Weinberg, JB; Peshu, N; Mwaikambo, ED; Marsh, K; Roberts, DJ; Anstey, NM
MLA Citation
Morahan, G, Boutlis, CS, Huang, D, Pain, A, Saunders, JR, Hobbs, MR, Granger, DL, Weinberg, JB, Peshu, N, Mwaikambo, ED, Marsh, K, Roberts, DJ, and Anstey, NM. "A promoter polymorphism in the gene encoding interleukin-12 p40 (IL12B) is associated with mortality from cerebral malaria and with reduced nitric oxide production." Genes Immun 3.7 (November 2002): 414-418.
PMID
12424623
Source
pubmed
Published In
Genes & Immunity
Volume
3
Issue
7
Publish Date
2002
Start Page
414
End Page
418
DOI
10.1038/sj.gene.6363909

Elevated chemokine responses are maintained in lungs after clearance of viral infection.

We observed two patterns of chemokine expression in the lungs of mice infected with murine gammaherpesvirus 68: peaks of chemokine expression correlated with or occurred after the peak of viral gene expression. Chemokine expression remained elevated through 29 days postinfection.

Authors
Weinberg, JB; Lutzke, ML; Efstathiou, S; Kunkel, SL; Rochford, R
MLA Citation
Weinberg, JB, Lutzke, ML, Efstathiou, S, Kunkel, SL, and Rochford, R. "Elevated chemokine responses are maintained in lungs after clearance of viral infection." Journal of virology 76.20 (October 2002): 10518-10523. (Academic Article)
Source
manual
Published In
Journal of virology
Volume
76
Issue
20
Publish Date
2002
Start Page
10518
End Page
10523

Induction of cyclooxygenase-2 by mechanical stress through a nitric oxide-regulated pathway.

OBJECTIVE: Biomechanical signals play important roles in regulating the homeostasis of articular cartilage, but under abnormal conditions may be a critical factor in the onset and progression of arthritis. Prostaglandin E(2) (PGE(2)) and nitric oxide (NO), derived from the enzymes cyclo-oxygenase 2 (COX2) and NO synthase 2 (NOS2), are inflammatory mediators that modulate numerous physiological and pathophysiological processes and are potentially important pharmacological targets in osteoarthritis. The goal of this study was to determine the effect of mechanical compression on PGE(2) production in the presence of selective NOS2 and COX2 inhibitors. METHODS: Articular cartilage explants harvested from 2-3-year-old pigs were subjected to intermittent compression at 0.5Hz over a range of stress magnitudes. PGE(2) and NO production into the media were determined in the presence and absence of the NOS2 inhibitor 1400W or the COX2 inhibitor NS398. COX2 protein levels were determined by immunoblot analysis. RESULTS: Mechanical compression significantly increased NO and PGE(2) synthesis in a manner that was dependent on the magnitude of stress. The selective COX2 inhibitor blocked compression-induced NO and PGE(2) production. Compression in the presence of 1400W further increased COX2 expression resulting in a 10-fold increase in PGE(2) production compared to uncompressed explants with 1400W and a 40-fold increase in PGE(2) compared to uncompressed explants without 1400W. CONCLUSION: Mechanical compression of articular cartilage increased COX2 and PGE(2) production through a NO-dependent pathway, and therefore pharmacological agents that target the NOS2 pathway in cartilage may have a significant influence on prostanoid production in the joint.

Authors
Fermor, B; Weinberg, JB; Pisetsky, DS; Misukonis, MA; Fink, C; Guilak, F
MLA Citation
Fermor, B, Weinberg, JB, Pisetsky, DS, Misukonis, MA, Fink, C, and Guilak, F. "Induction of cyclooxygenase-2 by mechanical stress through a nitric oxide-regulated pathway." Osteoarthritis Cartilage 10.10 (October 2002): 792-798.
PMID
12359165
Source
pubmed
Published In
Osteoarthritis and Cartilage
Volume
10
Issue
10
Publish Date
2002
Start Page
792
End Page
798

Immunity to malaria after administration of ultra-low doses of red cells infected with Plasmodium falciparum.

BACKGROUND: The ability of T cells, acting independently of antibodies, to control malaria parasite growth in people has not been defined. If such was shown to be effective, an additional vaccine strategy could be pursued. Our aim was to ascertain whether or not development of cell-mediated immunity to Plasmodium falciparum blood-stage infection could be induced in human beings by exposure to malaria parasites in very low density. METHODS: We enrolled five volunteers from the staff at our research institute who had never had malaria. We used a cryopreserved inoculum of red cells infected with P falciparum strain 3D7 to give them repeated subclinical infections of malaria that we then cured early with drugs, to induce cell-mediated immune responses. We tested for development of immunity by measurement of parasite concentrations in the blood of volunteers by PCR of the multicopy gene STEVOR and by following up the volunteers clinically, and by measuring antibody and cellular immune responses to the parasite. FINDINGS: After challenge and a extended period without drug cure, volunteers were protected against malaria as indicated by absence of parasites or parasite DNA in the blood, and absence of clinical symptoms. Immunity was characterised by absence of detectable antibodies that bind the parasite or infected red cells, but by the presence of a proliferative T-cell response, involving CD4+ and CD8+ T cells, a cytokine response, consisting of interferon gamma but not interleukin 4 or interleukin 10, induction of high concentrations of nitric oxide synthase activity in peripheral blood mononuclear cells, and a drop in the number of peripheral natural killer T cells. INTERPRETATION: People can be protected against the erythrocytic stage of malaria by a strong cell-mediated immune response, in the absence of detectable parasite-specific antibodies, suggesting an additional strategy for development of a malaria vaccine

Authors
Pombo, DJ; Lawrence, G; Hirunpetcharat, C; Rzepczyk, C; Bryden, M; Cloonan, N; Anderson, K; Mahakunkijcharoen, Y; Martin, LB; Wilson, D; Elliott, S; Elliott, S; Eisen, DP; Weinberg, JB; Saul, A; Good, MF
MLA Citation
Pombo, DJ, Lawrence, G, Hirunpetcharat, C, Rzepczyk, C, Bryden, M, Cloonan, N, Anderson, K, Mahakunkijcharoen, Y, Martin, LB, Wilson, D, Elliott, S, Elliott, S, Eisen, DP, Weinberg, JB, Saul, A, and Good, MF. "Immunity to malaria after administration of ultra-low doses of red cells infected with Plasmodium falciparum." Lancet 360.9333 (August 24, 2002): 610-617.
PMID
12241933
Source
pubmed
Published In
The Lancet
Volume
360
Issue
9333
Publish Date
2002
Start Page
610
End Page
617
DOI
10.1016/S0140-6736(02)09784-2

Influence of hypoxia and reoxygenation on cytokine-induced production of proinflammatory mediators in articular cartilage.

OBJECTIVE: Articular cartilage is an avascular tissue that functions at a lower oxygen tension than do most tissues. With mobilization, arthritic joints may undergo cycles of hypoxia and reoxygenation. The goal of this study was to determine the effects of hypoxia and reoxygenation on cytokine-induced nitric oxide (NO) and prostaglandin E(2) (PGE(2)) production in articular cartilage. METHODS: Porcine cartilage explants were incubated at 37 degrees C for 72 hours in either 1% O(2) (hypoxia) or 20% O(2) (normoxia) in media supplemented with interleukin-1alpha (IL-1alpha) or tumor necrosis factor alpha (TNFalpha), with or without the NO synthase 2 (NOS2) selective inhibitor 1400W. Culture media were then removed and replaced with freshly prepared media and incubated for a further 24 hours in normoxia. RESULTS: NO levels were significantly higher in explants supplemented with IL-1alpha and TNFalpha compared with controls, in both hypoxia and normoxia. Compared with normoxia, hypoxia decreased IL-1alpha- and TNFalpha-induced NO production significantly. Reoxygenation of hypoxic explants resulted in sustained significant NO production in response to either cytokine. However, comparably high levels of NO production were not sustained in explants cultured continuously in normoxia. Although IL-1alpha alone did not significantly increase PGE(2) production, significant PGE(2) superinduction occurred in cartilage stimulated with IL-1alpha and the NOS2 inhibitor 1400W compared with stimulation with IL-1alpha alone in hypoxia, but not in normoxia. CONCLUSION: Oxygen tension significantly affects cytokine-induced proinflammatory mediator production in articular cartilage. Furthermore, hypoxia alters NO mediation of PGE(2) production. Hypoxia and reoxygenation can affect cytokine-induced proinflammatory mediator production, suggesting that oxygen tension may influence inflammation associated with cartilage injury and disease.

Authors
Cernanec, J; Guilak, F; Weinberg, JB; Pisetsky, DS; Fermor, B
MLA Citation
Cernanec, J, Guilak, F, Weinberg, JB, Pisetsky, DS, and Fermor, B. "Influence of hypoxia and reoxygenation on cytokine-induced production of proinflammatory mediators in articular cartilage." Arthritis Rheum 46.4 (April 2002): 968-975.
PMID
11953974
Source
pubmed
Published In
Arthritis and Rheumatism
Volume
46
Issue
4
Publish Date
2002
Start Page
968
End Page
975

Inducible nitric oxide synthase expression by peritoneal macrophages in endometriosis-associated infertility.

OBJECTIVE: Determine whether peritoneal macrophages from women with endometriosis-associated infertility express more inducible nitric oxide synthase (NOS2) and produce more NO than fertile controls. DESIGN: Unblinded clinical study. PATIENT(S): Nine infertile women with endometriosis and nine normal fertile women undergoing laparoscopy. INTERVENTION(S): Peritoneal fluid and macrophages were collected. Cells were also cultured with the NOS2 inducers interferon-alpha (IFN-alpha) or IFN-gamma plus lipopolysaccharide (LPS). MAIN OUTCOME MEASURE(S): Peritoneal fluid NO levels, peritoneal macrophage NOS activity, and peritoneal macrophage NOS2 protein expression. RESULT(S): NOS enzyme activity was higher in peritoneal macrophages from endometriosis patients. Immunoblots demonstrated NOS2 protein only in peritoneal macrophages from women with endometriosis. Peritoneal fluid NO concentration was similar in the two groups, but total peritoneal fluid NO content was higher in endometriosis patients. After 3 days' culture, peritoneal macrophages from women with endometriosis produced more NO in response to IFN-alpha or IFN-gamma plus LPS than controls. CONCLUSION(S): Peritoneal macrophages from women with endometriosis-associated infertility express higher levels of NOS2, have higher NOS enzyme activity, and produce more NO in response to immune stimulation in vitro. As high levels of NO adversely affect sperm, embryos, implantation, and oviductal function, reducing peritoneal fluid NO production or blocking NO effects may improve fertility in women with endometriosis.

Authors
Osborn, BH; Haney, AF; Misukonis, MA; Weinberg, JB
MLA Citation
Osborn, BH, Haney, AF, Misukonis, MA, and Weinberg, JB. "Inducible nitric oxide synthase expression by peritoneal macrophages in endometriosis-associated infertility." Fertil Steril 77.1 (January 2002): 46-51.
PMID
11779590
Source
pubmed
Published In
Fertility and Sterility
Volume
77
Issue
1
Publish Date
2002
Start Page
46
End Page
51

Systemic nitric oxide production in human malaria. II. Analysis of mononuclear cell nitric oxide synthase type 2 antigen expression.

Authors
Saunders, JR; Misukonis, MA; Weinberg, JB; Anstey, NM
MLA Citation
Saunders, JR, Misukonis, MA, Weinberg, JB, and Anstey, NM. "Systemic nitric oxide production in human malaria. II. Analysis of mononuclear cell nitric oxide synthase type 2 antigen expression." Methods Mol Med 72 (2002): 469-474.
PMID
12125143
Source
pubmed
Published In
Methods in Molecular Medicine
Volume
72
Publish Date
2002
Start Page
469
End Page
474
DOI
10.1385/1-59259-271-6:469

Nitric oxide enhancement of fludarabine cytotoxicity for B-CLL lymphocytes.

Fludarabine is active but not curative in the treatment of chronic lymphocytic leukemia (B-CLL). Nitric oxide (NO) supplied from exogenous, NO-donating pro-drugs can also induce apoptosis and death of acute leukemia cells. This study investigated combinations of fludarabine with NO-donating pro-drugs for their cytotoxicity against freshly isolated B-CLL lymphocytes following a 72 h exposure in vitro. The median IC(50)for fludarabine was 2.2 microM (n = 85). The nitric oxide donors DETA-NO, PAPA-NO, and MAHMA-NO were also cytotoxic, and their effects were inversely related to rates of NO release. Neither DETA-NO depleted of NO nor DETA itself was effective, indicating that NO was required for cytotoxicity. Drug interactions were evaluated by a modified combination index method. Synergy was observed in combinations of fludarabine or nelarabine (506U78) with DETA-NO in 52% and 88% of samples, respectively. Interestingly, the combination of fludarabine and DETA-NO was more cytotoxic in B-CLL cells less sensitive to fludarabine. DETA-NO did not enhance the activity of other DNA anti-metabolites, topoisomerase I and II inhibitors, or alkylating agents. Finally, the anti-leukemic activity of fludarabine alone or in combination with DETA-NO was found to correlate with inhibition of cellular RNA synthesis. These results indicate that NO donors could enhance fludarabine therapy for B-CLL.

Authors
Adams, DJ; Levesque, MC; Weinberg, JB; Smith, KL; Flowers, JL; Moore, J; Colvin, OM; Silber, R
MLA Citation
Adams, DJ, Levesque, MC, Weinberg, JB, Smith, KL, Flowers, JL, Moore, J, Colvin, OM, and Silber, R. "Nitric oxide enhancement of fludarabine cytotoxicity for B-CLL lymphocytes." Leukemia 15.12 (December 2001): 1852-1859.
PMID
11753605
Source
pubmed
Published In
Leukemia
Volume
15
Issue
12
Publish Date
2001
Start Page
1852
End Page
1859

Host response to infection: the role of CpG DNA in induction of cyclooxygenase 2 and nitric oxide synthase 2 in murine macrophages.

Depending on sequence, bacterial and synthetic DNAs can activate the host immune system and influence the host response to infection. The purpose of this study was to determine the abilities of various phosphorothioate oligonucleotides with cytosine-guanosine-containing motifs (CpG DNA) to activate macrophages to produce nitric oxide (NO) and prostaglandin E(2) (PGE(2)) and to induce expression of NO synthase 2 (NOS2) and cyclooxygenase 2 (COX2). As little as 0.3 microg of CpG DNA/ml increased NO and PGE(2) production in a dose- and time-dependent fashion in cells of the mouse macrophage cell line J774. NO and PGE(2) production was noted by 4 to 8 h after initiation of cultures with the CpG DNA, with the kinetics of NO production induced by CpG DNA being comparable to that induced by a combination of lipopolysaccharide and gamma interferon. CpG DNA-treated J774 cells showed enhanced expression of NOS2 and COX2 proteins as determined by immunoblotting, with the relative potencies of the CpG DNAs generally corresponding to those noted for the induction of NO and PGE(2) production as well as to those noted for the induction of interleukin-6 (IL-6), IL-12, and tumor necrosis factor. Extracts from CpG DNA-treated cells converted L-arginine to L-citrulline, but the NOS inhibitor N(G)-monomethyl-L-arginine (NMMA) inhibited this reaction. The COX2-specific inhibitor NS398 inhibited CpG DNA-induced PGE(2) production and inhibited NO production to various degrees. The NOS inhibitors NMMA, 1400W, and N-iminoethyl-L-lysine effectively blocked NO production and increased the production of PGE(2) in a dose-dependent fashion. Thus, analogues of microbial DNA (i.e., CpG DNA) activate mouse macrophage lineage cells for the expression of NOS2 and COX2, with the production of NO and that of PGE(2) occurring in an interdependent manner.

Authors
Ghosh, DK; Misukonis, MA; Reich, C; Pisetsky, DS; Weinberg, JB
MLA Citation
Ghosh, DK, Misukonis, MA, Reich, C, Pisetsky, DS, and Weinberg, JB. "Host response to infection: the role of CpG DNA in induction of cyclooxygenase 2 and nitric oxide synthase 2 in murine macrophages." Infect Immun 69.12 (December 2001): 7703-7710.
PMID
11705951
Source
pubmed
Published In
Infection and immunity
Volume
69
Issue
12
Publish Date
2001
Start Page
7703
End Page
7710
DOI
10.1128/IAI.69.12.7703-7710.2001

Cytokine modulation of inducible nitric oxide synthase (NOS2) mRNA levels and apoptosis in B-cell chronic lymphocytic leukemia (B-CLL): A quantitative analysis.

Authors
Levesque, MC; O'Loughlin, CW; Wilson, DL; Misukonis, MA; Chen, YW; Beasley, BE; Weinberg, JB
MLA Citation
Levesque, MC, O'Loughlin, CW, Wilson, DL, Misukonis, MA, Chen, YW, Beasley, BE, and Weinberg, JB. "Cytokine modulation of inducible nitric oxide synthase (NOS2) mRNA levels and apoptosis in B-cell chronic lymphocytic leukemia (B-CLL): A quantitative analysis." BLOOD 98.11 (November 16, 2001): 362A-362A.
Source
wos-lite
Published In
Blood
Volume
98
Issue
11
Publish Date
2001
Start Page
362A
End Page
362A

Interleukin-1, tumor necrosis factor alpha, and interleukin-17 synergistically up-regulate nitric oxide and prostaglandin E2 production in explants of human osteoarthritic knee menisci.

OBJECTIVE: In osteoarthritis (OA), a combination of biochemical and biomechanical factors may damage both menisci and articular cartilage. Nitric oxide (NO) and prostaglandin E2 (PGE2) have been implicated as mediators of inflammation in OA. The goals of this study were to determine if menisci from patients with OA produce NO and PGE2, and if the proinflammatory cytokines interleukin-1beta (IL-1beta), tumor necrosis factor a (TNFalpha), and IL-17 augment NO and PGE2 production by these tissues. METHODS: Menisci were obtained from 17 patients (age 47-75 years) undergoing total knee replacement for OA. Tissue explants were cultured alone or with IL-1beta, IL-17, or TNFalpha, and the release of NO and PGE2 from the tissue as well as the presence of type 2 nitric oxide synthase (NOS2) and cyclooxygenase 2 (COX-2) antigens were measured. RESULTS: All menisci constitutively produced NO, and significant increases in NO production were observed in the presence of IL-1beta, TNFalpha, or IL-17 (P < 0.05). The combination of IL-17 and TNFalpha significantly increased NO production compared with either cytokine alone. Basal and cytokine-stimulated NO synthesis was inhibited by the NOS inhibitors NG-monomethyl-L-arginine or N-3-aminoethylbenzylacetamidine (1400W). IL-1beta significantly increased PGE2 production. The combination of IL-1beta and TNFalpha had an additive effect on PGE2 production, while addition of IL-17 to TNFalpha or IL-1beta synergistically enhanced PGE2 production. Inhibition of NO production by 1400W significantly increased IL-1beta-stimulated PGE2 production, and inhibition of PGE2 production by the COX-2 inhibitor N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide significantly increased IL-17-stimulated NO production. CONCLUSION: Menisci from humans with OA spontaneously produced NO and PGE2 in a manner that was synergistically or additively augmented by cytokines. NO and PGE2 exhibited reciprocal regulatory effects on one another, suggesting that pharmaceutical agents designed to inhibit NOS2 or COX-2 production may in fact be influencing both pathways.

Authors
LeGrand, A; Fermor, B; Fink, C; Pisetsky, DS; Weinberg, JB; Vail, TP; Guilak, F
MLA Citation
LeGrand, A, Fermor, B, Fink, C, Pisetsky, DS, Weinberg, JB, Vail, TP, and Guilak, F. "Interleukin-1, tumor necrosis factor alpha, and interleukin-17 synergistically up-regulate nitric oxide and prostaglandin E2 production in explants of human osteoarthritic knee menisci." Arthritis Rheum 44.9 (September 2001): 2078-2083.
PMID
11592370
Source
pubmed
Published In
Arthritis and Rheumatism
Volume
44
Issue
9
Publish Date
2001
Start Page
2078
End Page
2083
DOI
10.1002/1529-0131(200109)44:9<2078::AID-ART358>3.0.CO;2-J

Interplay of nitric oxide synthase (NOS), cyclooxygenase (COX) and lipoxygenase (LOX) pathways in response to mechanical compression of articular cartilage.

Authors
Fermor, B; Bodduluri, H; Weinberg, JB; Pisetsky, DS; Fink, C; Guilak, F
MLA Citation
Fermor, B, Bodduluri, H, Weinberg, JB, Pisetsky, DS, Fink, C, and Guilak, F. "Interplay of nitric oxide synthase (NOS), cyclooxygenase (COX) and lipoxygenase (LOX) pathways in response to mechanical compression of articular cartilage." JOURNAL OF BONE AND MINERAL RESEARCH 16 (September 2001): S330-S330.
Source
wos-lite
Published In
Journal of Bone and Mineral Research
Volume
16
Publish Date
2001
Start Page
S330
End Page
S330

Characterization of key residues in the subdomain encoded by exons 8 and 9 of human inducible nitric oxide synthase: a critical role for Asp-280 in substrate binding and subunit interactions.

Human inducible nitric oxide synthase (iNOS) is active as a dimer of two identical subunits. Each subunit has an amino-terminal oxygenase domain that binds the substrate l-Arg and the cofactors heme and tetrahydrobiopterin and a carboxyl-terminal reductase domain that binds FMN, FAD, and NADPH. We previously demonstrated that a subdomain in the oxygenase domain encoded by exons 8 and 9 is important for dimer formation and NO synthesis. Further, we identified Trp-260, Asn-261, Tyr-267, and Asp-280 as key residues in that subdomain. In this study, using an Escherichia coli expression system, we produced, purified, and characterized wild-type iNOS and iNOS-Ala mutants. Using H(2)O(2)-supported oxidation of N(omega)-hydroxy-l-Arg, we demonstrate that the iNOS mutants' inabilities to synthesize NO are due to selective defects in the oxygenase domain activity. Detailed characterization of the Asp-280-Ala mutant revealed that it retains a functional reductase domain, as measured by its ability to reduce cytochrome c. Gel permeation chromatography confirmed that the Asp-280-Ala mutant exists as a dimer, but, in contrast to wild-type iNOS, urea-generated monomers of the mutant fail to reassociate into dimers when incubated with l-Arg and tetrahydrobiopterin, suggesting inadequate subunit interaction. Spectral analysis reveals that the Asp-280-Ala mutant does not bind l-Arg. This indicates that, in addition to dimerization, proper subunit interaction is required for substrate binding. These data, by defining a critical role for Asp-280 in substrate binding and subunit interactions, give insights into the mechanisms of regulation of iNOS activity.

Authors
Ghosh, DK; Rashid, MB; Crane, B; Taskar, V; Mast, M; Misukonis, MA; Weinberg, JB; Eissa, NT
MLA Citation
Ghosh, DK, Rashid, MB, Crane, B, Taskar, V, Mast, M, Misukonis, MA, Weinberg, JB, and Eissa, NT. "Characterization of key residues in the subdomain encoded by exons 8 and 9 of human inducible nitric oxide synthase: a critical role for Asp-280 in substrate binding and subunit interactions." Proc Natl Acad Sci U S A 98.18 (August 28, 2001): 10392-10397.
PMID
11517317
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
98
Issue
18
Publish Date
2001
Start Page
10392
End Page
10397
DOI
10.1073/pnas.181251298

Nitric oxide synthase 2(Lambaréné) (G-954C), increased nitric oxide production, and protection against malaria.

A point mutation in the promoter of the nitric oxide synthase 2 gene (NOS2), termed NOS2(Lambaréné) (NOS2-G954C), protects heterozygous carriers against severe malaria as effectively as the sickle cell trait. In a prospective longitudinal study, 841 individual infections of initially 200 children (151 wild-type vs. 49 NOS2(Lambaréné) carriers) were monitored for 4 years, to assess the rates of malarial attacks in the 2 groups; carriers of the NOS2(Lambaréné) polymorphism were significantly less likely to experience malarial attacks than were others (P=.002). The distribution of the NOS2(Lambaréné) polymorphism was investigated in malaria-endemic areas. It was found to be present with the highest frequency in Africa and at a lower frequency in Asia. Ex vivo studies showed that cells isolated from people with this polymorphism have a 7-fold higher baseline NOS activity, compared with the levels detected in cells from subjects with the wild-type gene (P=.003).

Authors
Kun, JF; Mordmüller, B; Perkins, DJ; May, J; Mercereau-Puijalon, O; Alpers, M; Weinberg, JB; Kremsner, PG
MLA Citation
Kun, JF, Mordmüller, B, Perkins, DJ, May, J, Mercereau-Puijalon, O, Alpers, M, Weinberg, JB, and Kremsner, PG. "Nitric oxide synthase 2(Lambaréné) (G-954C), increased nitric oxide production, and protection against malaria." J Infect Dis 184.3 (August 1, 2001): 330-336.
PMID
11443559
Source
pubmed
Published In
Journal of Infectious Diseases
Volume
184
Issue
3
Publish Date
2001
Start Page
330
End Page
336
DOI
10.1086/322037

Use of serum-free media to minimize apoptosis of chronic lymphocytic leukemia cells during in vitro culture.

Authors
Levesque, MC; O'Loughlin, CW; Weinberg, JB
MLA Citation
Levesque, MC, O'Loughlin, CW, and Weinberg, JB. "Use of serum-free media to minimize apoptosis of chronic lymphocytic leukemia cells during in vitro culture." Leukemia 15.8 (August 2001): 1305-1307. (Letter)
PMID
11480577
Source
pubmed
Published In
Leukemia
Volume
15
Issue
8
Publish Date
2001
Start Page
1305
End Page
1307

Mechanical stress and nitric oxide influence leukotriene production in cartilage.

Nitric oxide (NO) and leukotrienes regulate a variety of processes in joint tissues and are frequently elevated in arthritis. Mechanical stress can induce biochemical and functional changes in cartilage that may influence mediator production. To investigate the relationship between mechanical stress and the production of leukotriene B(4) (LTB(4)) and NO, explants of porcine articular cartilage were subjected to mechanical compression for 1 h followed by 23 h recovery in the presence or absence of the NOS2 inhibitor 1400W. Dynamic compression significantly increased LTB(4) and LOX protein production in the presence of 1400W. The induced LTB(4) was functional as evidenced by its ability to promote chemotaxis of RBL-2H3 cells expressing the LTB(4) receptor. Increased LOX protein but not LTB(4) occurred in response to compression alone. These findings provide a direct link between mechanical stress and inflammation in cartilage and may have implications in the pathogenesis and treatment of arthritis.

Authors
Fermor, B; Haribabu, B; Weinberg, JB; Pisetsky, DS; Guilak, F
MLA Citation
Fermor, B, Haribabu, B, Weinberg, JB, Pisetsky, DS, and Guilak, F. "Mechanical stress and nitric oxide influence leukotriene production in cartilage." Biochem Biophys Res Commun 285.3 (July 20, 2001): 806-810.
PMID
11453664
Source
pubmed
Published In
Biochemical and Biophysical Research Communications
Volume
285
Issue
3
Publish Date
2001
Start Page
806
End Page
810
DOI
10.1006/bbrc.2001.5237

The effects of static and intermittent compression on nitric oxide production in articular cartilage explants.

Nitric oxide (NO) production and NO synthase (NOS) expression are increased in osteoarthritis and rheumatoid arthritis, suggesting that NO may play a role in the destruction of articular cartilage. To test the hypothesis that mechanical stress may increase NO production by chondrocytes, we measured the effects of physiological levels of static and intermittent compression on NOS activity, NO production, and NOS antigen expression by porcine articular cartilage explants. Static compression significantly increased NO production at 0.1 MPa stress for 24 h (P < 0.05). Intermittent compression at 0.5 Hz for 6 h followed by 18 h recovery also increased NO production and NOS activity at 1.0 MPa stress (P < 0.05). Intermittent compression at 0.5 Hz for 24 h at a magnitude of 0.1 or 0.5 MPa caused an increase in NO production and NOS activity (P < 0.05). Immunoblot analysis showed stress-induced upregulation of NOS2, but not NOS1 or NOS3. There was no loss in cell viability following any of the loading regimens. Addition of 2 mM 1400 W (a specific NOS2 inhibitor) reduced NO production by 51% with no loss of cell viability. These findings indicate that NO production by chondrocytes is influenced by mechanical compression in vitro and suggest that biomechanical factors may in part regulate NO production in vivo.

Authors
Fermor, B; Weinberg, JB; Pisetsky, DS; Misukonis, MA; Banes, AJ; Guilak, F
MLA Citation
Fermor, B, Weinberg, JB, Pisetsky, DS, Misukonis, MA, Banes, AJ, and Guilak, F. "The effects of static and intermittent compression on nitric oxide production in articular cartilage explants." J Orthop Res 19.4 (July 2001): 729-737.
PMID
11518285
Source
pubmed
Published In
Journal of Orthopaedic Research
Volume
19
Issue
4
Publish Date
2001
Start Page
729
End Page
737
DOI
10.1016/S0736-0266(00)00049-8

The effect of dynamic mechanical compression on nitric oxide production in the meniscus.

OBJECTIVE: The menisci play an important role in the biomechanics of the knee, and loss of meniscal function has been associated with progressive degenerative changes of the joint in rheumatoid arthritis as well as in osteoarthritis. However, little is known about the underlying mechanisms that link meniscal injury or degeneration to arthritis. Meniscal fibrochondrocytes respond to environmental mediators such as growth factors and cytokines, but the influence of mechanical stress on their metabolic activity is not well understood. Nitric oxide (NO) is believed to play a role in mechanical signal transduction, and there is also significant evidence of its role in cartilage and meniscus degeneration. The goal of this study was to determine if meniscal fibrochondrocytes respond to mechanical stress by increasing NO production in vitro. DESIGN: Explants of lateral and medial porcine menisci were dynamically compressed in a precisely controlled manner, and NO production, nitric oxide synthase antigen expression and cell viability were measured. The relative responses of the meniscal surface and deep layers to dynamic compression were also investigated separately. RESULTS: Meniscal NO production was significantly (P< 0.01) increased by dynamic compression in both the medial and lateral menisci. Dynamically compressed menisci contained inducible nitric oxide synthase antigen, while uncompressed menisci did not. Significant (P< 0.05) zonal differences were observed in basal and compression-induced NO production. DISCUSSION: Our findings provide direct evidence that dynamic mechanical stress influences the biological activity of meniscal cells. These results suggest that NO production in vivo may be in part regulated by mechanical stress acting upon the menisci. Since NO affects matrix metabolism in various intraarticular tissues, alterations in the distribution and magnitude of stress in the menisci may have important metabolic as well as biomechanical consequences on joint physiology and function.

Authors
Fink, C; Fermor, B; Weinberg, JB; Pisetsky, DS; Misukonis, MA; Guilak, F
MLA Citation
Fink, C, Fermor, B, Weinberg, JB, Pisetsky, DS, Misukonis, MA, and Guilak, F. "The effect of dynamic mechanical compression on nitric oxide production in the meniscus." Osteoarthritis Cartilage 9.5 (July 2001): 481-487.
PMID
11467897
Source
pubmed
Published In
Osteoarthritis and Cartilage
Volume
9
Issue
5
Publish Date
2001
Start Page
481
End Page
487
DOI
10.1053/joca.2001.0415

Loco-regional overexpression of nitric oxide synthase (NOS) in inflamed joints of HTLV-1 tax transgenic mice with inflammatory arthritis.

Authors
Liao, HX; Misukonis, MA; Thomasch, JR; Lapple, DM; Weinberg, JB
MLA Citation
Liao, HX, Misukonis, MA, Thomasch, JR, Lapple, DM, and Weinberg, JB. "Loco-regional overexpression of nitric oxide synthase (NOS) in inflamed joints of HTLV-1 tax transgenic mice with inflammatory arthritis." FASEB JOURNAL 15.5 (March 8, 2001): A1060-A1060.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
15
Issue
5
Publish Date
2001
Start Page
A1060
End Page
A1060

Modulation of nitric oxide synthase and cyclooxygenase 2 by CpG DNA in murine macrophages

Authors
Ghosh, DK; Misukonis, M; Mast, M; Reigh, C; Pisetsky, D; Weinberg, JB
MLA Citation
Ghosh, DK, Misukonis, M, Mast, M, Reigh, C, Pisetsky, D, and Weinberg, JB. "Modulation of nitric oxide synthase and cyclooxygenase 2 by CpG DNA in murine macrophages." FASEB JOURNAL 15.4 (March 7, 2001): A200-A200.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
15
Issue
4
Publish Date
2001
Start Page
A200
End Page
A200

Characterization of key residues in the region encoded by exons 8-9 of human inducible nitric oxide synthase: Asp280 is critical for substrate binding and subunit interactions

Authors
Ghosh, DK; Rashid, MB; Crane, B; Taskar, V; Mast, M; Misukonis, M; Weinberg, JB; Eissa, NT
MLA Citation
Ghosh, DK, Rashid, MB, Crane, B, Taskar, V, Mast, M, Misukonis, M, Weinberg, JB, and Eissa, NT. "Characterization of key residues in the region encoded by exons 8-9 of human inducible nitric oxide synthase: Asp280 is critical for substrate binding and subunit interactions." FASEB JOURNAL 15.4 (March 7, 2001): A536-A536.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
15
Issue
4
Publish Date
2001
Start Page
A536
End Page
A536

Inverse relationship of plasma prostaglandin E2 and blood mononuclear cell cyclooxygenase-2 with disease severity in children with Plasmodium falciparum malaria.

Prostaglandins (PGs) derived from inducible cyclooxygenase (COX)-2 are important proinflammatory mediators of the host-immune response to infection. Since the role of host-derived PG in human malaria is unknown, plasma bicyclo-PGE2 (a stable catabolite of PGE2), peripheral blood mononuclear cell COX-2 protein, and mRNA were measured in Gabonese children with and without malaria (n=129). Relative to healthy children, bicyclo-PGE2 and COX-2 protein were lower in children with mild (P=.007 and P=.026, respectively) and severe malaria (P=.002 and P=.010, respectively). COX-2 mRNA was also reduced in children with malaria. Investigation of COX-2 regulatory cytokines revealed an inverse correlation (P<.001) between plasma levels of bicyclo-PGE2 and interleukin (IL)-10, a cytokine that suppresses COX-2 expression. On the basis of these results, elevated PGE2 in healthy malaria-exposed children may protect against malaria, whereas IL-10-induced decreases in PGE2 during acute malaria may increase susceptibility to severe disease.

Authors
Perkins, DJ; Kremsner, PG; Weinberg, JB
MLA Citation
Perkins, DJ, Kremsner, PG, and Weinberg, JB. "Inverse relationship of plasma prostaglandin E2 and blood mononuclear cell cyclooxygenase-2 with disease severity in children with Plasmodium falciparum malaria." J Infect Dis 183.1 (January 1, 2001): 113-118.
PMID
11076710
Source
pubmed
Published In
Journal of Infectious Diseases
Volume
183
Issue
1
Publish Date
2001
Start Page
113
End Page
118
DOI
10.1086/317660

A review of polymorphisms in the human gene for inducible nitric oxide synthase (NOS2) in patients with malaria

Significant variability exists in host responses to malaria in different human populations. These epidemiological data have prompted a search for genetic variations that determine host responses to malaria. This review focuses on polymorphisms in the promoter region of inducible nitric oxide synthase (NOS2) as a source of genetic differences in the response of patients to infection with malaria. Nitric oxide (NO), a lipid soluble free radical, mediates host resistance to infectious organisms including parasites. NO is produced by three different NO synthases (NOS) in humans. Research on NO and malaria has focused on the cytokine inducible isoform of NOS (NOS2). The role of NO in host responses to infection and inflammation is likely to be both detrimental and beneficial to the host; this is reflected by the effects of NO on different host tissues and on parasite viability. Therefore, studies of the regulation of NOS2 transcription by different human cell types are important to gain a better understanding of the effects of malaria infection on different host tissues. Several important transcription factor binding sites in the NOS2 promoter region have been identified and represent potential sites of genetic heterogeneity in NOS2 transcription during malaria infection. Furthermore, a variety of studies have been performed to determine the role of NO in the pathogenesis of malaria in humans. Taken together, these studies suggest that high systemic NO production is associated with milder disease and increased parasite clearance while impaired systemic NO production (but increased central nervous system NOS2 expression) is associated with cerebral malaria. There are several possible mechanisms that might explain differences in NO production in malaria patients including functional polymorphisms in the promoter region of NOS2. To date, two NOS2 promoter polymorphisms, G-954C and a CCTTT microsatellite repeat, have been identified, and are associated with disease severity in populations of African patients with malaria. The relationship of these polymorphisms to malaria disease severity in other populations remains controversial and is the subject of ongoing studies. Likewise, the functional significance (relative to NO production) of these polymorphisms is unknown. Therefore, future studies will be necessary to determine whether other polymorphisms in the NOS2 gene are associated with malaria disease severity and to determine the functional effects of these polymorphisms on malaria disease severity and NOS2 transcription.

Authors
Levesque, MC; Hobbs, MR; Anstey, NM; Chancellor, JA; Misukonis, MAM; Granger, DL; Weinberg, JB
MLA Citation
Levesque, MC, Hobbs, MR, Anstey, NM, Chancellor, JA, Misukonis, MAM, Granger, DL, and Weinberg, JB. "A review of polymorphisms in the human gene for inducible nitric oxide synthase (NOS2) in patients with malaria." Sepsis 4.3 (2001): 217-231.
Source
scival
Published In
Sepsis
Volume
4
Issue
3
Publish Date
2001
Start Page
217
End Page
231
DOI
10.1023/A:1012913023602

Nitric oxide as a nonprotein regulator of hematopoietic cell proliferation and differentiation-relationship to malarial anemia.

Authors
Weinberg, JB; Perkins, DJ; Granger, DL; Kremsner, PG; Anstey, NM
MLA Citation
Weinberg, JB, Perkins, DJ, Granger, DL, Kremsner, PG, and Anstey, NM. "Nitric oxide as a nonprotein regulator of hematopoietic cell proliferation and differentiation-relationship to malarial anemia." BLOOD 96.11 (November 16, 2000): 14B-14B.
Source
wos-lite
Published In
Blood
Volume
96
Issue
11
Publish Date
2000
Start Page
14B
End Page
14B

Use of serum-free media to minimize apoptosis of chronic lymphocytic leukemia cells during in vitro culture.

Authors
Levesque, MC; O'Loughlin, CW; Weinberg, JB
MLA Citation
Levesque, MC, O'Loughlin, CW, and Weinberg, JB. "Use of serum-free media to minimize apoptosis of chronic lymphocytic leukemia cells during in vitro culture." BLOOD 96.11 (November 16, 2000): 754A-754A.
Source
wos-lite
Published In
Blood
Volume
96
Issue
11
Publish Date
2000
Start Page
754A
End Page
754A

Inverse relationship of plasma prostaglandin-E-2 and blood mononuclear cell cyclooxygenase-2 with disease severity in children with Plasmodium falciparum malaria.

Authors
Perkins, DJ; Weinberg, JB; Kremsner, PG
MLA Citation
Perkins, DJ, Weinberg, JB, and Kremsner, PG. "Inverse relationship of plasma prostaglandin-E-2 and blood mononuclear cell cyclooxygenase-2 with disease severity in children with Plasmodium falciparum malaria." BLOOD 96.11 (November 16, 2000): 31B-31B.
Source
wos-lite
Published In
Blood
Volume
96
Issue
11
Publish Date
2000
Start Page
31B
End Page
31B

Cytokine regulation of inducible nitric oxide synthase (NOS2) and NOS2 inhibitor-induced apoptosis and death in chronic lymphocytic leukemia cells.

Authors
Levesque, MC; Misukonis, MA; O'Loughlin, CW; Wilson, DL; Adams, DJ; Silber, R; Weinberg, JB
MLA Citation
Levesque, MC, Misukonis, MA, O'Loughlin, CW, Wilson, DL, Adams, DJ, Silber, R, and Weinberg, JB. "Cytokine regulation of inducible nitric oxide synthase (NOS2) and NOS2 inhibitor-induced apoptosis and death in chronic lymphocytic leukemia cells." BLOOD 96.11 (November 16, 2000): 159A-159A.
Source
wos-lite
Published In
Blood
Volume
96
Issue
11
Publish Date
2000
Start Page
159A
End Page
159A

Peroxynitrite formation and decreased catalase activity in autoimmune MRL-lpr/lpr mice.

BACKGROUND: (MRL)-lpr/lpr mice spontaneously develop autoimmune disease characterized by arthritis and glomerulonephritis. Nitric oxide is postulated to play a role in the disease pathogenesis, as mice treated with the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine (NMMA) show markedly reduced manifestations of the disease. The purpose of this study was to examine the role of peroxynitrite in disease development in MRL-lpr/lpr mice. MATERIALS AND METHODS: We examined kidney extracts from control and MRL-lpr/lpr mice for nitrotyrosine by immunoblot with a rabbit polyclonal anti-nitrotyrosine antibody. Catalase activity was determined spectrophotometrically or by activity staining of native polyacrylamide gels. In some experiments, we studied the ability of peroxynitrite and other agents to modify purified catalase in vitro. RESULTS: Kidney extracts from diseased mice had elevated levels of nitrotyrosine, and decreased levels of catalase activity and protein, relative to control mice. MRL-lpr/lpr mice treated with NMMA in vivo had decreased levels of nitrotyrosine, and demonstrated a partial restoration of both catalase activity and protein levels. Treatment of catalase in vitro with peroxynitrite or tetranitromethane at pH 8.0 resulted in protein nitration and a decrease in catalase activity. 1,3-morpholinosydnonimine (SIN-1), a peroxynitrite generator, also decreased the activity of catalase. CONCLUSIONS: These observations suggest that peroxynitrite formation, with an associated decrease in catalase activity and general decrease in antioxidant enzyme activity, may result in increased levels of hydrogen peroxide and other oxidants that can contribute to the pathogenesis of disease in MRL-lpr/lpr mice.

Authors
Keng, T; Privalle, CT; Gilkeson, GS; Weinberg, JB
MLA Citation
Keng, T, Privalle, CT, Gilkeson, GS, and Weinberg, JB. "Peroxynitrite formation and decreased catalase activity in autoimmune MRL-lpr/lpr mice." Mol Med 6.9 (September 2000): 779-792.
PMID
11071272
Source
pubmed
Published In
Molecular medicine (Cambridge, Mass.)
Volume
6
Issue
9
Publish Date
2000
Start Page
779
End Page
792

Reduced interleukin-12 and transforming growth factor-beta1 in severe childhood malaria: relationship of cytokine balance with disease severity.

Interleukin (IL)-12 and transforming growth factor (TGF)-beta1 regulate the balance between pro- and anti-inflammatory cytokines in animal models of malaria. Since the cytokine balance may be an important determinant of whether a protective or a pathogenic immune response develops, plasma cytokine ratios were examined in Gabonese children with various degrees of malarial severity. Severe disease was characterized by high-density parasitemia and severe anemia. IL-12 and TGF-beta1 were significantly lower, whereas tumor necrosis factor (TNF)-alpha and IL-10 were significantly higher in children with severe malaria. The ratios of TGF-beta1/IL-12 and IL-10/IL-12 were significantly higher in the severe, compared with the mild, malaria group. In contrast, ratios of TGF-beta1/TNF-alpha and IL-10/TNF-alpha were significantly lower in the severe malaria group. These results suggest that the inflammatory cascade in severe malaria is characterized by suppression of the protective effects of TGF-beta1 and IL-12, and that overproduction of TNF-alpha may promote deleterious effects, such as severe anemia.

Authors
Perkins, DJ; Weinberg, JB; Kremsner, PG
MLA Citation
Perkins, DJ, Weinberg, JB, and Kremsner, PG. "Reduced interleukin-12 and transforming growth factor-beta1 in severe childhood malaria: relationship of cytokine balance with disease severity." J Infect Dis 182.3 (September 2000): 988-992.
PMID
10950804
Source
pubmed
Published In
Journal of Infectious Diseases
Volume
182
Issue
3
Publish Date
2000
Start Page
988
End Page
992
DOI
10.1086/315762

Interferon-beta 1a-induced juvenile chronic arthritis in a genetically predisposed young patient with multiple sclerosis: comment on the case report by Levesque et al - Reply

Authors
Levesque, MC; Ward, FE; Jeffery, DR; Weinberg, JB
MLA Citation
Levesque, MC, Ward, FE, Jeffery, DR, and Weinberg, JB. "Interferon-beta 1a-induced juvenile chronic arthritis in a genetically predisposed young patient with multiple sclerosis: comment on the case report by Levesque et al - Reply." ARTHRITIS AND RHEUMATISM 43.5 (May 2000): 1190-1190.
Source
wos-lite
Published In
Arthritis and Rheumatism
Volume
43
Issue
5
Publish Date
2000
Start Page
1190
End Page
1190
DOI
10.1002/1529-0131(200005)43:5<1190::AID-ANR38>3.0.CO;2-9

Nitric oxide synthase 2 and cyclooxygenase 2 interactions in inflammation.

Nitric oxide (NO) and prostaglandin (PG) E2 produced by NO synthase type 2 (NOS2) and cyclooxygenase type 2 (COX2), respectively, are important mediators in inflammation. There is much information regarding their roles in models of inflammation in mice and in humans with diseases such as rheumatoid arthritis (RA). A variety of stimuli including cytokines, microbial components, immune complexes, and mechanical stress can induce both NOS2 and COX2 mRNA transcription and protein synthesis and enhance inflammation. This has been demonstrated in both mice and humans. NOS2-specific inhibitors reduce inflammation in mice, and COX2-specific inhibitors reduce inflammation in mice and in humans. There is significant cross-talk between PGE2/NO and COX2/NOS2. Treatments that inhibit both NOS2 and COX2 should provide the most potent antiinflammatory effects.

Authors
Weinberg, JB
MLA Citation
Weinberg, JB. "Nitric oxide synthase 2 and cyclooxygenase 2 interactions in inflammation." Immunol Res 22.2-3 (2000): 319-341. (Review)
PMID
11339365
Source
pubmed
Published In
Immunologic Research
Volume
22
Issue
2-3
Publish Date
2000
Start Page
319
End Page
341
DOI
10.1385/IR:22:2-3:319

Low interleukin-12 activity in severe Plasmodium falciparum malaria

We compared interleukin-12 (IL-12) and other cytokine activities during and after an acute clinical episode in a matched-pair case-control study of young African children who presented with either mild or severe Plasmodium falciparum malaria. The acute-phase, pretreatment plasma IL-12 and alpha interferon (IFN-α) levels, as well as the acute-phase mitogen-stimulated whole-blood production capacity of IL-12, were significantly lower in children with severe rather than mild malaria. IL-12 levels, in addition, showed strong inverse correlations both with parasitemia and with the numbers of circulating malaria pigment-containing neutrophils. Acute-phase plasma tumor necrosis factor (TNF) and IL-10 levels were significantly higher in those with severe malaria, and the concentrations of both of these cytokines were positively correlated both width parasitemia and with the numbers of pigment-containing phagocytes in the blood. Children with severe anemia had the highest levels of TNF in plasma. In all the children, the levels in plasma and production capacities of all cytokines normalized when they were healthy and parasite free. The results indicate that severe but not mild P. falciparum malaria in young, nonimmune African children is characterized by down-regulated IL-12 activity, contrasting markedly with the up-regulation of both TNF and IL-10 in the same children. A combination of disturbed phagocyte functions resulting from hemozoin consumption, along with reduced IFN-γ responses, may contribute to these differential effects.

Authors
Luty, AJF; Perkins, DJ; Lell, B; Schmidt-Ott, R; Lehman, LG; Luckner, D; Greve, B; Matousek, P; Herbich, K; Schmid, D; Weinberg, JB; Kremsner, PG
MLA Citation
Luty, AJF, Perkins, DJ, Lell, B, Schmidt-Ott, R, Lehman, LG, Luckner, D, Greve, B, Matousek, P, Herbich, K, Schmid, D, Weinberg, JB, and Kremsner, PG. "Low interleukin-12 activity in severe Plasmodium falciparum malaria." Infection and Immunity 68.7 (2000): 3909-3915.
PMID
10858202
Source
scival
Published In
Infection and Immunity
Volume
68
Issue
7
Publish Date
2000
Start Page
3909
End Page
3915
DOI
10.1128/IAI.68.7.3909-3915.2000

Inverse relationship of plasma prostaglandin-E2 and blood mononuclear cell cyclooxygenase-2 with disease severity in children with plasmodium falciparum malaria

Prostaglandins (PG) derived from inducible cyclooxygenase (COX-2) are important pro-inflammatory mediators of the host-immune response to infection. Since the role of host-derived PG in human malaria is unknown, plasma bicyclo-PGE2 (a stable catabolite of PGE,), and peripheral blood mononuclear cell COX-2 protein and mRNA were measured in Gabonese children with and without malaria (N=129) (see table). Relative to healthy children (N=25), bicyclo-PGE2 and COX-2 protein were lower in children with mild [p=0.007 (N=54) and 0.026 (N=19), respectively] and severe malaria [p=0.002 (N=50) and 0.010 (N=15), respectivelyJ. None of the children had ingested aspirin, and results were not influenced by a history of acetaminophen ingestion. Measurement of PBMC COX-2 mRNA showed detectable mRNA in 4/4 healthy children, 1/4 with mild malaria, and 0/4 with severe malaria. Investigation of cytokines with the potential to regulate COX-2 expression showed that IFNy, TNFa, and IL-10 significantly increased in parallel with disease severity. While IFNv and TNFa did not significantly correlate with plasma bicyclo-PGE, levels of bicyclo-PGE, and IL-10 (a cytokine known to suppress COX-2 expression) were significantly inversely correlated (P<0.001). Host resistance to malaria is promoted by pro-inflammatory cytokines such as IL-12, IFNy, and TNFa, while antiinflammatory cytokines such as IL-10 and TGFβ counter-regulate the pro-inflammatory response and may reduce resistance to disease. COX-2 expression is generally increased by pro-inflammatory cytokines and suppressed by anti-inflammatory cytokines. Based on our results, we postulate that basal PGE2 levels in healthy malaria-exposed children protects against malaria, while the IL-10-induced decreases in PGE2 during acute malaria increase susceptibility to severe disease. Future studies of PG and COX-2 in malaria should provide valuable information about disease pathogenesis, and may provide insights into the development of new treatments for this global disease. Mild Malaria Severe Malaria p value Parasitemia/uL 2770.1±4568 333772±25025 <0.0001 Hb(gm/dL) I0.3±0.3 6.8±0.3 <0.0001 Temp (°C) 38.2±0.3 39.0±0.2 <0.001 Number 54 50.

Authors
Perkins, DJ; Weinberg, JB; Kremsner, PG
MLA Citation
Perkins, DJ, Weinberg, JB, and Kremsner, PG. "Inverse relationship of plasma prostaglandin-E2 and blood mononuclear cell cyclooxygenase-2 with disease severity in children with plasmodium falciparum malaria." Blood 96.11 PART II (2000): 31b-.
Source
scival
Published In
Blood
Volume
96
Issue
11 PART II
Publish Date
2000
Start Page
31b

Cytokine regulation of inducffile nitric oxide synthase (nos2) and nos2 inhibitor-induced apoptosis and death in chronic lymphocytic leukemia cells

Chronic lymphocytic leukemia (B-CLL) is a malignancy of a mantle zone-based subpopulation of anergic, self-reactive, activated CD5+ B lymphocytes devoted to the production of polyreactive natural autoantibodies. B-CLL is characterized by the accumulation of long-lived non-dividing CD5+ B cells in G0 of the cell cycle. Nitric oxide (NO) is an important regulator of apoptosis, and the viability of cultured B-CLL cells is dependent on the autocrine production of NO by NOS2. Inhibition of NOS2 induces BCLL cell apoptosis. The purpose of this study to determine whether cytokine factors that prevent spontaneous in vitro apoptosis of B-CLL cells induce B-CLL cell NOS2 enzyme activity and NO production and prevent NOS2 inhibitor-induced B-CLL cell apoptosis. Cells were from patients with CD5+ B-CLL with WBC20,000/uL; all had not received leukemia therapy within the last 4 weeks. Peripheral blood mononuclear cells (PBMC) were isolated from blood using ficoll-Hypaque, and T cells and monocytes were depleted using magnetic beads coupled with anti-CD2 and anti-CD 14 antibodies. The resultant cells were 90±2% CD5+/CD19+ and 3±2% CD5-/CD19+ (N=45). We found that B-CLL cells expressed NOS2 as determined by an enzyme assay (8 fold greater expression in BCLL cells than in normal PBMC), by immunoblot (0/12 positive for NOS2 in normal PBMC vs 12/15 positive in CLL), and by RT-PCR analysis (0/10 positive for NOS2 in normal PBMC vs 13/13 positive in B-CLL cells). IL-4 and IFNy significantly increased BCLL cell NOS2 enzyme activity and protein expression during in vitro culture. However. IFNct, nerve growth factor, IL-6, IL-2, IL-8, and G-CSF had no significant effects. We were unable to detect increased concentrations of nitrite or nitrate (surrogate markers of NO production) in B-CLL cell cultures treated with IL-4 or IFNy. IL-4 and IFNy significantly inhibited NOS2 B-CLL cell death and apoptosis induced by the NOS2-specific inhibitor L-N6-(!-iminoethyl)-lysine (L-NIL) or the nonspecific NOS inhibitor NG-monomethylL-arginine (NMMA). In summary, we found that B-CLL cells expressed NOS2, that IL4 and IFNy increased B-CLL NOS2 expression, and that IL-4 and IFNy prevented NOS2 inhibitor-induced B-CLL cell death and apoptosis. Expression of NOS2 by B-CLL cells may promote their survival. NOS2 and NO may represent new molecular targets in the treatment of B-CLL.

Authors
Levesque, MC; Misukonis, MA; O'Loughlin, CW; Wilson, DL; Adams, DJ; Silber, R; Weinberg, JB
MLA Citation
Levesque, MC, Misukonis, MA, O'Loughlin, CW, Wilson, DL, Adams, DJ, Silber, R, and Weinberg, JB. "Cytokine regulation of inducffile nitric oxide synthase (nos2) and nos2 inhibitor-induced apoptosis and death in chronic lymphocytic leukemia cells." Blood 96.11 PART I (2000): 159a-.
Source
scival
Published In
Blood
Volume
96
Issue
11 PART I
Publish Date
2000
Start Page
159a

Nitric oxide asa nonprotein regulator of hematopoietic cell proliferation and differentiation-relationship to malarial anemia

Malaria is extremely important, with approximately 500 million people infected and 1.5 to 2.7 million dying from the disease each year. Deaths are usually related to cerebral malaria and malarial anemia. Malarial anemia is a multifactorial anemia related to lysis of parasitized erythrocytes, hypersplenism, coexisting iron deficiency or chronic disease, and to erythroid hypoproliferation and dyserythropoiesis. Nitric oxide (NO), produced by NO synthase (NOS), plays an important role in resistance to infections (including malaria). We and others have noted that NO production is increased in children with mild P. falciparum infection (Anstey, et al. J Exp Med 184:557, 1996). NO has many actions, including inhibition of cell proliferation. We have noted that NO inhibits normal human bone marrow cell colony formation (erythroid > myeloid) (Shami & Weinberg. Blood 87:977, 1996). Also, Mabbot and Sternberg have found that NO is causally related to the anemia in Trypanozoma brucei-infected mice (Infect Immun 63:1563, 1995). The purpose of the current study was to determine if total body NO production (measured as urinary nitrite+nitrate:creatinine excretion ratios) and peripheral blood mononuclear cell (PBMC) NOS activity (measured as conversion of 14-C-labeled L-arginine to L-citrulline in vitro) in children with P. falciparum malaria correlate with the degree of anemia. African children from two areas were studied: the Muhimbili Medical Center in Dar es Salaam, Tanzania in eastern Africa, and the Albert Schweitzer Hospital in Lambarene, Gabon in central Africa. In asymptomatic malaria-exposed Tanzanian children, there was an inverse relationship between NO production and blood hemoglobin (r=-0.92; p=0.03; N=45). In Gabonese children with mild or severe P. falciparum malaria, PBMC NOS activity was 477±34 pmol L-citrulline/mg, and Hb was 8.4±0.6 gm/dL (N=17). This NOS level was high compared to normal US adults [30±7 (N=12)]. Gabonese PBMC NOS correlated inversely with Hb (r=-0.534; p=0.03; N=17). These results suggest that while NO may be important for host resistance to malaria, NO may also contribute to the anemia noted in malaria. Novel strategies are needed to prevent the deleterious effects of NO on bone marrow cells, while preserving the antimicrobial effects of NO on parasites.

Authors
Weinberg, JB; Perkins, DJ; Granger, DL; Kremsner, PG; Anstey, NM
MLA Citation
Weinberg, JB, Perkins, DJ, Granger, DL, Kremsner, PG, and Anstey, NM. "Nitric oxide asa nonprotein regulator of hematopoietic cell proliferation and differentiation-relationship to malarial anemia." Blood 96.11 PART II (2000): 14b-.
Source
scival
Published In
Blood
Volume
96
Issue
11 PART II
Publish Date
2000
Start Page
14b

Nitric oxide synthase type 2 promoter polymorphisms, nitric oxide production, and disease severity in Tanzanian children with malaria.

Nitric oxide (NO) plays an important role in host resistance to infection with a variety of organisms. Two recent reports from Gabon and Gambia identified associations of malaria disease severity with the inducible NO synthase (NOS2) promoter G-954C and short allele (<11 repeats) pentanucleotide microsatellite polymorphisms, respectively. It was postulated that there would be a correlation of these polymorphisms with malaria disease severity and with measures of NO production in our cohort of Tanzanian children with malaria. In Tanzanian children, 15% were heterozygous or homozygous for the G-954C polymorphism, and 13% had the short-allele microsatellite polymorphism. There was no significant correlation of either polymorphism with disease severity or with measures of NO production and NOS2 expression. Black and white Americans differed significantly in the frequencies of these polymorphisms. The various association of these gene polymorphisms with malaria severity in different populations underscores the complexity of host resistance to malaria.

Authors
Levesque, MC; Hobbs, MR; Anstey, NM; Vaughn, TN; Chancellor, JA; Pole, A; Perkins, DJ; Misukonis, MA; Chanock, SJ; Granger, DL; Weinberg, JB
MLA Citation
Levesque, MC, Hobbs, MR, Anstey, NM, Vaughn, TN, Chancellor, JA, Pole, A, Perkins, DJ, Misukonis, MA, Chanock, SJ, Granger, DL, and Weinberg, JB. "Nitric oxide synthase type 2 promoter polymorphisms, nitric oxide production, and disease severity in Tanzanian children with malaria." J Infect Dis 180.6 (December 1999): 1994-2002.
PMID
10558957
Source
pubmed
Published In
Journal of Infectious Diseases
Volume
180
Issue
6
Publish Date
1999
Start Page
1994
End Page
2002
DOI
10.1086/315140

Inducible nitric oxide synthase (NOS2) inhibitors induce high level CLL cell apoptosis and death.

Authors
Levesque, MC; Misukonis, MA; Weinberg, JB
MLA Citation
Levesque, MC, Misukonis, MA, and Weinberg, JB. "Inducible nitric oxide synthase (NOS2) inhibitors induce high level CLL cell apoptosis and death." BLOOD 94.10 (November 15, 1999): 703A-703A.
Source
wos-lite
Published In
Blood
Volume
94
Issue
10
Publish Date
1999
Start Page
703A
End Page
703A

Blood mononuclear cell nitric oxide production and plasma cytokine levels in healthy gabonese children with prior mild or severe malaria.

Plasmodium falciparum malaria is an important cause of morbidity and mortality in children. Factors that determine the development of mild versus severe malaria are not fully understood. Since host-derived nitric oxide (NO) has antiplasmodial properties, we measured NO production and NO synthase (NOS) activity in peripheral blood mononuclear cells (PBMC) from healthy Gabonese children with a history of prior mild malaria (PMM) or prior severe malaria (PSM) caused by P. falciparum. The PMM group had significantly higher levels of NOS activity in freshly isolated PBMC and higher NO production and NOS activity in cultured PBMC. The investigation of NO-modulating cytokines (e.g., interleukin 12, gamma interferon, tumor necrosis factor alpha [TNF-alpha], and transforming growth factor beta1) as an explanation for differing levels of NOS activity revealed that plasma levels of TNF-alpha were significantly higher in the PSM group. Our results suggest that NOS/ NO and TNF-alpha are markers for prior disease severity and important determinants of resistance to malaria.

Authors
Perkins, DJ; Kremsner, PG; Schmid, D; Misukonis, MA; Kelly, MA; Weinberg, JB
MLA Citation
Perkins, DJ, Kremsner, PG, Schmid, D, Misukonis, MA, Kelly, MA, and Weinberg, JB. "Blood mononuclear cell nitric oxide production and plasma cytokine levels in healthy gabonese children with prior mild or severe malaria." Infect Immun 67.9 (September 1999): 4977-4981.
PMID
10456963
Source
pubmed
Published In
Infection and immunity
Volume
67
Issue
9
Publish Date
1999
Start Page
4977
End Page
4981

Nitric oxide, malaria, and anemia: inverse relationship between nitric oxide production and hemoglobin concentration in asymptomatic, malaria-exposed children.

The cause of the anemia associated with chronic, intermittent, asymptomatic, low-level parasitemia in children in malaria-endemic endemic areas is not well understood. Nitric oxide (NO) decreases erythropoiesis, and it is likely an important mediator of anemia of chronic disease. Production of NO is decreased in acute uncomplicated and cerebral malaria, but it is increased in asymptomatic Tanzanian children (with or without parasitemia). We hypothesized that chronic overproduction of NO in these asymptomatic children contributes to the anemia associated with subclinical/subpatent malaria. In 44 fasting, asymptomatic, malaria-exposed, Tanzanian children, NO production (measured using fasting urine NOx excretion) was inversely associated with hemoglobin concentration (P = 0.03, controlling for age and gender). Using multiple linear regression, hemoglobin concentration was negatively associated with parasitemia (P = 0.005). After controlling for age and parasitemia, NO was no longer an independent predictor of anemia. One of the mechanisms of parasite-related anemia in such children may be through the adverse hematologic effects of parasite-induced NO production.

Authors
Anstey, NM; Granger, DL; Hassanali, MY; Mwaikambo, ED; Duffy, PE; Weinberg, JB
MLA Citation
Anstey, NM, Granger, DL, Hassanali, MY, Mwaikambo, ED, Duffy, PE, and Weinberg, JB. "Nitric oxide, malaria, and anemia: inverse relationship between nitric oxide production and hemoglobin concentration in asymptomatic, malaria-exposed children." Am J Trop Med Hyg 61.2 (August 1999): 249-252.
PMID
10463675
Source
pubmed
Published In
American Journal of Tropical Medicine and Hygiene
Volume
61
Issue
2
Publish Date
1999
Start Page
249
End Page
252

Effects of age and parasitemia on nitric oxide production/leukocyte nitric oxide synthase type 2 expression in asymptomatic, malaria-exposed children.

Age appears to influence not only the acquisition of clinical immunity to malaria but also the susceptibility to and clinical manifestations of severe malaria. Asymptomatic malaria-exposed Tanzanian children have high production of nitric oxide (NO) and universal expression of leukocyte NO synthase type 2 (NOS2), which may protect against disease. To determine the effects of age and parasitemia on NO production, we measured urine and plasma NO metabolites and leukocyte NOS2 expression in 45 fasting, asymptomatic, malaria-exposed children of different ages, stratifying parasitemia by thick film and polymerase chain reaction (PCR) analysis. Although NO production was significantly higher in thick film-positive children than in thick film-negative children, after adjusting for age and gender, we were unable to detect a difference in NO production in thick film-negative children between those who were PCR positive and PCR negative. The relationship between age and NO production was determined using a generalized additive model adjusted for the effects of gender and parasitemia. Production of NO using all three measures was highest in infancy, decreasing after the first year of life, and then increasing again after 5 years of age. This pattern of age-related NO production is the reverse of the pattern of age-related morbidity from cerebral malaria in coastal Tanzanian children. Elevated production of NO in both infants and older children may be related to age per se and malaria infection respectively, and may be one of the mediators of the anti-disease immunity found most commonly in these two age groups.

Authors
Anstey, NM; Weinberg, JB; Wang, Z; Mwaikambo, ED; Duffy, PE; Granger, DL
MLA Citation
Anstey, NM, Weinberg, JB, Wang, Z, Mwaikambo, ED, Duffy, PE, and Granger, DL. "Effects of age and parasitemia on nitric oxide production/leukocyte nitric oxide synthase type 2 expression in asymptomatic, malaria-exposed children." Am J Trop Med Hyg 61.2 (August 1999): 253-258.
PMID
10463676
Source
pubmed
Published In
American Journal of Tropical Medicine and Hygiene
Volume
61
Issue
2
Publish Date
1999
Start Page
253
End Page
258

Interferon-beta1A-induced polyarthritis in a patient with the HLA-DRB1*0404 allele.

Human interferon-alpha (IFNalpha) and IFNbeta are administered for treatment of several diseases, including viral infections, malignancies, and multiple sclerosis (MS). IFNalpha therapy has been associated with the production of autoantibodies and the development of a variety of autoimmune disorders, including polyarthritis. This report describes the development of seronegative, symmetric polyarthritis in a patient with relapsing-remitting MS, after 8 weeks of therapy with IFNbeta1a. HLA phenotyping analysis of the patient revealed the presence of HLA-DRB1*0404, an allele known to be associated with the development of rheumatoid arthritis. Therefore, IFNbeta1a may have induced arthritis in a patient who was genetically predisposed to develop arthritis on the basis of HLA determinants. The English-language literature regarding IFNalpha- and IFNbeta-induced polyarthritis is reviewed, and possible mechanisms for IFNalpha- and IFNbeta-induced autoimmunity, including the contribution of HLA determinants and nitric oxide overproduction, are discussed.

Authors
Levesque, MC; Ward, FE; Jeffery, DR; Weinberg, JB
MLA Citation
Levesque, MC, Ward, FE, Jeffery, DR, and Weinberg, JB. "Interferon-beta1A-induced polyarthritis in a patient with the HLA-DRB1*0404 allele." Arthritis Rheum 42.3 (March 1999): 569-573. (Review)
PMID
10088781
Source
pubmed
Published In
Arthritis and Rheumatism
Volume
42
Issue
3
Publish Date
1999
Start Page
569
End Page
573
DOI
10.1002/1529-0131(199904)42:3<569::AID-ANR23>3.0.CO;2-M

Measuring nitric oxide production in human clinical studies.

Authors
Granger, DL; Anstey, NM; Miller, WC; Weinberg, JB
MLA Citation
Granger, DL, Anstey, NM, Miller, WC, and Weinberg, JB. "Measuring nitric oxide production in human clinical studies." Methods Enzymol 301 (1999): 49-61. (Review)
PMID
9919553
Source
pubmed
Published In
Methods in Enzymology
Volume
301
Publish Date
1999
Start Page
49
End Page
61

Reduction of NOS2 overexpression in rheumatoid arthritis patients treated with anti-tumor necrosis factor alpha monoclonal antibody (cA2).

OBJECTIVE: Peripheral blood mononuclear cells (PBMC) from patients with rheumatoid arthritis (RA) have increased expression of nitric oxide synthase type 2 (NOS2) protein and enhanced formation of nitric oxide (NO) that correlate with disease activity. NO may play a role in the inflammation of RA. Treatment of RA patients with a chimeric monoclonal antibody against tumor necrosis factor alpha (TNFalpha; cA2) results in clinical improvement in the majority of patients. The present study was designed to determine if cA2 therapy decreases PBMC NOS2 protein expression and NOS enzyme activity in RA patients. METHODS: RA patients receiving background oral methotrexate participated in a double-blind, placebo-controlled clinical trial in which they were randomly assigned to receive a single infusion of either placebo or cA2 at 5, 10, or 20 mg/kg. NOS2 protein and NOS enzyme activity were measured in PBMC at baseline and 4 weeks following cA2 therapy. These results were compared with the degree of clinical change in disease activity. RESULTS: At baseline, elevated levels of NOS2 protein and NOS enzyme activity were more frequently detected in PBMC from RA patients than in those from healthy controls. Treatment of the RA patients with cA2 significantly reduced NOS2 protein expression and NOS enzyme activity. Changes in NOS activity following treatment correlated significantly with changes in the number of tender joints. CONCLUSION: These results indicate that TNFalpha likely plays an important role in enhancing NOS2 expression in RA, and that the antiinflammatory effects of cA2 treatment may be mediated by a reduction of NO overproduction.

Authors
Perkins, DJ; St Clair, EW; Misukonis, MA; Weinberg, JB
MLA Citation
Perkins, DJ, St Clair, EW, Misukonis, MA, and Weinberg, JB. "Reduction of NOS2 overexpression in rheumatoid arthritis patients treated with anti-tumor necrosis factor alpha monoclonal antibody (cA2)." Arthritis Rheum 41.12 (December 1998): 2205-2210.
PMID
9870877
Source
pubmed
Published In
Arthritis and Rheumatism
Volume
41
Issue
12
Publish Date
1998
Start Page
2205
End Page
2210
DOI
10.1002/1529-0131(199812)41:12<2205::AID-ART16>3.0.CO;2-Q

Enhanced fludarabine cytotoxicity in B-CLL lymphocytes by combination with nitric oxide donors or doxorubicin.

Authors
Adams, DJ; Levesque, MC; Misukonis, MA; Weinberg, JB; Flowers, JL; Colvin, OM; Silber, R
MLA Citation
Adams, DJ, Levesque, MC, Misukonis, MA, Weinberg, JB, Flowers, JL, Colvin, OM, and Silber, R. "Enhanced fludarabine cytotoxicity in B-CLL lymphocytes by combination with nitric oxide donors or doxorubicin." BLOOD 92.10 (November 15, 1998): 596A-596A.
Source
wos-lite
Published In
Blood
Volume
92
Issue
10
Publish Date
1998
Start Page
596A
End Page
596A

Detection of inducible nitric oxide synthase (NOS2) mRNA, antigen and enzyme activity in leukemia cells from patients with CLL.

Authors
Levesque, MC; Adams, DJ; Misukonis, MA; Flowers, J; Silber, R; Weinberg, JB
MLA Citation
Levesque, MC, Adams, DJ, Misukonis, MA, Flowers, J, Silber, R, and Weinberg, JB. "Detection of inducible nitric oxide synthase (NOS2) mRNA, antigen and enzyme activity in leukemia cells from patients with CLL." BLOOD 92.10 (November 15, 1998): 431A-431A.
Source
wos-lite
Published In
Blood
Volume
92
Issue
10
Publish Date
1998
Start Page
431A
End Page
431A

Nitric oxide as an inflammatory mediator in autoimmune MRL-lpr/lpr mice.

Nitric oxide (.NO) may exhibit proinflammatory features. .NO synthase type 2 (NOS2) is overexpressed and .NO overproduced in rodent models of induced inflammation. Blockage of .NO production by administration of NOS inhibitors prevents or reduces various types of induced inflammation in mice and rats. We have shown that autoimmune MRL-lpr/lpr mice overexpress NOS2 and overproduce .NO in an age-dependent fashion that parallels expression of arthritis, glomerulonephritis, and vasculitis. Blocking .NO production by oral administration of the NOS inhibitor NG-monomethyl-L-arginine reduced the arthritis, glomerulonephritis, and vasculitis, but it did not modify serum anti-DNA antibody levels or glomerular deposition of immune complexes. When mice with genetically disrupted NOS2 were backcrossed to MRL-lpr/lpr mice, the resultant (-/-) mice expressed no NOS2 and produced no .NO, the wild-type (+/+) mice overexpressed NOS2 and overproduced .NO (in comparison to normal, control mice), and the heterozygous (+/-) mice expressed and produced intermediate levels. Nephritis and arthritis in the (-/-) mice were comparable to that in MRL-lpr/lpr mice, but vasculitis was markedly decreased. Levels of anti-DNA antibodies were comparable in all mice, but IgG rheumatoid factor production was markedly reduced in the (-/-) mice. These results of studies in MRL-lpr/lpr mice with genetically disrupted NOS2 highlight the heterogeneity and complexity of the role of NOS2 and .NO in inflammation.

Authors
Weinberg, JB
MLA Citation
Weinberg, JB. "Nitric oxide as an inflammatory mediator in autoimmune MRL-lpr/lpr mice." Environ Health Perspect 106 Suppl 5 (October 1998): 1131-1137. (Review)
PMID
9788887
Source
pubmed
Published In
Environmental health perspectives
Volume
106 Suppl 5
Publish Date
1998
Start Page
1131
End Page
1137

Nitric oxide production and nitric oxide synthase type 2 expression by human mononuclear phagocytes: a review.

Authors
Weinberg, JB
MLA Citation
Weinberg, JB. "Nitric oxide production and nitric oxide synthase type 2 expression by human mononuclear phagocytes: a review." Mol Med 4.9 (September 1998): 557-591. (Review)
PMID
9848075
Source
pubmed
Published In
Molecular medicine (Cambridge, Mass.)
Volume
4
Issue
9
Publish Date
1998
Start Page
557
End Page
591

Schedule and concentration-dependent induction of apoptosis in leukemia cells by nitric oxide.

Nitric oxide (NO) has potent antiproliferative properties. In previous work we have shown that NO inhibits growth, induces differentiation and modulates gene expression in acute nonlymphocytic leukemia (ANLL) cells. The goal of this work was to determine whether the rate of NO delivery affected its growth inhibition of ANLL cells. We also wanted to determine whether the NO inhibition of ANLL cell growth is associated with the induction of apoptosis. We treated HL-60 and U937 cells with three compounds that generate the same amount of NO but at different rates. MAMA-NO, PAPA-NO and DETA-NO have half-lives of NO delivery of 2 and 30 min, and 20 h, respectively. The compound with the longest t(1/2) of NO delivery (DETA-NO) was the most potent inhibitor of leukemia cell and colony growth. Furthermore, the NO-induced growth inhibition was associated with apoptosis in a rate and concentration-dependent fashion.

Authors
Shami, PJ; Sauls, DL; Weinberg, JB
MLA Citation
Shami, PJ, Sauls, DL, and Weinberg, JB. "Schedule and concentration-dependent induction of apoptosis in leukemia cells by nitric oxide." Leukemia 12.9 (September 1998): 1461-1466.
PMID
9737697
Source
pubmed
Published In
Leukemia
Volume
12
Issue
9
Publish Date
1998
Start Page
1461
End Page
1466

Sulfasalazine, sulfapyridine, and 5-aminosalicyclic acid decrease prostaglandin production and nitric oxide synthase activity in Ex vivo cultures of peripheral blood mononuclear cells from patients with rheumatoid arthritis.

Authors
Perkins, DJ; St Clair, EW; Kelly, MA; Misukonis, M; Sundy, JS; Pisetsky, DS; Weinberg, JB
MLA Citation
Perkins, DJ, St Clair, EW, Kelly, MA, Misukonis, M, Sundy, JS, Pisetsky, DS, and Weinberg, JB. "Sulfasalazine, sulfapyridine, and 5-aminosalicyclic acid decrease prostaglandin production and nitric oxide synthase activity in Ex vivo cultures of peripheral blood mononuclear cells from patients with rheumatoid arthritis." ARTHRITIS AND RHEUMATISM 41.9 (September 1998): S159-S159.
Source
wos-lite
Published In
Arthritis and Rheumatism
Volume
41
Issue
9
Publish Date
1998
Start Page
S159
End Page
S159

Normalization of NOS2 overexpression in rheumatoid arthritis patients treated with anti-TNF monoclonal antibody (cA2).

Authors
Perkins, DJ; St Clair, EW; Misukonis, MA; Weinberg, JB
MLA Citation
Perkins, DJ, St Clair, EW, Misukonis, MA, and Weinberg, JB. "Normalization of NOS2 overexpression in rheumatoid arthritis patients treated with anti-TNF monoclonal antibody (cA2)." ARTHRITIS AND RHEUMATISM 41.9 (September 1998): S58-S58.
Source
wos-lite
Published In
Arthritis and Rheumatism
Volume
41
Issue
9
Publish Date
1998
Start Page
S58
End Page
S58

Cobalamin inhibition of HIV-1 integrase and integration of HIV-1 DNA into cellular DNA.

Our prior studies showed that certain cobalamins inhibit productive HIV-1 infection of primary cultures of blood lymphocytes and monocytes. We demonstrate here that this antiviral activity may be mediated by an inhibition of HIV-1 integrase, an enzyme required for productive infection. Purified recombinant HIV-1 integrase activity was inhibited in vitro by hydroxocobalamin (OH-Cbl), methylcobalamin (Me-Cbl), adenosylcobalamin (Ado-Cbl), and dicyanocobinamide (CN2-Cbi) with IC50 values of approximately 17, 17, 17, and 4 microM, respectively. The agents inhibited HIV-1 infection of cultured monocytes (IC50 values for OH-Cbl, Me-Cbl, Ado-Cbl, and CN2-Cbi of 6, 7, 4, and 1 microM, respectively) and of cultured lymphocytes (IC50 values of 60, 50, 60, and 11 microM, respectively). Experiments using cultured monocytes or lymphocytes demonstrated that OH-Cbl inhibited integration of HIV-1 DNA into cellular DNA. Thus, cobalamins and cobinamides represent novel inhibitors of HIV-1 integrase. These or related agents may be useful as anti-viral treatments that target HIV-1 integrase.

Authors
Weinberg, JB; Shugars, DC; Sherman, PA; Sauls, DL; Fyfe, JA
MLA Citation
Weinberg, JB, Shugars, DC, Sherman, PA, Sauls, DL, and Fyfe, JA. "Cobalamin inhibition of HIV-1 integrase and integration of HIV-1 DNA into cellular DNA." Biochem Biophys Res Commun 246.2 (May 19, 1998): 393-397.
PMID
9610370
Source
pubmed
Published In
Biochemical and Biophysical Research Communications
Volume
246
Issue
2
Publish Date
1998
Start Page
393
End Page
397
DOI
10.1006/bbrc.1998.8629

Nitrosylation of blood hemoglobin and renal nonheme proteins in autoimmune MRL-lpr/lpr mice.

MRL-lpr/lpr mice spontaneously develop manifestations of autoimmunity including arthritis, vasculitis, and glomerulonephritis. The paramagnetic molecule nitric oxide has been implicated as an effector molecule in initiation and propagation of these inflammatory conditions. In this study, we utilized electron paramagnetic resonance spectroscopy to directly detect nitrosylated protein complexes as products of nitric oxide in whole blood and in kidneys of MRL-lpr/lpr mice. Electron paramagnetic resonance spectra of blood samples from MRL-lpr/lpr mice showed nitrosyl hemoglobin species. Amounts of blood nitrosyl hemoglobin in MRL-lpr/lpr mice were significantly increased as compared to age-matched control mice. Electron paramagnetic resonance spectra of MRL-lpr/lpr kidney tissue exhibited a signal characteristic of a dinitrosyl-iron-dithiolate complex at g approximately 2.04. Formation of nitrosylated nonheme protein in diseased kidneys is associated with development of glomerulonephritis in the autoimmune mice. The presence of nitrosylated nonheme protein indicates the formation of nitric oxide within the kidneys of the diseased mice signifying in situ renal nitric oxide formation.

Authors
Weinberg, JB; Gilkeson, GS; Mason, RP; Chamulitrat, W
MLA Citation
Weinberg, JB, Gilkeson, GS, Mason, RP, and Chamulitrat, W. "Nitrosylation of blood hemoglobin and renal nonheme proteins in autoimmune MRL-lpr/lpr mice." Free Radic Biol Med 24.1 (January 1, 1998): 191-196.
PMID
9436630
Source
pubmed
Published In
Free Radical Biology & Medicine
Volume
24
Issue
1
Publish Date
1998
Start Page
191
End Page
196

Acquired DNA mutations in adults with myeloproliferative disorders receiving hydroxyurea therapy.

Authors
Hanft, VN; Fruchtman, S; Heumayer, S; Weinberg, JB; Howard, TA; Ware, RE
MLA Citation
Hanft, VN, Fruchtman, S, Heumayer, S, Weinberg, JB, Howard, TA, and Ware, RE. "Acquired DNA mutations in adults with myeloproliferative disorders receiving hydroxyurea therapy." BLOOD 90.10 (November 15, 1997): 1542-1542.
Source
wos-lite
Published In
Blood
Volume
90
Issue
10
Publish Date
1997
Start Page
1542
End Page
1542

Interferon (IFN)-alpha activation of human blood mononuclear cells in vitro and in vivo for nitric oxide synthase (NOS) type 2 mRNA and protein expression: possible relationship of induced NOS2 to the anti-hepatitis C effects of IFN-alpha in vivo.

Although researchers have noted high level activation of rodent mononuclear phagocytes for nitric oxide (NO) synthase type 2 (S2) expression and NO production with a variety of agents such as interferon (IFN) gamma and endotoxin, it has been difficult to demonstrate activation of human mononuclear phagocytes. The purpose of this study was to determine if IFN-alpha serves as an activator in vitro and in vivo in humans. Treatment of normal monocytes or mononuclear cells in vitro with IFN-alpha caused a dose-dependent increase in monocyte NOS2 activity and NO production, and increased expression of NOS2 protein and mRNA expression. To determine if in vivo administration of IFN-alpha also modulated NOS2, we studied blood cells from patients with hepatitis C before and after IFN-alpha therapy. Untreated patients with chronic hepatitis C virus infection had levels of NOS activity and NOS2 antigen in freshly isolated mononuclear cells similar to those of healthy subjects, and they expressed minimal or no NOS2 mRNA. However, IFN-alpha treatment of patients with hepatitis C infection was associated with a significant elevation in mononuclear cell NOS activity, NOS2 antigen content, and NOS2 mRNA content. IFN-alpha-treated patients had significant decreases in levels of serum alanine aminotransferase and plasma hepatitis C mRNA. The degree of IFN-alpha-enhanced mononuclear cell NOS2 antigen content correlated significantly with the degree of reduction in serum alanine aminotransferase levels. Thus, IFN-alpha treatment of cells in vitro or administration of IFN-alpha to hepatitis C patients in vivo increases expression of mononuclear cell NOS2 mRNA expression, NOS activity, NOS2 antigen expression, and NO production. Since NO has been reported to have antiviral activity for a variety of viruses, we speculate that induced NO production may be related to the antiviral action(s) of IFN-alpha in hepatitis C infection.

Authors
Sharara, AI; Perkins, DJ; Misukonis, MA; Chan, SU; Dominitz, JA; Weinberg, JB
MLA Citation
Sharara, AI, Perkins, DJ, Misukonis, MA, Chan, SU, Dominitz, JA, and Weinberg, JB. "Interferon (IFN)-alpha activation of human blood mononuclear cells in vitro and in vivo for nitric oxide synthase (NOS) type 2 mRNA and protein expression: possible relationship of induced NOS2 to the anti-hepatitis C effects of IFN-alpha in vivo." J Exp Med 186.9 (November 3, 1997): 1495-1502.
PMID
9348307
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
186
Issue
9
Publish Date
1997
Start Page
1495
End Page
1502

Clinical and serologic manifestations of autoimmune disease in MRL-lpr/lpr mice lacking nitric oxide synthase type 2.

Nitric oxide (NO) is an important mediator of the inflammatory response. MRL-lpr/lpr mice overexpress inducible nitric oxide synthase (NOS2) and overproduce NO in parallel with the development of an autoimmune syndrome with a variety of inflammatory manifestations. In previous studies, we showed that inhibiting NO production with the nonselective nitric oxide synthase (NOS) inhibitor NG-monomethyl-arginine reduced glomerulonephritis, arthritis, and vasculitis in MRL-lpr/lpr mice. To define further the role of NO and NOS2 in disease in MRL-lpr/lpr mice, mice with targeted disruption of NOS2 were produced by homologous recombination and bred to MRL-lpr/lpr mice to the N4 generation. MRL-lpr/lpr littermates homozygous for disrupted NOS2 (-/-), heterozygous for disrupted NOS2 (+/-), or wildtype (+/+) were derived for this study. Measures of NO production were markedly decreased in the MRL-lpr/lpr (-/-) mice compared with MRL-lpr/lpr (+/+) mice, with intermediate production by the MRL-lpr/lpr (+/-) mice. There was no detectable NOS2 protein by immunoblot analysis of the spleen, liver, kidney, and peritoneal macrophages of the (-/-) animals, whereas that of (+/+) was high and (+/-) intermediate. The (-/-) mice developed glomerular and synovial pathology similar to that of the (+/-) and (+/+) mice. However, (-/-) mice and (+/-) mice had significantly less vasculitis of medium-sized renal vessels than (+/+) mice. IgG rheumatoid factor levels were significantly lower in the (-/-) mice as compared with (+/+) mice, but levels of anti-DNA antibodies were comparable in all groups. Our findings show that NO derived from NOS2 has a variable impact on disease manifestations in MRL-lpr/lpr mice, suggesting heterogeneity in disease mechanisms.

Authors
Gilkeson, GS; Mudgett, JS; Seldin, MF; Ruiz, P; Alexander, AA; Misukonis, MA; Pisetsky, DS; Weinberg, JB
MLA Citation
Gilkeson, GS, Mudgett, JS, Seldin, MF, Ruiz, P, Alexander, AA, Misukonis, MA, Pisetsky, DS, and Weinberg, JB. "Clinical and serologic manifestations of autoimmune disease in MRL-lpr/lpr mice lacking nitric oxide synthase type 2." J Exp Med 186.3 (August 4, 1997): 365-373.
PMID
9236188
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
186
Issue
3
Publish Date
1997
Start Page
365
End Page
373

Secretory leukocyte protease inhibitor blocks infectivity of primary monocytes and mononuclear cells with both monocytotropic and lymphocytotropic strains of human immunodeficiency virus type I.

Saliva contains factors that inhibit infection with the human immunodeficiency virus type 1 (HIV-1) in vitro. One of these factors was recently identified as secretory leukocyte protease inhibitor (SLPI), a salivary protein which blocked HIV-1 infectivity of monocytes and primary T cells at physiologic concentrations (J Clin Invest 1995; 96: 456). Here, we confirm and extend the original report by demonstrating that SLPI protects primary monocytes and peripheral blood mononuclear cells against infection with HIV-1 Ba-L, IIIB and NL4-3. Thus, SLPI may provide a natural barrier against oral transmission of HIV-1.

Authors
Shugars, DC; Sauls, DL; Weinberg, JB
MLA Citation
Shugars, DC, Sauls, DL, and Weinberg, JB. "Secretory leukocyte protease inhibitor blocks infectivity of primary monocytes and mononuclear cells with both monocytotropic and lymphocytotropic strains of human immunodeficiency virus type I." Oral diseases 3 Suppl 1 (May 1997): S70-S72. (Academic Article)
PMID
9456661
Source
manual
Published In
Oral Diseases
Volume
3 Suppl 1
Publish Date
1997
Start Page
S70
End Page
S72

Nitrate levels in malaria.

Authors
Anstey, NM; Granger, DL; Weinberg, JB
MLA Citation
Anstey, NM, Granger, DL, and Weinberg, JB. "Nitrate levels in malaria." Trans R Soc Trop Med Hyg 91.2 (March 1997): 238-240. (Letter)
PMID
9196781
Source
pubmed
Published In
Transactions of The Royal Society of Tropical Medicine and Hygiene
Volume
91
Issue
2
Publish Date
1997
Start Page
238
End Page
240

Nitrate levels in malaria (multiple letters) [1]

Authors
Anstey, NM; Granger, DL; Weinberg, JB; Prada, J; Kremsner, PG; Al-Yaman, F; Clark, IA
MLA Citation
Anstey, NM, Granger, DL, Weinberg, JB, Prada, J, Kremsner, PG, Al-Yaman, F, and Clark, IA. "Nitrate levels in malaria (multiple letters) [1]." Transactions of the Royal Society of Tropical Medicine and Hygiene 91.2 (1997): 238-240.
Source
scival
Published In
Transactions of The Royal Society of Tropical Medicine and Hygiene
Volume
91
Issue
2
Publish Date
1997
Start Page
238
End Page
240

Inhibitory of HIV by secretory leukocyte protein inhibitor.

Authors
Shugars, DC; Sauls, DL; Weinberg, JB
MLA Citation
Shugars, DC, Sauls, DL, and Weinberg, JB. "Inhibitory of HIV by secretory leukocyte protein inhibitor." JOURNAL OF DENTAL RESEARCH 76 (1997): 1990-1990.
Source
wos-lite
Published In
Journal of Dental Research
Volume
76
Publish Date
1997
Start Page
1990
End Page
1990

Schedule dependent growth inhibition and induction of apoptosis by nitric oxide in leukemia cells.

Authors
Shami, PJ; Weinberg, JB
MLA Citation
Shami, PJ, and Weinberg, JB. "Schedule dependent growth inhibition and induction of apoptosis by nitric oxide in leukemia cells." BLOOD 88.10 (November 15, 1996): 269-269.
Source
wos-lite
Published In
Blood
Volume
88
Issue
10
Publish Date
1996
Start Page
269
End Page
269

Nitric oxide interactions with cobalamins: biochemical and functional consequences.

Nitric oxide (NO) is a paramagnetic gas that has been implicated in a wide range of biologic functions. The common pathway to evoke the functional response frequently involves the formation of an iron-nitrosyl complex in a target (heme) protein. In this study, we report on the interactions between NO and cobalt-containing vitamin B12 derivatives. Absorption spectroscopy showed that of the four Co(III) derivatives (cyanocobalamin [CN-Cbl], aquocobalamin [H2O-Cbl], adenosylcobalamin [Ado-Cbl], and methylcobalamin [MeCbl]), only the H2O-Cbl combined with NO. In addition, electron paramagnetic resonance spectroscopy of H2O-Cbl preparations showed the presence of a small amount of Cob-(II)alamin that was capable of combining with NO. The Co(III)-NO complex was very stable, but could transfer its NO moiety to hemoglobin (Hb). The transfer was accompanied by a reduction of the Co(III) to Co(II), indicating that NO+ (nitrosonium) was the leaving group. In accordance with this, the NO did not combine with the Hb Fe(II)-heme, but most likely with the Hb cysteine-thiolate. Similarly, the Co(III)-NO complex was capable of transferring its NO to glutathione. Ado-Cbl and Me-Cbl were susceptible to photolysis, but CN-Cbl and H2O-Cbl were not. The homolytic cleavage of the Co(III)-Ado or Co(III)-Me bond resulted in the reduction of the metal. When photolysis was performed in the presence of NO, formation of NO-Co(II) was observed. Co(II)-nitrosyl oxidized slowly to form Co(III)-nitrosyl. The capability of aquocobalamin to combine with NO had functional consequences. We found that nitrosylcobalamin had diminished ability to serve as a cofactor for the enzyme methionine synthase, and that aquocobalamin could quench NO-mediated inhibition of cell proliferation. Our in vitro studies therefore suggest that interactions between NO and cobalamins may have important consequences in vivo.

Authors
Brouwer, M; Chamulitrat, W; Ferruzzi, G; Sauls, DL; Weinberg, JB
MLA Citation
Brouwer, M, Chamulitrat, W, Ferruzzi, G, Sauls, DL, and Weinberg, JB. "Nitric oxide interactions with cobalamins: biochemical and functional consequences." Blood 88.5 (September 1, 1996): 1857-1864.
PMID
8781445
Source
pubmed
Published In
Blood
Volume
88
Issue
5
Publish Date
1996
Start Page
1857
End Page
1864

Increased expression of blood mononuclear cell nitric oxide synthase type 2 in rheumatoid arthritis patients.

Nitric oxide (NO) is an important inflammatory mediator in nonhuman animal models of rheumatoid arthritis (RA). The purpose of the present study was to determine whether blood mononuclear cells from patients with active RA (as compared to control subjects) have higher levels of NO synthase type 2 (NOS2) and produce more NO in vitro. Leukocytes from 25 RA patients and 20 normal subjects were examined. Arthritis activity was assessed by tender and swollen joint counts, duration of morning stiffness, patient assessment of pain, physician and patient global assessment of disease activity, the modified Stanford Health Assessment Questionnaire, and by blood levels of acute phase reactants. Blood mononuclear cell NOS enzyme activity/antigen content and nitrite/nitrate formation in vitro were measured. Blood mononuclear cells from RA patients had increased NOS activity and increased NOS2 antigen content as compared to those from normal subjects, and responded to interferon-gamma with increased NOS expression and nitrite/nitrate production in vitro. NOS activity of freshly isolated blood mononuclear cells correlated significantly with disease activity, as assessed by render and swollen joint counts. Our results demonstrate that patients with RA have systemic activation for NOS2 expression, and that the degree of activation correlates with disease activity. Increased NOS2 expression and NO generation may be important in the pathogenesis of RA.

Authors
St Clair, EW; Wilkinson, WE; Lang, T; Sanders, L; Misukonis, MA; Gilkeson, GS; Pisetsky, DS; Granger, DI; Weinberg, JB
MLA Citation
St Clair, EW, Wilkinson, WE, Lang, T, Sanders, L, Misukonis, MA, Gilkeson, GS, Pisetsky, DS, Granger, DI, and Weinberg, JB. "Increased expression of blood mononuclear cell nitric oxide synthase type 2 in rheumatoid arthritis patients." J Exp Med 184.3 (September 1, 1996): 1173-1178.
PMID
9064335
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
184
Issue
3
Publish Date
1996
Start Page
1173
End Page
1178

Increased expression of nitric oxide synthase (NOS) type 2 by blood mononuclear cells (MNCs) in rheumatoid arthritis

Authors
StClair, EW; Wilkinson, WE; Lang, T; Sanders, L; Misukonis, MA; Gilkeson, GS; Pisetsky, DS; Weinberg, JB
MLA Citation
StClair, EW, Wilkinson, WE, Lang, T, Sanders, L, Misukonis, MA, Gilkeson, GS, Pisetsky, DS, and Weinberg, JB. "Increased expression of nitric oxide synthase (NOS) type 2 by blood mononuclear cells (MNCs) in rheumatoid arthritis." ARTHRITIS AND RHEUMATISM 39.9 (September 1996): 1019-1019.
Source
wos-lite
Published In
Arthritis and Rheumatism
Volume
39
Issue
9
Publish Date
1996
Start Page
1019
End Page
1019

Nitric oxide in Tanzanian children with malaria: inverse relationship between malaria severity and nitric oxide production/nitric oxide synthase type 2 expression.

Nitric oxide (NO)-related activity has been shown to be protective against Plasmodium falciparum in vitro. It has been hypothesized, however, that excess NO production contributes to the pathogenesis of cerebral malaria. The purpose of this study was to compare markers of NO production [urinary and plasma nitrate + nitrite (NOx)], leukocyte-inducible nitric oxide synthase type 2 (NOS2), and plasma TNF-alpha and IL-10 levels with disease severity in 191 Tanzanian children with and without malaria. Urine NOx excretion and plasma NOx levels (corrected for renal impairment) were inversely related to disease severity, with levels highest in subclinical infection and lowest in fatal cerebral malaria. Results could not be explained by differences in dietary nitrate ingestion among the groups. Plasma levels of IL-10, a cytokine known to suppress NO synthesis, increased with disease severity. Leukocyte NOS2 antigen was detectable in all control children tested and in all those with subclinical infection, but was undetectable in all but one subject with cerebral malaria. This suppression of NO synthesis in cerebral malaria may contribute to pathogenesis. In contrast, high fasting NOx levels and leukocyte NOS2 in healthy controls and asymptomatic infection suggest that increased NO synthesis might protect against clinical disease. NO appears to have a protective rather than pathological role in African children with malaria.

Authors
Anstey, NM; Weinberg, JB; Hassanali, MY; Mwaikambo, ED; Manyenga, D; Misukonis, MA; Arnelle, DR; Hollis, D; McDonald, MI; Granger, DL
MLA Citation
Anstey, NM, Weinberg, JB, Hassanali, MY, Mwaikambo, ED, Manyenga, D, Misukonis, MA, Arnelle, DR, Hollis, D, McDonald, MI, and Granger, DL. "Nitric oxide in Tanzanian children with malaria: inverse relationship between malaria severity and nitric oxide production/nitric oxide synthase type 2 expression." J Exp Med 184.2 (August 1, 1996): 557-567.
PMID
8760809
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
184
Issue
2
Publish Date
1996
Start Page
557
End Page
567

Potent inhibition of HIV type 1 infection of mononuclear phagocytes by synthetic peptide analogs of HIV type 1 protease substrates.

The HIV-1 genome encodes a protease that is required for viral processing of the precursor polyproteins Pr55gag and Pr160gag-pol. Interference with this process in human lymphocytes inhibits production of infectious virus. We tested the ability of several protease inhibitors to decrease replication of HIV-1BaL in human monocytes and peritoneal macrophages. The compounds tested are oligopeptide analogs of HIV-1 protease substrates in which the scissile dipeptide has been replaced by a hydroxyethylene isostere. The protease inhibitors were added only once, 1 hr prior to inoculation with virus. Every 3-5 days, half the medium was replaced with fresh medium. Inhibition of virus production was assessed by measuring reverse transcriptase (RT) activity in supernatant medium 14 days after infection. The concentration of drug required to inhibit infection by 50% (IC50) in monocytes ranged from 0.17 to 2.99 microM; IC50 values for peritoneal macrophages ranged from 0.21 to 1.9 microM. The IC50 values for these compounds were 1.1- to 10-fold higher when tested in monocytes compared to their inhibitory effect in lymphocytes, although still potently effective in the dosage range that appeared nontoxic to cells. Cell toxicity was seen only at concentrations greater than 10 microM, and varied among the drugs tested. Immunoblot analysis of two of the drugs (SB205700 and SB108922) confirmed inhibition of polyprotein processing. In control cells, 22% of viral protein pr55 was processed to p24 by 24 hr, and 51% was processed by 48 hr. In cells treated with the protease inhibitors (2 microM), Pr55 processing was inhibited 77% at 24 hr and 89% at 48 hr. Thus, these synthetic peptide analogs potently inhibit productive infection of mononuclear phagocytes by HIV-1. Drugs of this class may be useful for the treatment of HIV-1 infection in humans.

Authors
Dukes, CS; Matthews, TJ; Lambert, DM; Dreyer, GB; Petteway, SR; Weinberg, JB
MLA Citation
Dukes, CS, Matthews, TJ, Lambert, DM, Dreyer, GB, Petteway, SR, and Weinberg, JB. "Potent inhibition of HIV type 1 infection of mononuclear phagocytes by synthetic peptide analogs of HIV type 1 protease substrates." AIDS Res Hum Retroviruses 12.9 (June 10, 1996): 777-782.
PMID
8738429
Source
pubmed
Published In
AIDS Research and Human Retroviruses
Volume
12
Issue
9
Publish Date
1996
Start Page
777
End Page
782
DOI
10.1089/aid.1996.12.777

Differential effects of nitric oxide on erythroid and myeloid colony growth from CD34+ human bone marrow cells.

Nitric oxide (NO) is a reactive molecule with numerous physiologic and pathophysiologic roles affecting the nervous, cardiovascular, and immune systems. In previous work, we have demonstrated that NO inhibits the growth and induces the monocytic differentiation of cells of the HL-60 cell line. We have also demonstrated that NO inhibits the growth of acute nonlymphocytic leukemia cells freshly isolated from untreated patients and increases monocytic differentiation antigens in some. In the present work, we studied the effect of NO on the growth and differentiation of normal human bone marrow cells in vitro. Mononuclear cells isolated from human bone marrow were cultured in semisolid media and treated with the NO-donating agents sodium nitroprusside (SNP) or S-nitroso-acetyl penicillamine (SNAP) (0.25 to 1 mmol/L). Both agents decreased colony-forming unit-erythroid (CFU-E) and colony-forming unit-granulocyte macrophage (CFU-GM) formation by 34% to 100%. When CD34+ cells were examined, we noted that these cells responded to SNP and SNAP differently than did the mononuclear cells. At a concentration range of 0.25 to 1 mmol/L, SNP inhibited the growth of CFU-E by 30% to 75%. However, at the same concentration range, SNP increased the number of CFU-GM by up to 94%. At concentrations of 0.25 to 1 mmol/L, SNAP inhibited the growth of CFU-E by 33% to 100%. At a concentration of 0.25 mmol/L, SNAP did not affect CFU-GM. At higher concentrations, SNAP inhibited the growth of CFU-GM. Although SNP increased intracellular levels of cGMP in bone marrow cells, increasing cGMP in cells by addition of 8-Br-cGMP (a membrane permeable cGMP analogue) did not reproduce the observed NO effects on bone marrow colonies. These results demonstrate that NO can influence the growth and differentiation of normal human bone marrow cells. NO (generated in the bone marrow microenvironment) may play an important role modulating the growth and differentiation of bone marrow cells in vivo.

Authors
Shami, PJ; Weinberg, JB
MLA Citation
Shami, PJ, and Weinberg, JB. "Differential effects of nitric oxide on erythroid and myeloid colony growth from CD34+ human bone marrow cells." Blood 87.3 (February 1, 1996): 977-982.
PMID
8562969
Source
pubmed
Published In
Blood
Volume
87
Issue
3
Publish Date
1996
Start Page
977
End Page
982

Update on the issues of HIV vaccine development.

Major scientific obstacles blocking the development of a successful preventive HIV vaccine are the extraordinary variability of HIV, the lack of an exact animal model of HIV-induced AIDS, and the lack of understanding of the correlates of positive immunity to HIV. Current HIV vaccines containing the HIV gp120 envelope have been tested in phase I and II trials but they have had a major limitation of neutralizing only T-cell tropic laboratory-adapted HIV strains grown in T-cell lines, but not neutralizing HIV primary isolates. Phase III trials of monovalent HIV gp120 envelope vaccines are being planned in the US and Thailand, but concern has been raised that recombinant monovalent gp120 may not be an appropriate immunogen for an efficious HIV vaccine. Because the immune response is probably responsible for controlling the viral load in some long-term survivors of HIV infection, studies are now being carried out to induce similar immunity against a broad spectrum of strains of HIV primary isolates with targeted HIV experimental immunogens.

Authors
Haynes, BF; Putman, SB; Weinberg, JB
MLA Citation
Haynes, BF, Putman, SB, and Weinberg, JB. "Update on the issues of HIV vaccine development." Ann Med 28.1 (February 1996): 39-41.
PMID
8932504
Source
pubmed
Published In
Annals of Medicine (Informa)
Volume
28
Issue
1
Publish Date
1996
Start Page
39
End Page
41

Inhibition of HIV-1 integrase by hydroxocobalamin

Authors
Weinberg, JB; Fyfe, JA; Sherman, PA
MLA Citation
Weinberg, JB, Fyfe, JA, and Sherman, PA. "Inhibition of HIV-1 integrase by hydroxocobalamin." BLOOD 86.10 (November 15, 1995): 2231-2231.
Source
wos-lite
Published In
Blood
Volume
86
Issue
10
Publish Date
1995
Start Page
2231
End Page
2231

A novel insert at the 5' end of the human inducible nitric oxide synthase gene.

Authors
Shami, PJ; Dittman, WA; Weinberg, JB
MLA Citation
Shami, PJ, Dittman, WA, and Weinberg, JB. "A novel insert at the 5' end of the human inducible nitric oxide synthase gene." BLOOD 86.10 (November 15, 1995): 115-115.
Source
wos-lite
Published In
Blood
Volume
86
Issue
10
Publish Date
1995
Start Page
115
End Page
115

Nitric oxide and cobalamins: NO-Cb1 interactions with light, oxygen, hemoglobin, and glutathione.

Authors
Weinberg, JB; Ferruzzi, G; Brouwer, M
MLA Citation
Weinberg, JB, Ferruzzi, G, and Brouwer, M. "Nitric oxide and cobalamins: NO-Cb1 interactions with light, oxygen, hemoglobin, and glutathione." BLOOD 86.10 (November 15, 1995): 494-494.
Source
wos-lite
Published In
Blood
Volume
86
Issue
10
Publish Date
1995
Start Page
494
End Page
494

Inhibition of productive human immunodeficiency virus-1 infection by cobalamins.

Various cobalamins act as important enzyme cofactors and modulate cellular function. We investigated cobalamins for their abilities to modify productive human immunodeficiency virus-1 (HIV-1) infection of hematopoietic cells in vitro. We show that hydroxocobalamin (OH-Cbl), methylcobalamin (Me-Cbl), and adenosylcobalamin Ado-Cbl (Ado-Cbl) inhibit HIV-1 infection of normal human blood monocytes and lymphocytes. The inhibitory effects were noted when analyzing the monocytotropic strains HIV-1-BaL and HIV-1-ADA as well as the lymphocytotropic strain HIV-1-LAI. Cobalamins did not modify binding of gp120 to CD4 or block early steps in viral life cycle, inhibit reverse transcriptase, inhibit induction of HIV-1 expression from cells with established or latent infection, or modify monocyte interferon-alpha production. Because of the ability to achieve high blood and tissue levels of cobalamins in vivo and the general lack of toxicity, cobalamins should be considered as potentially useful agents for the treatment of HIV-1 infection.

Authors
Weinberg, JB; Sauls, DL; Misukonis, MA; Shugars, DC
MLA Citation
Weinberg, JB, Sauls, DL, Misukonis, MA, and Shugars, DC. "Inhibition of productive human immunodeficiency virus-1 infection by cobalamins." Blood 86.4 (August 15, 1995): 1281-1287.
PMID
7632933
Source
pubmed
Published In
Blood
Volume
86
Issue
4
Publish Date
1995
Start Page
1281
End Page
1287

Human mononuclear phagocyte inducible nitric oxide synthase (iNOS): analysis of iNOS mRNA, iNOS protein, biopterin, and nitric oxide production by blood monocytes and peritoneal macrophages.

Nitric oxide (NO) is produced by numerous different cell types, and it is an important regulator and mediator of many processes including smooth muscle relaxation, neurotransmission, and murine macrophage-mediated cytotoxicity for microbes and tumor cells. Although murine macrophages produce NO readily after activation, human monocytes and tissue macrophages have been reported to produce only low levels of NO in vitro. The purpose of this study was to determine if stimulated human mononuclear phagocytes produce inducible nitric oxide synthase (iNOS) mRNA, protein, and enzymatic activity. By reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, we show that human monocytes can be induced to express iNOS mRNA after treatment with lipopolysaccharide (LPS) and/or interferon-gamma (IFN-gamma). By immunofluorescence and immunoblot analyses, we show monocytes and peritoneal macrophages contain detectable levels of iNOS antigen after stimulations with cytokines in vitro. Control monocytes or those cultured with LPS and/or various cytokines have low levels of NOS functional activity as measured by the ability of cell extracts to convert L-arginine to L-citrulline, and they produce low levels of the NO catabolites nitrite and nitrate. Peritoneal macrophages have significantly enhanced nitrite/nitrate production and NOS activity after treatment with LPS and/or IFN-gamma, whereas monocyte nitrite/nitrate production and NOS activity are not altered by the treatments. Monocytes cultured with various live or heat-killed bacteria, fungi, or human immunodeficiency virus (HIV)-1 do not produce high levels of nitrite/nitrate. Antibodies against transforming growth factor-beta (TGF-beta), a factor known to inhibit iNOS expression and NO production in mouse macrophages, do not enhance NO production in human monocytes or macrophages. Biopterin, an obligate cofactor of iNOS enzymatic activity, is undetectable in freshly isolated or cultured human monocytes and peritoneal macrophages. However, replenishment of intracellular levels of tetrahydrobiopterin by culture with the cell-permeable, nontoxic precursor sepiapterin does not enhance the abilities of the human mononuclear phagocytes to produce NO in vitro. Mixing experiments show no evidence of a functional NOS inhibitor in human mononuclear phagocytes. Thus, we demonstrate that human mononuclear phagocytes can produce iNOS mRNA and protein, and (despite this) their abilities to generate NO are very low.

Authors
Weinberg, JB; Misukonis, MA; Shami, PJ; Mason, SN; Sauls, DL; Dittman, WA; Wood, ER; Smith, GK; McDonald, B; Bachus, KE
MLA Citation
Weinberg, JB, Misukonis, MA, Shami, PJ, Mason, SN, Sauls, DL, Dittman, WA, Wood, ER, Smith, GK, McDonald, B, and Bachus, KE. "Human mononuclear phagocyte inducible nitric oxide synthase (iNOS): analysis of iNOS mRNA, iNOS protein, biopterin, and nitric oxide production by blood monocytes and peritoneal macrophages." Blood 86.3 (August 1, 1995): 1184-1195.
PMID
7542498
Source
pubmed
Published In
Blood
Volume
86
Issue
3
Publish Date
1995
Start Page
1184
End Page
1195

Extracellular acetylcholine is increased in the nucleus accumbens following the presentation of an aversively conditioned taste stimulus.

To determine if acetylcholine (ACh) is released in the nucleus accumbens in response to a conditioned stimulus (CS) that reminds the animal of an aversive event, in vivo microdialysis was used to monitor extracellular ACh during conditioned taste aversion. Saccharin flavored water (2.5 mM saccharin) was paired twice with nausea induced by i.p. lithium chloride (100 mg/kg). This is normally sufficient to create an aversion to the taste of saccharin, but instead of a preference test, the saccharin solution was squirted directly into the rat's mouth via a cheek catheter during nucleus accumbens microdialysis. The result was a 40% increase in extracellular ACh. We reported earlier that dopamine changes in the opposite direction; it decreases. This suggests that high synaptic ACh and low DA are correlated with an aversive state and cessation of behavior.

Authors
Mark, GP; Weinberg, JB; Rada, PV; Hoebel, BG
MLA Citation
Mark, GP, Weinberg, JB, Rada, PV, and Hoebel, BG. "Extracellular acetylcholine is increased in the nucleus accumbens following the presentation of an aversively conditioned taste stimulus." Brain research 688.1-2 (August 1995): 184-188. (Academic Article)
Source
manual
Published In
Brain Research
Volume
688
Issue
1-2
Publish Date
1995
Start Page
184
End Page
188

Nitric oxide inhibition of human sperm motility.

OBJECTIVE: To determine the effect of nitric oxide (NO) on sperm motility in vitro. DESIGN: Normal human sperm separated by centrifugation through a discontinuous Percoll gradient and subsequent swim-up were incubated for up to 24 hours with NO donors, with and without the known NO quencher hemoglobin, as well as with agents that raise intracellular cyclic 3',5'-guanosine monophosphate (cGMP). Sperm respiration was determined by a tetrazolium-formazan spectrophotometric assay. SETTING: Andrology laboratory. MAIN OUTCOME MEASURES: Absolute sperm motility and respiration. RESULTS: Sperm incubated with the NO donors 1 mM nitroprusside, 100 to 125 microM 3-morpholinosydnonimine, and 25 to 125 microM pure nitric oxide gas dissolved in buffer were inhibited in motility in a dose-dependent fashion. The inhibition could be reversed by the NO quencher hemoglobin. Agents that raise cellular cGMP (dibutyryl cGMP or 8-bromo-cGMP) did not inhibit motility. Nitric oxide inhibited sperm respiration, as measured by the tetrazolium-formazan assay. CONCLUSIONS: Nitric oxide reduces sperm motility, possibly by a mechanism involving inhibition of cellular respiration independent of an elevation of intracellular cGMP. Nitric oxide elaborated in the female or male genital tract in vivo could adversely influence sperm function and fertility.

Authors
Weinberg, JB; Doty, E; Bonaventura, J; Haney, AF
MLA Citation
Weinberg, JB, Doty, E, Bonaventura, J, and Haney, AF. "Nitric oxide inhibition of human sperm motility." Fertil Steril 64.2 (August 1995): 408-413.
PMID
7615122
Source
pubmed
Published In
Fertility and Sterility
Volume
64
Issue
2
Publish Date
1995
Start Page
408
End Page
413

Nitric oxide modulation of the growth and differentiation of freshly isolated acute non-lymphocytic leukemia cells.

Freshly isolated acute non-lymphocytic leukemia (ANLL) cells were treated with the nitric oxide (NO)-liberating compounds sodium nitroprusside or S-nitrosoacetyl penicillamine and analyzed for viability, growth, and differentiation at 3-5 days. NO decreased the viability and the growth of freshly isolated ANLL cells in vitro. NO treatment significantly increased expression of CD14 in blast cells from patients with M5 ANLL, and increased at least one differentiation parameter in M4 or M5 cells. It had little or no effect on parameters of differentiation in other ANLL cells. We conclude that in vitro culture with NO decreases the growth and viability of most freshly isolated ANLL cells. NO also induces the differentiation of ANLL cells with a monocytic phenotype.

Authors
Shami, PJ; Moore, JO; Gockerman, JP; Hathorn, JW; Misukonis, MA; Weinberg, JB
MLA Citation
Shami, PJ, Moore, JO, Gockerman, JP, Hathorn, JW, Misukonis, MA, and Weinberg, JB. "Nitric oxide modulation of the growth and differentiation of freshly isolated acute non-lymphocytic leukemia cells." Leuk Res 19.8 (August 1995): 527-533.
PMID
7658698
Source
pubmed
Published In
Leukemia Research
Volume
19
Issue
8
Publish Date
1995
Start Page
527
End Page
533

Differential effects of interleukin-1 alpha, tumor necrosis factor-alpha, indomethacin, hydrocortisone, and macrophage co-culture on the proliferation of human fibroblasts and peritoneal mesothelial cells.

OBJECTIVE: We sought to determine whether human fibroblasts and peritoneal mesothelial cells (PMC) are under comparable proliferative controls. METHODS: Human PMC and human fibroblasts were obtained from primary culture of excised explants from infertile women. The proliferation of PMC, as determined by tritiated thymidine incorporation, was compared with that of fibroblasts in the presence of human peritoneal macrophages, interleukin-1 alpha (IL-1), tumor necrosis factor-alpha (TNF), indomethacin, and hydrocortisone. Data were analyzed by one-way and multifactorial analyses of variance, with Bonferroni adjustments for multiple comparisons. RESULTS: Disparate proliferation was observed between fibroblasts and mesothelial cells with the additives studied. Proliferation of fibroblasts was inhibited (P < .001) when co-cultured with macrophages, IL-1, and TNF. Indomethacin and hydrocortisone overcame the inhibitory effects of macrophage co-culture. By contrast, PMC increased proliferation when cultured with macrophages (P < .001) but were unaffected by IL-1 or TNF and were not altered when indomethacin or hydrocortisone was added to the macrophage co-culture. CONCLUSION: Human PMC and fibroblasts differentially proliferate in response to putative regulatory controls. This suggests that these cells, which play critical roles in peritoneal wound repair, should be considered separately in developing medical strategies to prevent postsurgical adhesions.

Authors
Bachus, KE; Doty, E; Haney, AF; Weinberg, JB
MLA Citation
Bachus, KE, Doty, E, Haney, AF, and Weinberg, JB. "Differential effects of interleukin-1 alpha, tumor necrosis factor-alpha, indomethacin, hydrocortisone, and macrophage co-culture on the proliferation of human fibroblasts and peritoneal mesothelial cells." J Soc Gynecol Investig 2.4 (July 1995): 636-642.
PMID
9420870
Source
pubmed
Published In
Journal of the Society for Gynecologic Investigation (Elsevier)
Volume
2
Issue
4
Publish Date
1995
Start Page
636
End Page
642

Cellular CD44S as a determinant of human immunodeficiency virus type 1 infection and cellular tropism.

CD4 is the predominant cell membrane protein that binds human immunodeficiency virus type 1 (HIV-1) gp120 and facilitates HIV-1 infection, but other membrane-associated molecules may be involved in determining HIV-1 cellular infection. Our prior work had suggested that CD44, the transmembrane receptor for hyaluronan, might play a role in the infection of mononuclear phagocytes with HIV-1. In the present work, we have used cells of the CD4-positive, CD44-negative human T-lymphoblast cell line Jurkat to study the role of CD44 in HIV-1 infection and tropism. Cells were transfected with cDNA for the standard (S, or hematopoietic) CD44 isoform CD44S or the epithelial isoform CD44E. The resultant lines expressed appropriate CD44S or CD44E mRNA and protein. While the parent Jurkat cells, those transfected with vector alone, and those transfected with CD44E could be productively infected with only the lymphocytotropic strain HIV-1-LAI, cells transfected with CD44S were rendered susceptible to productive infection with the monocytotropic strains HIV-1-BaL and HIV-1-ADA. Also, CD44S-transfected cells displayed higher levels of infection with HIV-1-LAI than did the other transfected Jurkat cells. The transfected cell line cells all had comparable growth rates and expressed similar levels of the membrane antigens CD4, CD7, major histocompatibility complex (MHC) class I, MHC class II, and CD11a, while levels of CD3 were slightly higher in cells transfected with vector alone and in one of the clones transfected with CD44S. Hyaluronan binding was increased in cells transfected with either CD44S or CD44E. Mouse NIH 3T3 fibroblasts transfected with human CD4, human CD44S, or both human CD4 and CD44S displayed the appropriate antigens, but they could not be productively infected with lymphocytotropic or monocytotropic strains of HIV-1. The results indicate that in human leukocytes, CD44S is an important determinant of HIV-1 productive infection and may be involved in viral cellular tropism.

Authors
Dukes, CS; Yu, Y; Rivadeneira, ED; Sauls, DL; Liao, HX; Haynes, BF; Weinberg, JB
MLA Citation
Dukes, CS, Yu, Y, Rivadeneira, ED, Sauls, DL, Liao, HX, Haynes, BF, and Weinberg, JB. "Cellular CD44S as a determinant of human immunodeficiency virus type 1 infection and cellular tropism." J Virol 69.7 (July 1995): 4000-4005.
PMID
7539503
Source
pubmed
Published In
Journal of virology
Volume
69
Issue
7
Publish Date
1995
Start Page
4000
End Page
4005

Inhibition of HIV type 1 infection of mononuclear phagocytes by anti-CD44 antibodies.

Cellular CD4 is the primary membrane molecule that binds HIV-1 through interaction with viral gp120. Membrane glycolipids and cell adhesion molecules have also been noted to be involved in the interaction of HIV-1 with cells and in syncytium formation in infected cells. The purpose of this study was to determine the role of the cell adhesion molecule CD44 in HIV-1 infection of cells. Both normal blood monocytes and lymphocytes expressed CD44 as determined by flow cytometry using the anti-CD44 antibody A3D8. Anti-CD44 monoclonal antibodies A3D8, A1G3, and 5F12 [ascites, purified IgG, and F(ab')2] inhibited infection of monocytes and peritoneal macrophages with HIV-1-BaL and HIV-1-ADA, but had no effect on HIV-1-IIIB infection of mitogen-stimulated lymphocytes, or cells of a T lymphocyte line. CD44 monoclonal antibodies were not toxic for monocytes, and the observed inhibitory effect of CD44 monoclonal antibodies was not dependent on complement. These results suggest that CD44 may be a determinant of HIV-1 infection of mononuclear phagocytes in vitro.

Authors
Rivadeneira, ED; Sauls, DL; Yu, Y; Haynes, BF; Weinberg, JB
MLA Citation
Rivadeneira, ED, Sauls, DL, Yu, Y, Haynes, BF, and Weinberg, JB. "Inhibition of HIV type 1 infection of mononuclear phagocytes by anti-CD44 antibodies." AIDS Res Hum Retroviruses 11.5 (May 1995): 541-546.
PMID
7576909
Source
pubmed
Published In
AIDS Research and Human Retroviruses
Volume
11
Issue
5
Publish Date
1995
Start Page
541
End Page
546
DOI
10.1089/aid.1995.11.541

PIG-A, DAF AND PROTOONCOGENE EXPRESSION IN PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA-ASSOCIATED ACUTE MYELOGENOUS LEUKEMIA BLASTS

Authors
STAFFORD, HA; NAGARAJAN, S; WEINBERG, JB; MEDOF, ME
MLA Citation
STAFFORD, HA, NAGARAJAN, S, WEINBERG, JB, and MEDOF, ME. "PIG-A, DAF AND PROTOONCOGENE EXPRESSION IN PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA-ASSOCIATED ACUTE MYELOGENOUS LEUKEMIA BLASTS." BRITISH JOURNAL OF HAEMATOLOGY 89.1 (January 1995): 72-78.
PMID
7530480
Source
wos-lite
Published In
British Journal of Haematology
Volume
89
Issue
1
Publish Date
1995
Start Page
72
End Page
78

Increased levels of laminin in ascitic fluid of patients with ovarian cancer

Laminin is a component of the extracellular matrix and is associated with tumor cell metastasis. Present studies show that the ovarian cancer cell lines produce significant amounts of laminin (54-140 ng/ml) in culture. Since ovarian cancer is associated with ascites production, laminin levels were then determined in ascites and serum. The results indicate that the ascites from patients with serous adenocarcinoma of the ovary had higher levels of laminin than the normal peritoneal fluid (P < 0.0001). However, the serum levels of laminin did not differ significantly between the control population and ovarian cancer patients. © 1995.

Authors
Byers, LJ; Osborne, JL; Carson, LF; Carter, JR; Haney, AF; Weinberg, JB; Ramakrishnan, S
MLA Citation
Byers, LJ, Osborne, JL, Carson, LF, Carter, JR, Haney, AF, Weinberg, JB, and Ramakrishnan, S. "Increased levels of laminin in ascitic fluid of patients with ovarian cancer." Cancer Letters 88.1 (1995): 67-72.
PMID
7850775
Source
scival
Published In
Cancer Letters
Volume
88
Issue
1
Publish Date
1995
Start Page
67
End Page
72

NITRIC-OXIDE COBALAMIN INTERACTIONS - IMPLICATIONS REGARDING VITAMIN-B12 DEFICIENCY STATES

Authors
WEINBERG, JB; BONAVENTURA, J; FERRUZZI, G; SAULS, DL; MASON, RP; CHAMULITRAT, W
MLA Citation
WEINBERG, JB, BONAVENTURA, J, FERRUZZI, G, SAULS, DL, MASON, RP, and CHAMULITRAT, W. "NITRIC-OXIDE COBALAMIN INTERACTIONS - IMPLICATIONS REGARDING VITAMIN-B12 DEFICIENCY STATES." BLOOD 84.10 (November 15, 1994): A118-A118.
Source
wos-lite
Published In
Blood
Volume
84
Issue
10
Publish Date
1994
Start Page
A118
End Page
A118

COBALAMINS AND AIDS - POTENT INHIBITION OF HIV-1 INFECTION OF HUMAN MONOCYTES, PERITONEAL-MACROPHAGES, AND BLOOD MONONUCLEAR-CELLS IN-VITRO BY HYDROXOCOBALAMIN, METHYLCOBALAMIN, OR ADENOSYLCOBALAMIN

Authors
WEINBERG, JB; SAULS, DL; MISUKONIS, MA
MLA Citation
WEINBERG, JB, SAULS, DL, and MISUKONIS, MA. "COBALAMINS AND AIDS - POTENT INHIBITION OF HIV-1 INFECTION OF HUMAN MONOCYTES, PERITONEAL-MACROPHAGES, AND BLOOD MONONUCLEAR-CELLS IN-VITRO BY HYDROXOCOBALAMIN, METHYLCOBALAMIN, OR ADENOSYLCOBALAMIN." BLOOD 84.10 (November 15, 1994): A480-A480.
Source
wos-lite
Published In
Blood
Volume
84
Issue
10
Publish Date
1994
Start Page
A480
End Page
A480

NITRIC-OXIDE INHIBITS THE GROWTH OF HUMAN BONE-MARROW COLONIES BY A DIRECT EFFECT ON CD34+ CELLS

Authors
SHAMI, PJ; WEINBERG, JB
MLA Citation
SHAMI, PJ, and WEINBERG, JB. "NITRIC-OXIDE INHIBITS THE GROWTH OF HUMAN BONE-MARROW COLONIES BY A DIRECT EFFECT ON CD34+ CELLS." BLOOD 84.10 (November 15, 1994): A268-A268.
Source
wos-lite
Published In
Blood
Volume
84
Issue
10
Publish Date
1994
Start Page
A268
End Page
A268

Neopterin production by HIV-1-infected mononuclear phagocytes.

Neopterin is a pteridine produced by human mononuclear phagocytes, usually in response to interferon-gamma (IFN-gamma) stimulation. Increasing serum levels of neopterin correlate with clinical progression to AIDS in HIV-infected people, but the factors that contribute to these elevated levels are not established. We performed in vitro experiments to investigate the possibility that HIV-1 infection of mononuclear phagocytes directly induces enhanced neopterin production. We found that HIV-1-infected monocytes and peritoneal macrophages produced neopterin in quantities similar to amounts produced by uninfected cells. The HIV-infected cells responded to stimulation with IFN-gamma as well as uninfected cells, with a 6- to 12-fold increase in neopterin production. We conclude that elevated serum levels of neopterin in HIV-infected individuals are not caused by HIV-1 infection of mononuclear phagocytes but may be a result of the normal response to mononuclear phagocytes to increased levels of IFN-gamma.

Authors
Dukes, CS; Matthews, TJ; Rivadeneira, ED; Weinberg, JB
MLA Citation
Dukes, CS, Matthews, TJ, Rivadeneira, ED, and Weinberg, JB. "Neopterin production by HIV-1-infected mononuclear phagocytes." J Leukoc Biol 56.5 (November 1994): 650-653.
PMID
7964172
Source
pubmed
Published In
Journal of leukocyte biology
Volume
56
Issue
5
Publish Date
1994
Start Page
650
End Page
653

Human immunodeficiency virus (HIV)-infected human blood monocytes and peritoneal macrophages have reduced anticryptococcal activity whereas HIV-infected alveolar macrophages retain normal activity.

Human immunodeficiency virus type 1 (HIV-1) infection causes immune dysfunction. Mononuclear phagocytes (MNP) are immune effector cells against some intracellular pathogens and reservoirs for HIV-1. This study determined effects of HIV-1 on MNP-mediated antifungal function. MNP from seronegative volunteers were inoculated with HIVBal or HIVIIIB. MNP were infected with an avirulent clone of Cryptococcus neoformans; 48 h later, MNP were lysed and yeasts were counted. Viral replication was determined by reverse transcriptase and by visualization of cytopathic effects. Monocytes and peritoneal macrophages exhibited reduced anticryptococcal activity 14 days after infection with HIVBal but retained normal activity when infected with HIVIIIB. Loss of anticryptococcal activity correlated with viral replication. Alveolar macrophages retained normal anticryptococcal activity whether infected with HIVBal or HIVIIIB. In vitro MNP-mediated antifungal activity may be altered by HIV-1 infection; this altered activity appears to depend on viral tropism, viral replication, and MNP tissue origin.

Authors
Cameron, ML; Granger, DL; Matthews, TJ; Weinberg, JB
MLA Citation
Cameron, ML, Granger, DL, Matthews, TJ, and Weinberg, JB. "Human immunodeficiency virus (HIV)-infected human blood monocytes and peritoneal macrophages have reduced anticryptococcal activity whereas HIV-infected alveolar macrophages retain normal activity." J Infect Dis 170.1 (July 1994): 60-67.
PMID
8014521
Source
pubmed
Published In
Journal of Infectious Diseases
Volume
170
Issue
1
Publish Date
1994
Start Page
60
End Page
67

CHRONIC BLOCKAGE OF NITRIC-OXIDE OVERPRODUCTION IN MRL-LPR MICE BY ORAL N(G) MONOMETHYL L-ARGININE (NMMA) PREVENTS INFLAMMATORY RENAL-DISEASE AND ENHANCES RENAL BLOOD-FLOW

Authors
GILKESON, GS; PISETSKY, DS; COFFMAN, TM; SPURNEY, RF; BEST, C; WEINBERG, JB
MLA Citation
GILKESON, GS, PISETSKY, DS, COFFMAN, TM, SPURNEY, RF, BEST, C, and WEINBERG, JB. "CHRONIC BLOCKAGE OF NITRIC-OXIDE OVERPRODUCTION IN MRL-LPR MICE BY ORAL N(G) MONOMETHYL L-ARGININE (NMMA) PREVENTS INFLAMMATORY RENAL-DISEASE AND ENHANCES RENAL BLOOD-FLOW." CLINICAL RESEARCH 42.2 (April 1994): A139-A139.
Source
wos-lite
Published In
Clinical Research
Volume
42
Issue
2
Publish Date
1994
Start Page
A139
End Page
A139

The role of nitric oxide in the pathogenesis of spontaneous murine autoimmune disease: increased nitric oxide production and nitric oxide synthase expression in MRL-lpr/lpr mice, and reduction of spontaneous glomerulonephritis and arthritis by orally administered NG-monomethyl-L-arginine.

MRL-lpr/lpr mice spontaneously develop various manifestations of autoimmunity including an inflammatory arthropathy and immune complex glomerulonephritis. This study examines the role of nitric oxide, a molecule with proinflammatory actions, in the pathogenesis of MRL-lpr/lpr autoimmune disease. MRL-lpr/lpr mice excreted more urinary nitrite/nitrate (an in vivo marker of nitric oxide production) than did mice of normal strains and MRL-(+/+) and B6-lpr/lpr congenic strains. In addition, MRL-lpr/lpr peritoneal macrophages had an enhanced capacity to produce nitric oxide in vitro as well as increased nitric oxide synthase activity, and certain tissues from MRL-lpr/lpr mice had increased expression of inducible nitric oxide synthase (NOS) mRNA and increased amounts of material immunoreactive for inducible NOS. Oral administration of NG-monomethyl-L-arginine, a nitric oxide synthase inhibitor, prevented the development of glomerulonephritis and reduced the intensity of inflammatory arthritis in MRL-lpr/lpr mice. By using interspecific backcross mice, the gene for inducible NOS (Nosi) was mapped to mouse chromosome 11. This chromosomal localization was different from those loci that we have previously demonstrated to be linked to enhanced susceptibility to renal disease in an MRL-lpr/lpr cross. However, the chromosomal location of the NOS gene was consistent with an insulin-dependent diabetes locus identified in an analysis of nonobese diabetic (NOD) mice. These results suggest that elevated nitric oxide production could be important in the pathogenesis of autoimmunity, and that treatments to block the production of nitric oxide or block its effects might be valuable therapeutically.

Authors
Weinberg, JB; Granger, DL; Pisetsky, DS; Seldin, MF; Misukonis, MA; Mason, SN; Pippen, AM; Ruiz, P; Wood, ER; Gilkeson, GS
MLA Citation
Weinberg, JB, Granger, DL, Pisetsky, DS, Seldin, MF, Misukonis, MA, Mason, SN, Pippen, AM, Ruiz, P, Wood, ER, and Gilkeson, GS. "The role of nitric oxide in the pathogenesis of spontaneous murine autoimmune disease: increased nitric oxide production and nitric oxide synthase expression in MRL-lpr/lpr mice, and reduction of spontaneous glomerulonephritis and arthritis by orally administered NG-monomethyl-L-arginine." J Exp Med 179.2 (February 1, 1994): 651-660.
PMID
7507509
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
179
Issue
2
Publish Date
1994
Start Page
651
End Page
660

EFFECT OF NITRIC-OXIDE (NO) ON THE GROWTH AND DIFFERENTIATION OF FRESHLY ISOLATED ACUTE NONLYMPHOCYTIC LEUKEMIA (ANLL) CELLS

Authors
SHAMI, PJ; GOCKERMAN, JP; HATHORN, JW; MOORE, JO; MISUKONIS, MA; WEINBERG, JB
MLA Citation
SHAMI, PJ, GOCKERMAN, JP, HATHORN, JW, MOORE, JO, MISUKONIS, MA, and WEINBERG, JB. "EFFECT OF NITRIC-OXIDE (NO) ON THE GROWTH AND DIFFERENTIATION OF FRESHLY ISOLATED ACUTE NONLYMPHOCYTIC LEUKEMIA (ANLL) CELLS." BLOOD 82.10 (November 15, 1993): A491-A491.
Source
wos-lite
Published In
Blood
Volume
82
Issue
10
Publish Date
1993
Start Page
A491
End Page
A491

LOCALIZATION OF THE GENE FOR INDUCIBLE NITRIC-OXIDE SYNTHASE TO DISTAL MOUSE CHROMOSOME-11 - RELEVANCE TO INFLAMMATION, ARTHRITIS, DIABETES-MELLITUS, AND AUTOIMMUNITY

Authors
WEINBERG, JB; GILKESON, GS; PISETSKY, DS; SELDIN, MF; MISUKONIS, MA; WOOD, ER; GRANGER, DL
MLA Citation
WEINBERG, JB, GILKESON, GS, PISETSKY, DS, SELDIN, MF, MISUKONIS, MA, WOOD, ER, and GRANGER, DL. "LOCALIZATION OF THE GENE FOR INDUCIBLE NITRIC-OXIDE SYNTHASE TO DISTAL MOUSE CHROMOSOME-11 - RELEVANCE TO INFLAMMATION, ARTHRITIS, DIABETES-MELLITUS, AND AUTOIMMUNITY." BLOOD 82.10 (November 15, 1993): A29-A29.
Source
wos-lite
Published In
Blood
Volume
82
Issue
10
Publish Date
1993
Start Page
A29
End Page
A29

HUMAN MONONUCLEAR PHAGOCYTE NITRIC-OXIDE SYNTHASE (NOS) - EVIDENCE FOR INDUCTION OF NOS MESSENGER-RNA AND PROTEIN WITHOUT DETECTABLE CAPACITY FOR NITRIC-OXIDE PRODUCTION

Authors
WEINBERG, JB; MISUKONIS, MA; WOOD, ER; SMITH, GL; SHAMI, PL; MASON, SN; GRANGER, DL
MLA Citation
WEINBERG, JB, MISUKONIS, MA, WOOD, ER, SMITH, GL, SHAMI, PL, MASON, SN, and GRANGER, DL. "HUMAN MONONUCLEAR PHAGOCYTE NITRIC-OXIDE SYNTHASE (NOS) - EVIDENCE FOR INDUCTION OF NOS MESSENGER-RNA AND PROTEIN WITHOUT DETECTABLE CAPACITY FOR NITRIC-OXIDE PRODUCTION." BLOOD 82.10 (November 15, 1993): A186-A186.
Source
wos-lite
Published In
Blood
Volume
82
Issue
10
Publish Date
1993
Start Page
A186
End Page
A186

TRIMETHOPRIM-SULFAMETHOXAZOLE PROPHYLAXIS IN GRANULOCYTOPENIC PATIENTS WITH ACUTE-LEUKEMIA - EVALUATION OF SERUM ANTIBIOTIC LEVELS IN A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED DEPARTMENT-OF-VETERANS-AFFAIRS COOPERATIVE STUDY

Authors
WARD, TT; THOMAS, RG; FYE, CL; ARBEIT, R; COLTMAN, CA; CRAIG, W; DANA, BW; FINEGOLD, SM; LENTINO, J; PENN, RL; WEINBERG, JB; CHOW, B; OCHI, S; WEBER, JH; LAYARD, MW; CHANG, P; GREENBERG, P; RIMLAND, D; BALDIWIN, V; MIREAULT, K; LAWRENCE, W; STANKO, S; HOBBS, E; OLMSTEAD, C; INGRAMDRAKE, L; NEILL, HB; DISNEY, C; YU, V; HAMILTON, R; LYMAN, GH; LYMAN, C; GALGIANI, J; KIZZIER, F; AMON, M; GRINICH, K; SEWELL, D; BASSETT, R; JACOBSON, I; JAMES, KE; FETTER, R; MONTANO, L; HICKS, R; SATHER, MR et al.
MLA Citation
WARD, TT, THOMAS, RG, FYE, CL, ARBEIT, R, COLTMAN, CA, CRAIG, W, DANA, BW, FINEGOLD, SM, LENTINO, J, PENN, RL, WEINBERG, JB, CHOW, B, OCHI, S, WEBER, JH, LAYARD, MW, CHANG, P, GREENBERG, P, RIMLAND, D, BALDIWIN, V, MIREAULT, K, LAWRENCE, W, STANKO, S, HOBBS, E, OLMSTEAD, C, INGRAMDRAKE, L, NEILL, HB, DISNEY, C, YU, V, HAMILTON, R, LYMAN, GH, LYMAN, C, GALGIANI, J, KIZZIER, F, AMON, M, GRINICH, K, SEWELL, D, BASSETT, R, JACOBSON, I, JAMES, KE, FETTER, R, MONTANO, L, HICKS, R, and SATHER, MR et al. "TRIMETHOPRIM-SULFAMETHOXAZOLE PROPHYLAXIS IN GRANULOCYTOPENIC PATIENTS WITH ACUTE-LEUKEMIA - EVALUATION OF SERUM ANTIBIOTIC LEVELS IN A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED DEPARTMENT-OF-VETERANS-AFFAIRS COOPERATIVE STUDY." CLINICAL INFECTIOUS DISEASES 17.3 (September 1993): 323-332.
PMID
8218671
Source
wos-lite
Published In
Clinical Infectious Diseases
Volume
17
Issue
3
Publish Date
1993
Start Page
323
End Page
332

Human immunodeficiency virus type 1 infection of human monocytes and macrophages does not alter their ability to generate an oxidative burst.

Human immunodeficiency virus type 1 (HIV-1) infects mononuclear phagocytes, cells that may serve as a reservoir for viral persistence. Infection with HIV-1 leads to progressive compromise of the immune system, resulting in infections with opportunistic pathogens and eventual death. Experiments were designed to determine if in vitro HIV-1 infection of mononuclear phagocytes would diminish their oxidative capabilities, thus decreasing their antimicrobial effectiveness. Blood monocytes and peritoneal macrophages were obtained from uninfected donors and inoculated with a monocytotropic strain of HIV-1. Hydrogen peroxide production and reduction of nitroblue tetrazolium were measured after acute stimulation of cells with PMA or a phagocytic stimulus. Despite vigorous virus production, no difference was seen in oxidative burst between uninfected cells and infected cells or between monocyte-derived and peritoneal macrophages. In conclusion, reduced antimicrobial activity of HIV-infected mononuclear phagocytes is probably not secondary to decreased ability to generate reactive oxygen species.

Authors
Dukes, CS; Matthews, TJ; Weinberg, JB
MLA Citation
Dukes, CS, Matthews, TJ, and Weinberg, JB. "Human immunodeficiency virus type 1 infection of human monocytes and macrophages does not alter their ability to generate an oxidative burst." J Infect Dis 168.2 (August 1993): 459-462.
PMID
8335985
Source
pubmed
Published In
Journal of Infectious Diseases
Volume
168
Issue
2
Publish Date
1993
Start Page
459
End Page
462

Synovial mononuclear phagocytes in rheumatoid arthritis and osteoarthritis: quantitative and functional aspects.

Macrophages are normal constituents of synovial tissue, and in inflammatory synovitis the number of synovial macrophages increases. Synovial macrophages and their secretory products are important in initiating, propagating, and maintaining the synovial inflammation in rheumatoid arthritis (RA). The purpose of this study was to determine the absolute numbers of macrophages in synovia resected from patients with RA and osteoarthritis (OA) and to determine their abilities to produce and/or functionally express tumor necrosis factor (TNF), interleukin-1 (IL-1), and tissue factor (thromboplastin). Results demonstrate that synovial tissue from RA patients (as compared to that from OA patients) weighed more, contained more cells, more macrophages, and more multinucleated giant cells (macrophage polykaryons). Also, isolated cells from both OA and RA patients had tissue factor activity and could produce TNF and IL-1 with in vitro culture, but these parameters were not different in cells from OA and RA patients. RA patients receiving glucocorticoid treatment for their arthritis had fewer total synovial cells than did patients not on glucocorticoids, but treatment with nonsteroidal anti-inflammatory agents did not alter cell numbers. Patient treatment with glucocorticoids or non-steroidal anti-inflammatory drugs did not influence the ability of their isolated cells to produce TNF or IL-1.

Authors
Weinberg, JB; Wortham, TS; Misukonis, MA; Patton, KL; Chitneni, SR
MLA Citation
Weinberg, JB, Wortham, TS, Misukonis, MA, Patton, KL, and Chitneni, SR. "Synovial mononuclear phagocytes in rheumatoid arthritis and osteoarthritis: quantitative and functional aspects." Immunol Invest 22.5 (July 1993): 365-374.
PMID
8406626
Source
pubmed
Published In
Immunological Investigations (Informa)
Volume
22
Issue
5
Publish Date
1993
Start Page
365
End Page
374

Tumor necrosis factor alpha as an autocrine and paracrine growth factor for ovarian cancer: monokine induction of tumor cell proliferation and tumor necrosis factor alpha expression.

Ovarian tumor cells produce macrophage colony stimulating factor, a potent chemoattractant for monocytes. Monocytes and macrophages produce tumor necrosis factor alpha (TNF-alpha) and interleukin 1 alpha or interleukin 1 beta (IL-1 beta) that can stimulate ovarian tumor cell growth. The present study has explored whether paracrine stimulation by monocyte derived cytokines might induce autocrine growth stimulation of normal and malignant ovarian epithelial cells. Endogenous expression of TNF-alpha mRNA was detected in ascites ovarian cancer cells isolated directly from patients, but not in established cultures of normal or malignant ovarian epithelial cells. When ascites tumor cells were cultured for 7 days, TNF-alpha expression ceased but could be reinduced by treatment with TNF-alpha or IL-1 beta. Ascites fluid contained concentrations of the cytokines that could mediate these effects. Similarly, treatment of normal or malignant ovarian epithelial cells with purified recombinant IL-1 beta or TNF-alpha induced transcription of TNF-alpha mRNA within 1 h. TNF-alpha protein could be detected by enzyme-linked immunosorbent assay in conditioned medium from IL-1 beta treated ovarian cancer cells. [3H]thymidine incorporation by normal or malignant ovarian epithelial cells was stimulated by a 24-h incubation with IL-1 beta or TNF-alpha. Stimulation of proliferation by IL-1 beta could be partially blocked by an antibody against TNF-alpha or by soluble TNF-alpha-receptor. Thus, TNF-alpha may function as both an autocrine and a paracrine growth factor in ovarian cancer.

Authors
Wu, S; Boyer, CM; Whitaker, RS; Berchuck, A; Wiener, JR; Weinberg, JB; Bast, RC
MLA Citation
Wu, S, Boyer, CM, Whitaker, RS, Berchuck, A, Wiener, JR, Weinberg, JB, and Bast, RC. "Tumor necrosis factor alpha as an autocrine and paracrine growth factor for ovarian cancer: monokine induction of tumor cell proliferation and tumor necrosis factor alpha expression." Cancer Res 53.8 (April 15, 1993): 1939-1944.
PMID
8385577
Source
pubmed
Published In
Cancer Research
Volume
53
Issue
8
Publish Date
1993
Start Page
1939
End Page
1944

DIFFERENTIAL MODULATION OF HIV-1 INFECTION OF A T-CELL LINE BY EXPRESSION OF TRANSFECTED CD44E AND CD44H ISOFORMS

Authors
RIVADENEIRA, ED; LIAO, HX; SAULS, DL; HAYNES, BF; WEINBERG, JB
MLA Citation
RIVADENEIRA, ED, LIAO, HX, SAULS, DL, HAYNES, BF, and WEINBERG, JB. "DIFFERENTIAL MODULATION OF HIV-1 INFECTION OF A T-CELL LINE BY EXPRESSION OF TRANSFECTED CD44E AND CD44H ISOFORMS." CLINICAL RESEARCH 41.2 (April 1993): A322-A322.
Source
wos-lite
Published In
Clinical Research
Volume
41
Issue
2
Publish Date
1993
Start Page
A322
End Page
A322

POTENT INHIBITION OF HIV-1 INFECTION OF MONONUCLEAR PHAGOCYTES BY SYNTHETIC PEPTIDE ANALOGS OF HIV-1 PROTEASE

Authors
DUKES, CS; MATTHEWS, TJ; LAMBERT, DM; DREYER, GB; PETTEWAY, SR; WEINBERG, JB
MLA Citation
DUKES, CS, MATTHEWS, TJ, LAMBERT, DM, DREYER, GB, PETTEWAY, SR, and WEINBERG, JB. "POTENT INHIBITION OF HIV-1 INFECTION OF MONONUCLEAR PHAGOCYTES BY SYNTHETIC PEPTIDE ANALOGS OF HIV-1 PROTEASE." JOURNAL OF CELLULAR BIOCHEMISTRY (March 29, 1993): 14-14.
Source
wos-lite
Published In
Journal of Cellular Biochemistry
Publish Date
1993
Start Page
14
End Page
14

Serum and ascitic fluid levels of interleukin-1, interleukin-6, and tumor necrosis factor-alpha in patients with ovarian epithelial cancer

Background. Recent studies have shown that multiple cytokines are secreted by ovarian epithelial cancer cells. Previous studies have shown that the cancer cell lines secrete macrophage colony-stimulating factor (M-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 (IL- 1), interleukin-6 (IL-6), and transforming growth factor-alpha (TGF-α). Concomitantly, the serum levels of one of the growth factors (M-CSF) was found to be significantly elevated in patients with primary ovarian cancer and in second-look patients. The authors evaluated the serum levels of IL-1 α, IL-1 β, IL-6, and tumor necrosis factor-alpha (TNF-α) in patients with primary ovarian epithelial cancer. These levels were then compared with cytokine concentration found in normal peritoneal fluid. Methods. Enzyme- linked immunosorbent assay (ELISA) was used to determine the levels of cytokines in normal peritoneal fluid, ascites, and serum. Results. In serum, TNF-α and IL-6 were significantly increased in primary ovarian cancer patients when compared with control subjects (P < 0.0001 for both cytokines). TNF-α and IL-6 were also significantly higher than the levels found in second-look patients (P < 0.007 for TNF-α, and P = 0.0002 for IL-6). The levels of IL-1 α and β were not elevated in ovarian cancer. TNF-α in the ascites was higher when compared with normal peritoneal fluid and was statistically significantly different when a cut-off point between 71-110 pg was selected (P < 0.005). The levels of IL-6 in ascites from patients with primary ovarian cancer also showed a marked increase (P < 0.0001) when compared with peritoneal fluid from control subjects. Conclusions. Levels of IL-1, IL-6, and TNF-α were determined in normal peritoneal fluid, ovarian malignant ascites, normal serum, and serum from patients with ovarian cancer. This study showed that the patients with ovarian cancer have elevated levels of IL-6 and TNF-α in serum and ascitic fluid. A larger study would help in evaluating the potential use of cytokines as tumor markers in ovarian cancer.

Authors
Moradi, MM; Carson, LF; Weinberg, JB; Haney, AF; Twiggs, LB; Ramakrishnan, S
MLA Citation
Moradi, MM, Carson, LF, Weinberg, JB, Haney, AF, Twiggs, LB, and Ramakrishnan, S. "Serum and ascitic fluid levels of interleukin-1, interleukin-6, and tumor necrosis factor-alpha in patients with ovarian epithelial cancer." Cancer 72.8 (1993): 2433-2440.
PMID
8402460
Source
scival
Published In
Cancer
Volume
72
Issue
8
Publish Date
1993
Start Page
2433
End Page
2440

Nitric oxide modulation of human leukemia cell differentiation and gene expression.

Nitric oxide (NO) functions as an intercellular messenger molecule in such varied contexts as neurotransmission, immune regulation, and the control of vascular tone. We report that NO, delivered as purified gas or released from the pharmacologic NO donors sodium nitroprusside or 6-morpholino-sydnonimine, caused monocytic differentiation of cells of the human myeloid leukemia cell line HL-60 and altered gene expression. The treated cells stopped proliferating, became spread and vacuolated, had increased expression of nonspecific esterase and the monocyte marker CD14, and displayed increased capacity to produce hydrogen peroxide. Furthermore, these treated cells had increased steady-state expression of messenger RNA (mRNA) for tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta), but decreased expression of mRNA for the proto-oncogenes c-myc and c-myb. The increase in TNF-alpha and IL-1 beta mRNA levels was due (at least in part) to a new transcription of these specific mRNAs. NO elaborated in the bone marrow microenvironment may have a role in normal and malignant hematopoietic cell growth and differentiation.

Authors
Magrinat, G; Mason, SN; Shami, PJ; Weinberg, JB
MLA Citation
Magrinat, G, Mason, SN, Shami, PJ, and Weinberg, JB. "Nitric oxide modulation of human leukemia cell differentiation and gene expression." Blood 80.8 (October 15, 1992): 1880-1884.
PMID
1382708
Source
pubmed
Published In
Blood
Volume
80
Issue
8
Publish Date
1992
Start Page
1880
End Page
1884

Disease severity in rheumatoid arthritis: relationships of plasma tumor necrosis factor-alpha, soluble interleukin 2-receptor, soluble CD4/CD8 ratio, neopterin, and fibrin D-dimer to traditional severity and functional measures.

Rheumatoid arthritis is a complex inflammatory disease of unknown cause. Although various laboratory and clinical measurements are useful in managing these patients, there is a need for better tests to quantitatively assess disease activity. The purpose of this study was to investigate the association of certain immune and inflammation (I-I) parameters with four traditional disease severity measures and a functional measure in rheumatoid arthritis patients. A single set of patient blood samples was analyzed, and four traditional disease severity measures and patient functional statuses were determined from 64 consecutive outpatients with rheumatoid arthritis. Plasma tumor necrosis factor-alpha (TNF), soluble interleukin-2 receptor (sIL-2R), sCD4 and sCD8 (and the sCD4/sCD8 ratio), neopterin, and fibrin D-dimer were analyzed in relationship to Westergren erythrocyte sedimentation rate (ESR), physician assessment of disease activity, joint pain count, grip strength, and Arthritis Impact Measurement Scale (AIMS) scores. Rheumatoid arthritis patients had higher mean levels of all I-I measures (except sCD4) compared to healthy subjects. Initial significant correlations between TNF, sIL-2R, and D-dimer and several disease severity and functional measures were detected. When we controlled for the covariates age, gender, race, and medications, regression analyses indicated that, as a group, the I-I measures were significantly related to grip strength, physician disease severity rating, ESR, and total joint pain. When the predictive values of the I-I measures were tested controlling for the covariates and ESR, D-dimer was independently and significantly associated with variability in grip strength, physician disease severity, and AIMS physical disability, while TNF was associated with a significant amount of variability in total joint pain.(ABSTRACT TRUNCATED AT 250 WORDS)

Authors
Beckham, JC; Caldwell, DS; Peterson, BL; Pippen, AM; Currie, MS; Keefe, FJ; Weinberg, JB
MLA Citation
Beckham, JC, Caldwell, DS, Peterson, BL, Pippen, AM, Currie, MS, Keefe, FJ, and Weinberg, JB. "Disease severity in rheumatoid arthritis: relationships of plasma tumor necrosis factor-alpha, soluble interleukin 2-receptor, soluble CD4/CD8 ratio, neopterin, and fibrin D-dimer to traditional severity and functional measures." J Clin Immunol 12.5 (September 1992): 353-361.
PMID
1430106
Source
pubmed
Published In
Journal of Clinical Immunology
Volume
12
Issue
5
Publish Date
1992
Start Page
353
End Page
361

Nuclear expression of the 50- and 65-kD Rel-related subunits of nuclear factor-kappa B is differentially regulated in human monocytic cells.

The nuclear factor (NF)-kappa B transcription factor system is composed of at least four inducible nucleoprotein adducts termed p50, p55 (NF-kappa B p50), p75 (NF-kappa B p65), and p85 (c-Rel). These proteins are expressed in the nuclei of activated T cells in a distinctly biphasic fashion, with p55 and p75 induction occurring within minutes whereas the induction of p50 and p85 occurs after several hours. In contrast, p50 and p55 are constitutively expressed in the nuclei of U937 and THP-1 monocytic cells. However, cellular activation is required for the nuclear expression of p75 in these cells. Additionally, activation of monocytic cells does not result in a significant induction of p85. Tumor necrosis factor alpha induces the nuclear expression of p55 and p75 in these monocytic cells within 20 min, presumably reflecting the liberation of these proteins from I kappa B. In contrast, phorbol myristate acetate (PMA) induces the expression of these proteins with delayed kinetics, raising the possibility that PMA is incapable of mediating the efficient release of p55 and p75 from I kappa B in these cells. These findings highlight important differences in the regulation of these proteins in monocytic cells versus T cells and suggest that the induced expression of NF-kappa B p65 in monocytes may play a central role in the activation of HIV-1 gene expression.

Authors
Kaufman, PA; Weinberg, JB; Greene, WC
MLA Citation
Kaufman, PA, Weinberg, JB, and Greene, WC. "Nuclear expression of the 50- and 65-kD Rel-related subunits of nuclear factor-kappa B is differentially regulated in human monocytic cells." J Clin Invest 90.1 (July 1992): 121-129.
PMID
1634604
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
90
Issue
1
Publish Date
1992
Start Page
121
End Page
129
DOI
10.1172/JCI115824

Inhibition of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) messenger RNA (mRNA) expression in HL-60 leukemia cells by pentoxifylline and dexamethasone: dissociation of acivicin-induced TNF-alpha and IL-1 beta mRNA expression from acivicin-induced monocytoid differentiation.

We have previously noted that the glutamine antagonist acivicin (alpha S,5S-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid) induces monocytoid differentiation of freshly isolated human myeloid leukemia cells and cells of the myeloid leukemia cell line HL-60, and that the differentiation is accompanied by increases in expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta). Because we also showed that TNF-alpha and IL-1 beta can act synergistically to cause monocytoid differentiation of HL-60 cells, we hypothesized that acivicin-induced TNF-alpha and IL-1 beta, in an autocrine manner, caused the differentiation. The purpose of the present study was to determine the causal roles of TNF-alpha and IL-1 beta in the acivicin-induced differentiation of HL-60 cells by the use of dexamethasone (DEX) and pentoxifylline (PTX), two drugs that effectively inhibit expression of TNF-alpha and IL-1 beta. Acivicin caused a monocytoid differentiation of the cells as manifest by diminished cell growth, morphologic maturation of the cells, increased ability to generate hydrogen peroxide in response to acute treatment with phorbol myristate acetate, and increased expression of nonspecific esterase and the surface antigens CD14 and CD11b. Acivicin treatment also caused the cells to have diminished steady-state expression of messenger RNA (mRNA) for c-myc and c-myb, and increased expression of mRNA for TNF-alpha and IL-1 beta. DEX and PTX did not alter cell growth, and did not block the acivicin-induced block in growth. PTX caused a slight increase in nonspecific esterase expression, but DEX had no effect on this, and neither drug diminished the acivicin-induced increase in nonspecific esterase. Although neither drug alone lessened the acivicin enhancement of hydrogen peroxide production, DEX and PTX together reduced this. DEX did not modify the acivicin-induced morphologic maturation of the cells, but PTX alone or PTX with DEX potentiated the acivicin-induced increase in mature cells. Basal CD14 and CD11b expression were slightly reduced by DEX and PTX, but neither drug modified the acivicin-induced increases. DEX and PTX reduced the acivicin-induced increases in TNF-alpha and IL-1 beta mRNA expression, but they had little or no effect on the acivicin-induced decreases in expression of mRNA for c-myc and c-myb. Thus, DEX and PTX effectively block the acivicin-induced expression of TNF-alpha and IL-1 beta, but they have little influence on the acivicin-induced differentiation process.(ABSTRACT TRUNCATED AT 250 WORDS)

Authors
Weinberg, JB; Mason, SN; Wortham, TS
MLA Citation
Weinberg, JB, Mason, SN, and Wortham, TS. "Inhibition of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) messenger RNA (mRNA) expression in HL-60 leukemia cells by pentoxifylline and dexamethasone: dissociation of acivicin-induced TNF-alpha and IL-1 beta mRNA expression from acivicin-induced monocytoid differentiation." Blood 79.12 (June 15, 1992): 3337-3343.
PMID
1596574
Source
pubmed
Published In
Blood
Volume
79
Issue
12
Publish Date
1992
Start Page
3337
End Page
3343

Flow cytometric analysis of nitric oxide production in human neutrophils using dichlorofluorescein diacetate in the presence of a calmodulin inhibitor.

Dichlorofluorescein (DCFH) oxidation assay measures hydrogen peroxide (H2O2), which is a derivative of superoxide anion. We found that a calmodulin antagonist, W-13, which is known to inhibit superoxide anion generation enhanced the capacity of human neutrophils to oxidize DCFH. To investigate this discrepancy we studied the role of nitric oxide (NO) in DCFH oxidation. Pure NO was capable of oxidizing DCFH, and the product formed had spectral properties identical to oxidized DCFH produced by H2O2. The arginine analog, NG-monomethyl-L-arginine (NMMA), which inhibits NO production, in combination with W-13 completely inhibited the stimulus-induced increase in DCFH oxidation. We conclude that the oxidation of DCFH in human neutrophils can occur by either H2O2 or NO.

Authors
Rao, KM; Padmanabhan, J; Kilby, DL; Cohen, HJ; Currie, MS; Weinberg, JB
MLA Citation
Rao, KM, Padmanabhan, J, Kilby, DL, Cohen, HJ, Currie, MS, and Weinberg, JB. "Flow cytometric analysis of nitric oxide production in human neutrophils using dichlorofluorescein diacetate in the presence of a calmodulin inhibitor." J Leukoc Biol 51.5 (May 1992): 496-500.
PMID
1602242
Source
pubmed
Published In
Journal of leukocyte biology
Volume
51
Issue
5
Publish Date
1992
Start Page
496
End Page
500

The lack of effect of tumor necrosis factor-alpha, interleukin-1-alpha, and interferon-gamma on human sperm motility in vitro.

Whether cytokines present in human peritoneal fluid reduce sperm motility, and thus contribute to infertility, is investigated. The human recombinant cytokines, tumor necrosis factor-alpha, interleukin-1-alpha, and interferon-gamma, were incubated with motile human sperm obtained from fertile men and separated by the swim-up technique. These cytokines, alone or in combination, in higher doses than those observed in vivo (greater than or equal to 25,000 U/ml), did not alter the percentage of motile sperm after 90 minutes, 24 hours, and 48 hours under standard culture conditions. Similarly, penetration of a column of bovine cervical mucus was unchanged after preincubation of the sperm with individual cytokines or combinations of several cytokines for 24 hours. In contrast to those given in previous reports, these dta do not support a direct effect of tumor necrosis factor-alpha, interleukin-1-alpha, or interferon-gamma on sperm motility, and suggest that other soluble factors are responsible for the observed effects of peritoneal fluid on sperm motility in vitro.

Authors
Haney, AF; Hughes, SF; Weinberg, JB
MLA Citation
Haney, AF, Hughes, SF, and Weinberg, JB. "The lack of effect of tumor necrosis factor-alpha, interleukin-1-alpha, and interferon-gamma on human sperm motility in vitro." J Androl 13.3 (May 1992): 249-253.
PMID
1601744
Source
pubmed
Published In
Journal of Andrology
Volume
13
Issue
3
Publish Date
1992
Start Page
249
End Page
253

NITRIC-OXIDE MODULATION OF HUMAN LEUKEMIA-CELL DIFFERENTIATION - INDUCTION OF TUMOR-NECROSIS-FACTOR MESSENGER-RNA BY NITRIC-OXIDE

Authors
MAGRINAT, GC; MASON, SN; SHAMI, PJ; WEINBERG, JB
MLA Citation
MAGRINAT, GC, MASON, SN, SHAMI, PJ, and WEINBERG, JB. "NITRIC-OXIDE MODULATION OF HUMAN LEUKEMIA-CELL DIFFERENTIATION - INDUCTION OF TUMOR-NECROSIS-FACTOR MESSENGER-RNA BY NITRIC-OXIDE." CLINICAL RESEARCH 40.2 (April 1992): A297-A297.
Source
wos-lite
Published In
Clinical Research
Volume
40
Issue
2
Publish Date
1992
Start Page
A297
End Page
A297

Stimulation of ovarian tumor cell proliferation with monocyte products including interleukin-1, interleukin-6, and tumor necrosis factor-alpha.

OBJECTIVE: We investigated whether monocyte-derived factors could stimulate the growth of ovarian cancer cells. STUDY DESIGN: Human peripheral blood monocytes or human monocyte-like cell lines THP-1 and U-937 were cultured with or without macrophage colony-stimulating factor, lipopolysaccharide, or phorbol myristate acetate. Culture supernatants or recombinant cytokines were assayed for growth stimulation of ovarian cancer cell lines by tritium-thymidine incorporation and direct cell counts followed by statistical analysis with Student t test. RESULTS: Conditioned medium from peripheral blood monocytes or from THP-1 or U-937 cells stimulated ovarian cancer cell growth. Interleukin-1 alpha, tumor necrosis factor-alpha, and interleukin-6 also stimulated ovarian cancer cell growth, whereas macrophage, granulocyte, and granulocyte-macrophage colony-stimulating factor did not. Concentrations of tumor necrosis factor, interleukin-1, and interleukin-6 in conditioned medium could not account for all the growth stimulation, and activity remained after neutralization of tumor necrosis factor, interleukin-1, and interleukin-6 with antibodies. CONCLUSIONS: Interleukin-1, interleukin-6, tumor necrosis factor, and additional monocyte factor(s) could provide paracrine growth stimulation when monocytes are attracted to ovarian cancers that produce macrophage colony-stimulating factor.

Authors
Wu, S; Rodabaugh, K; Martinez-Maza, O; Watson, JM; Silberstein, DS; Boyer, CM; Peters, WP; Weinberg, JB; Berek, JS; Bast, RC
MLA Citation
Wu, S, Rodabaugh, K, Martinez-Maza, O, Watson, JM, Silberstein, DS, Boyer, CM, Peters, WP, Weinberg, JB, Berek, JS, and Bast, RC. "Stimulation of ovarian tumor cell proliferation with monocyte products including interleukin-1, interleukin-6, and tumor necrosis factor-alpha." Am J Obstet Gynecol 166.3 (March 1992): 997-1007.
PMID
1550178
Source
pubmed
Published In
American Journal of Obstetrics & Gynecology
Volume
166
Issue
3
Publish Date
1992
Start Page
997
End Page
1007

Thrombomodulin expression by human blood monocytes and by human synovial tissue lining macrophages.

Thrombomodulin is an essential cofactor for the activation of the anticoagulant protein C by thrombin. We have identified the expression of thrombomodulin messenger RNA (mRNA) and protein in peripheral blood monocytes. While untreated monocytes expressed thrombomodulin mRNA by Northern blot analysis, lipopolysaccharide-treated cells had decreased mRNA expression. Thrombomodulin antigen was shown in the cytoplasm and on the surface of monocytes by immunohistochemical staining, and thrombomodulin activity was shown on the surface of intact monocytes. One population of synovial lining cells that normally expressed mononuclear phagocyte antigens also expressed thrombomodulin in both noninflamed osteoarthritic synovium and in inflamed rheumatoid arthritis synovium. However, these cells did not express another endothelial protein, von Willebrand factor. We conclude that both circulating and tissue mononuclear phagocytes are capable of expressing thrombomodulin.

Authors
McCachren, SS; Diggs, J; Weinberg, JB; Dittman, WA
MLA Citation
McCachren, SS, Diggs, J, Weinberg, JB, and Dittman, WA. "Thrombomodulin expression by human blood monocytes and by human synovial tissue lining macrophages." Blood 78.12 (December 15, 1991): 3128-3132.
PMID
1660324
Source
pubmed
Published In
Blood
Volume
78
Issue
12
Publish Date
1991
Start Page
3128
End Page
3132

Productive human immunodeficiency virus type 1 (HIV-1) infection of nonproliferating human monocytes.

Human immunodeficiency virus type 1 (HIV-1) infection of T lymphocytes requires cellular proliferation and DNA synthesis. Human monocytes were shown to have low DNA synthesis rates, yet the monocytotropic BaL isolate of HIV-1 was able to infect these cells efficiently. Monocytes that were irradiated to assure no DNA synthesis could also be readily infected with HIV-1BaL. Such infections were associated with the integration of HIV-1BaL DNA into the high molecular weight, chromosomal DNA of monocytes. Thus, normal, nonproliferating monocytes differ from T lymphocytes in that a productive HIV-1 infection can occur independently of cellular DNA synthesis. These results suggest that normal nonproliferating mononuclear phagocytes, which are relatively resistant to the destructive effects of this virus, may serve as persistent and productive reservoirs for HIV-1 in vivo.

Authors
Weinberg, JB; Matthews, TJ; Cullen, BR; Malim, MH
MLA Citation
Weinberg, JB, Matthews, TJ, Cullen, BR, and Malim, MH. "Productive human immunodeficiency virus type 1 (HIV-1) infection of nonproliferating human monocytes." J Exp Med 174.6 (December 1, 1991): 1477-1482.
PMID
1720811
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
174
Issue
6
Publish Date
1991
Start Page
1477
End Page
1482

The stimulus responsible for the peritoneal fluid inflammation observed in infertile women with endometriosis.

OBJECTIVE: We tested the hypothesis that menstrual debris from ectopic endometrium is the stimulus responsible for eliciting the peritoneal fluid (PF) inflammation observed in infertile women with endometriosis. DESIGN, SETTING, PATIENTS: The extent of endometriosis was correlated with the PF volume and total PF cell count retrospectively in 135 infertile women with endometriosis. RESULTS: The volume and total cell count were positively correlated, whereas the total cell count was negatively correlated with the extent of endometriosis. Despite a similar negative trend, no statistically significant correlation was noted between the volume and the extent of endometriosis. These relationships did not change when the data were reanalyzed deleting those pathological features contributing to the endometriosis score but not capable of producing intraperitoneal menstrual debris, i.e., adhesions and encapsulated ovarian endometriomas. CONCLUSIONS: These findings indicate that menstrual debris from ectopic endometrium is probably not a major factor in the elicitation of the observed PF inflammation in infertile women with endometriosis and suggest an inverse relationship may exist between PF inflammation and the extent of endometriosis.

Authors
Haney, AF; Jenkins, S; Weinberg, JB
MLA Citation
Haney, AF, Jenkins, S, and Weinberg, JB. "The stimulus responsible for the peritoneal fluid inflammation observed in infertile women with endometriosis." Fertil Steril 56.3 (September 1991): 408-413.
PMID
1894017
Source
pubmed
Published In
Fertility and Sterility
Volume
56
Issue
3
Publish Date
1991
Start Page
408
End Page
413

Lack of enhancing effect of human anti-human immunodeficiency virus type 1 (HIV-1) antibody on HIV-1 infection of human blood monocytes and peritoneal macrophages.

The influence of human anti-human immunodeficiency virus type 1 (HIV-1) antibody on HIV-1 infection of freshly isolated normal human peritoneal macrophages and blood monocytes was examined. Each of 14 HIV antibody-positive human serum samples was found to block the infection of four virus isolates (human T-cell lymphotropic virus type IIIBa-L [HTLV-IIIBa-L], HTLV-IIIB, D.U. 6587-7, and D.U. 7887-8) at serum dilutions ranging from 10(-1) to 10(-2). Three of these isolates (HTLV-IIIBa-L, D.U. 6587-7, and D.U. 7887-8) infected cultures of monocytes and macrophages rapidly and produced high levels of virus reverse transcriptase and p24 antigen. A fourth virus isolate (HTLV-IIIB) infected the monocytes and macrophages more slowly and produced low levels of viral protein. More dilute HIV antibody-positive sera had no significant effect on the overall level or rate of virus infection or expression. Complement did not appear to influence the course of infection by any combination of antisera or virus examined. Successful HIV-1 infection of the peritoneal macrophages and blood monocytes under the conditions tested showed strict dependence on CD4 since a recombinant CD4 polypeptide and an anti-CD4 monoclonal antibody effectively blocked the process.

Authors
Shadduck, PP; Weinberg, JB; Haney, AF; Bartlett, JA; Langlois, AJ; Bolognesi, DP; Matthews, TJ
MLA Citation
Shadduck, PP, Weinberg, JB, Haney, AF, Bartlett, JA, Langlois, AJ, Bolognesi, DP, and Matthews, TJ. "Lack of enhancing effect of human anti-human immunodeficiency virus type 1 (HIV-1) antibody on HIV-1 infection of human blood monocytes and peritoneal macrophages." J Virol 65.8 (August 1991): 4309-4316.
PMID
1712861
Source
pubmed
Published In
Journal of virology
Volume
65
Issue
8
Publish Date
1991
Start Page
4309
End Page
4316

Extravascular fibrin formation and dissolution in synovial tissue of patients with osteoarthritis and rheumatoid arthritis.

Fibrin deposition is a prominent finding in the synovium of patients with rheumatoid arthritis (RA). Macrophages are found in increased numbers in RA synovium, and these cells are known to produce a variety of procoagulant and anticoagulant molecules. Using immunohistologic techniques, the content and distribution of several important components of the coagulation system in the synovium of patients with RA, osteoarthritis (OA), or traumatic joint abnormalities requiring surgery were investigated. Samples from 3 patients from each category were examined in detail. RA synovium (compared with that of patients with OA or joint trauma) had increased numbers of macrophages and increased expression/content of fibrinogen, tissue factor, factor XIII, tissue transglutaminase, cross-linked fibrin (fibrin D dimer), urokinase-type plasminogen activator, and alpha 2-plasmin inhibitor. Macrophage content in RA synovium was increased in both the lining cell areas and the interstitial cell areas. Fibrinogen was distributed throughout the tissue in all samples and was greater in RA synovium. In trauma and OA synovia, tissue factor was seen only in association with vessels (endothelial cells), but in RA synovium, it was markedly increased throughout the tissues. While fibrin D dimer was seen in small amounts in synovial lining cell areas of trauma and OA synovia, it was present in increased amounts in the lining cell and interstitial cell areas of RA synovium. Factor XIII and tissue transglutaminase were present in scant amounts in trauma and OA synovia, but there were increased amounts of both (especially tissue transglutaminase) in RA synovium in the vessel, lining cell, and interstitial cell areas. Urokinase and alpha 2-plasmin inhibitor were also markedly increased in RA synovium. These results suggest that in inflamed synovium, there is ongoing extravascular tissue fibrin formation and dissolution that correlates with the degree of inflammation and macrophage content. Extravascular coagulation/fibrinolysis in RA represents a potential target for therapeutic intervention in this disease.

Authors
Weinberg, JB; Pippen, AM; Greenberg, CS
MLA Citation
Weinberg, JB, Pippen, AM, and Greenberg, CS. "Extravascular fibrin formation and dissolution in synovial tissue of patients with osteoarthritis and rheumatoid arthritis." Arthritis Rheum 34.8 (August 1991): 996-1005.
PMID
1677574
Source
pubmed
Published In
Arthritis and Rheumatism
Volume
34
Issue
8
Publish Date
1991
Start Page
996
End Page
1005

Peritoneal fluid and plasma levels of human macrophage colony-stimulating factor in relation to peritoneal fluid macrophage content.

The peritoneal fluid (PF) of women with infertility (especially in the presence of endometriosis) contains increased numbers of leukocytes, 90% to 95% of which are macrophages. The high numbers of peritoneal macrophages presumably result from an influx of blood monocytes into the peritoneum, and/or from local proliferation of peritoneal macrophages. Once in the peritoneal cavity, monocytes differentiate into tissue macrophages. Mononuclear phagocyte proliferation and differentiation are influenced by different cytokines, including macrophage colony-stimulating factor (M-CSF). The purpose of this study was to determine the relationship of M-CSF levels in human PF and plasma to the macrophage content, and to the patient diagnoses. Mean concentrations of PF M-CSF were higher than plasma levels (2.44 +/- 0.13 v 0.95 +/- 0.06 ng/mL, respectively). The mean concentrations of plasma M-CSF did not differ in samples from women of different diagnostic groups (normal, peritoneal adhesions, endometriosis, inactive pelvic inflammatory disease, uterine fibroids, and idiopathic infertility), but the PF concentration was slightly higher in normal women. The absolute (total) amount of PF M-CSF in normal women was lower than in those of the other diagnostic groups. The total amount of PF M-CSF in all women correlated closely with the total number of peritoneal macrophages. The tubal patency status (open versus closed) did not influence the plasma and PF concentrations of M-CSF, nor the PF absolute amount of M-CSF. The PF M-CSF may have come from peritoneal macrophages, fibroblasts, mesothelial cells, or endothelial cells. PF M-CSF may play important roles in the proliferation and/or the differentiation of peritoneal mononuclear phagocytes.

Authors
Weinberg, JB; Haney, AF; Xu, FJ; Ramakrishnan, S
MLA Citation
Weinberg, JB, Haney, AF, Xu, FJ, and Ramakrishnan, S. "Peritoneal fluid and plasma levels of human macrophage colony-stimulating factor in relation to peritoneal fluid macrophage content." Blood 78.2 (July 15, 1991): 513-516.
PMID
2070087
Source
pubmed
Published In
Blood
Volume
78
Issue
2
Publish Date
1991
Start Page
513
End Page
516

POSSIBLE ROLE OF THE HYALURONATE RECEPTOR (CD44) IN THE INVITRO INFECTION OF HUMAN MONOCYTES WITH HIV-1

Authors
RIVADENEIRA, ED; MATTHEWS, TJ; HAYNES, BF; WEINBERG, JB
MLA Citation
RIVADENEIRA, ED, MATTHEWS, TJ, HAYNES, BF, and WEINBERG, JB. "POSSIBLE ROLE OF THE HYALURONATE RECEPTOR (CD44) IN THE INVITRO INFECTION OF HUMAN MONOCYTES WITH HIV-1." CLINICAL RESEARCH 39.2 (April 1991): A382-A382.
Source
wos-lite
Published In
Clinical Research
Volume
39
Issue
2
Publish Date
1991
Start Page
A382
End Page
A382

MONOCYTES FROM HIV-1 SEROPOSITIVE INDIVIDUALS HAVE NORMAL ANTI-CRYPTOCOCCAL ACTIVITY

Authors
CAMERON, ML; SEBASTIAN, MW; GRANGER, DL; MATTHEWS, TJ; WEINHOLD, KJ; WEINBERG, JB
MLA Citation
CAMERON, ML, SEBASTIAN, MW, GRANGER, DL, MATTHEWS, TJ, WEINHOLD, KJ, and WEINBERG, JB. "MONOCYTES FROM HIV-1 SEROPOSITIVE INDIVIDUALS HAVE NORMAL ANTI-CRYPTOCOCCAL ACTIVITY." April 1991.
Source
wos-lite
Published In
Clinical Research
Volume
39
Issue
2
Publish Date
1991
Start Page
A361
End Page
A361

THE NF-KAPPA B (NF-KB) FAMILY OF TRANSCRIPTION FACTORS ARE REGULATED IN A DISTINCT MANNER IN HUMAN MONOCYTIC CELLS

Authors
KAUFMAN, PA; WEINBERG, JB; GREENE, WC
MLA Citation
KAUFMAN, PA, WEINBERG, JB, and GREENE, WC. "THE NF-KAPPA B (NF-KB) FAMILY OF TRANSCRIPTION FACTORS ARE REGULATED IN A DISTINCT MANNER IN HUMAN MONOCYTIC CELLS." CLINICAL RESEARCH 39.2 (April 1991): A209-A209.
Source
wos-lite
Published In
Clinical Research
Volume
39
Issue
2
Publish Date
1991
Start Page
A209
End Page
A209

ANALYSIS OF HYDROGEN-PEROXIDE PRODUCTION IN HUMAN MONOCYTES INFECTED INVITRO WITH HIV-1

Authors
DUKES, CS; MATTHEWS, TJ; WEINBERG, JB
MLA Citation
DUKES, CS, MATTHEWS, TJ, and WEINBERG, JB. "ANALYSIS OF HYDROGEN-PEROXIDE PRODUCTION IN HUMAN MONOCYTES INFECTED INVITRO WITH HIV-1." CLINICAL RESEARCH 39.2 (April 1991): A361-A361.
Source
wos-lite
Published In
Clinical Research
Volume
39
Issue
2
Publish Date
1991
Start Page
A361
End Page
A361

Relationship of acivicin-induced monocytoid differentiation of human myeloid leukemia cells to acivicin-induced modulation of growth factor, cytokine, and protooncogene mRNA expression.

We have previously noted that the glutamine antagonist acivicin (alpha S,5S-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid) induces monocytoid differentiation of freshly isolated human myeloid leukemia cells and HL-60 cells. This study was designed to determine the effects of acivicin on the levels of HL-60 cell mRNA transcripts of several cytokines, growth factors, and protooncogenes implicated in the control of hematopoietic cell proliferation and differentiation. Control HL-60 cells did not express mRNA for granulocyte-colony-stimulating factor, granulocyte-macrophage-colony-stimulating factor, interleukin 3, or interleukin 6, and acivicin or phorbol myristate acetate did not induce their expression. Phorbol myristate acetate reduced expression of c-myc, c-myb, and heat shock protein 70 and enhanced those of macrophage-colony-stimulating factor and c-fms. Acivicin caused a decreased expression of c-myc, and an increased expression of mRNA for interleukin 1 beta and tumor necrosis factor alpha (TNF-alpha). The drug also caused an initial increase in c-myb, followed by a subsequent decrease below baseline levels. Supernatants and lysates of acivicin-treated HL-60 cells contained increased levels of interleukin 1 beta. Both TNF-alpha and interleukin 1 beta have been shown previously to influence hematopoietic cell differentiation. In our experiments, exogenous interleukin 1 added to HL-60 cells did not induce differentiation, but the combination of interleukin 1 and TNF synergistically enhanced the process. Pretreatment of the cells with TNF enhanced their responsiveness to subsequent treatment with interleukin 1. Our results demonstrate that the glutamine antagonist acivicin modulates HL-60 cell expression of TNF-alpha, interleukin 1 beta, c-myc, and c-myb and suggest that interleukin 1 beta and TNF-alpha might (in an autocrine manner) cause the differentiation.

Authors
Weinberg, JB; Mason, SN
MLA Citation
Weinberg, JB, and Mason, SN. "Relationship of acivicin-induced monocytoid differentiation of human myeloid leukemia cells to acivicin-induced modulation of growth factor, cytokine, and protooncogene mRNA expression." Cancer Res 51.4 (February 15, 1991): 1202-1209.
PMID
1997162
Source
pubmed
Published In
Cancer Research
Volume
51
Issue
4
Publish Date
1991
Start Page
1202
End Page
1209

Human alveolar and peritoneal macrophages mediate fungistasis independently of L-arginine oxidation to nitrite or nitrate.

Human alveolar macrophages (HAM) from 28 normal volunteers were found to inhibit replication of Cryptococcus neoformans. Conditions under which fungistasis occurred were different than those required for mouse peritoneal macrophage-mediated fungistasis. Inhibition of fungal replication by mouse peritoneal macrophages (MPM) requires that the macrophages are activated and that the cocultures of C. neoformans and macrophages be done in the presence of serum, L-arginine, and endotoxin. During MPM-mediated fungistasis and tumor cell killing, L-arginine is oxidized to NO2-, NO3-, and L-citrulline. In addition, MPM have arginase activity that converts L-arginine to L-ornithine and urea. HAM-mediated fungistasis was similar to that mediated by MPM in terms of the serum requirement, but HAM did not require L-arginine or endotoxin. HAM did not produce NO2- or NO3- detectable by colorimetric and bioassay, nor did HAM produce L-citrulline or L-ornithine from 14C-radiolabeled L-arginine as detectable by reverse-phase ion-pairing HPLC of macrophage-C. neoformans coculture supernatants. HAM had no detectable arginase activity, hence there was no evidence for L-arginine nitrogen metabolism in HAM. HAM-mediated fungistasis was not enhanced by endotoxin or by recombinant human interferon-gamma (rHIFN-gamma). The combination of endotoxin and rHIFN-gamma inhibited the fungistatic effect of HAM. Human peritoneal macrophages (HPM) from women undergoing laparoscopy were tested for fungistasis and L-arginine nitrogen oxidation. Partial inhibition of cryptococcal replication occurred; however, there was no evidence of L-arginine metabolism to NO2- or NO3-.(ABSTRACT TRUNCATED AT 250 WORDS)

Authors
Cameron, ML; Granger, DL; Weinberg, JB; Kozumbo, WJ; Koren, HS
MLA Citation
Cameron, ML, Granger, DL, Weinberg, JB, Kozumbo, WJ, and Koren, HS. "Human alveolar and peritoneal macrophages mediate fungistasis independently of L-arginine oxidation to nitrite or nitrate." Am Rev Respir Dis 142.6 Pt 1 (December 1990): 1313-1319.
PMID
2123614
Source
pubmed
Published In
American Review of Respiratory Disease
Volume
142
Issue
6 Pt 1
Publish Date
1990
Start Page
1313
End Page
1319
DOI
10.1164/ajrccm/142.6_Pt_1.1313

HIV-1 INFECTION AND EXPRESSION IN NORMAL HUMAN MONOCYTES DOES NOT REQUIRE CELLULAR PROLIFERATION OR DNA-SYNTHESIS

Authors
WEINBERG, JB; MATTHEWS, TS
MLA Citation
WEINBERG, JB, and MATTHEWS, TS. "HIV-1 INFECTION AND EXPRESSION IN NORMAL HUMAN MONOCYTES DOES NOT REQUIRE CELLULAR PROLIFERATION OR DNA-SYNTHESIS." CLINICAL RESEARCH 38.2 (April 1990): A279-A279.
Source
wos-lite
Published In
Clinical Research
Volume
38
Issue
2
Publish Date
1990
Start Page
A279
End Page
A279

EXTRAVASCULAR FIBRIN FORMATION AND DISSOLUTION IN SYNOVIA FROM HUMANS WITH OSTEOARTHRITIS AND RHEUMATOID-ARTHRITIS - THE ROLE OF MACROPHAGES

Authors
WEINBERG, JB; PIPPEN, AM; WORTHAM, TS; GREENBERG, CS
MLA Citation
WEINBERG, JB, PIPPEN, AM, WORTHAM, TS, and GREENBERG, CS. "EXTRAVASCULAR FIBRIN FORMATION AND DISSOLUTION IN SYNOVIA FROM HUMANS WITH OSTEOARTHRITIS AND RHEUMATOID-ARTHRITIS - THE ROLE OF MACROPHAGES." CLINICAL RESEARCH 38.2 (April 1990): A589-A589.
Source
wos-lite
Published In
Clinical Research
Volume
38
Issue
2
Publish Date
1990
Start Page
A589
End Page
A589

HUMAN MONOCYTES INFECTED WITH HIV-1 HAVE REDUCED ANTICRYPTOCOCCAL ACTIVITY

Authors
CAMERON, ML; GRANGER, DL; WEINBERG, JB; MATTHEWS, TS
MLA Citation
CAMERON, ML, GRANGER, DL, WEINBERG, JB, and MATTHEWS, TS. "HUMAN MONOCYTES INFECTED WITH HIV-1 HAVE REDUCED ANTICRYPTOCOCCAL ACTIVITY." CLINICAL RESEARCH 38.2 (April 1990): A362-A362.
Source
wos-lite
Published In
Clinical Research
Volume
38
Issue
2
Publish Date
1990
Start Page
A362
End Page
A362

CA 125 in peritoneal fluid and serum from patients with benign gynecologic conditions and ovarian cancer

CA 125 was measured in peritoneal fluid from 200 patients with primary ovarian malignancies (35) and benign gynecologic conditions (165). In 86 patients CA 125 was measured both in peritoneal fluid and in serum. Patients with ovarian cancer had markedly greater serum CA 125 levels compared to patients with benign disease. CA 125 levels in peritoneal fluid were usually higher than serum levels. Twenty-six (93%) of 28 patients with ovarian cancer had peritoneal fluid levels which exceeded serum levels in paired samples. Peritoneal fluid CA 125 values greater than 200 U/ml identified ovarian cancer patients with 96% sensitivity and 99% specificity. Serum CA 125 values greater than 35 U/ml identified ovarian cancer patients bearing ascites with a sensitivity of 99% and specificity of 94%. Only 2 of 165 patients with benign gynecological conditions had peritoneal fluid values above 200 U/ml. By contrast, only two values below 200 U/ml were found in ascitic fluids from 35 patients with ovarian cancer. CA 125 levels in peritoneal fluid deserve further evaluation for follow-up of patients with ovarian cancer. © 1990.

Authors
Hunter, VJ; Weinberg, JB; Haney, AF; Soper, JT; Lavin, P; Metsch, L; Knapp, RC; Jr, RCB
MLA Citation
Hunter, VJ, Weinberg, JB, Haney, AF, Soper, JT, Lavin, P, Metsch, L, Knapp, RC, and Jr, RCB. "CA 125 in peritoneal fluid and serum from patients with benign gynecologic conditions and ovarian cancer." Gynecologic Oncology 36.2 (1990): 161-165.
PMID
2404835
Source
scival
Published In
Gynecologic Oncology
Volume
36
Issue
2
Publish Date
1990
Start Page
161
End Page
165

Human alveolar and peritoneal macrophages mediate fungistasis independently of L-arginine oxidation to nitrite or nitrate

Human alveolar macrophages (HAM) from 28 normal volunteers were found to inhibit replication of Cryptococcus neoformans. Conditions under which fungistasis occurred were different than those required for mouse peritoneal macrophage-mediated fungistasis. Inhibition of fungal replication by mouse peritoneal macrophages (MPM) requires that the macrophages are activated and that the cocultures of C. neoformans and macrophages be done in the presence of serum, L-arginine, and endotoxin. During MPM-mediated fungistasis and tumor cell killing, L-arginine is oxidized to NO-/2, NO-/3, and L-citrulline. In addition, MPM have arginase activity that converts L-arginine to L-ornithine and urea. HAM-mediated fungistasis was similar to that mediated by MPM in terms of the serum requirement, but HAM did not require L-arginine or endotoxin. HAM did not produce NO-/2 or NO-/3 detectable by colorimetric and bioassay, nor did HAM produce L-citrulline or L-ornithine from 14C-radiolabeled L-arginine as detectable by reverse-phase ion-pairing HPLC of macrophage-C. neoformans coculture supernatants. HAM had no detectable arginase activity, hence there was no evidence for L-arginine nitrogen metabolism in HAM. HAM-mediated fungistasis was not enhanced by endotoxin or by recombinant human interferon-γ (rHIFN-γ). The combination of endotoxin and rHIFN-γ inhibited the fungistatic effect of HAM. Human peritoneal macrophages (HPM) from women undergoing laparoscopy were tested for fungistasis and L-arginine nitrogen oxidation. Partial inhibition of cryptococcal replication occurred; however, there was no evidence of L-arginine metabolism to NO-/2 or NO-/3. The absence of L-arginine-dependent nitrogen oxidation in HAM and HPM, compared to MPM, during conditions under which fungistasis occurs suggests that this phenomenon is species specific rather than specific to the tissue origin of the macrophages.

Authors
Cameron, ML; Granger, DL; Weinberg, JB; Kozumbo, WJ; Koren, HS
MLA Citation
Cameron, ML, Granger, DL, Weinberg, JB, Kozumbo, WJ, and Koren, HS. "Human alveolar and peritoneal macrophages mediate fungistasis independently of L-arginine oxidation to nitrite or nitrate." American Review of Respiratory Disease 142.6 (1990): 1313-1319.
Source
scival
Published In
American Review of Respiratory Disease
Volume
142
Issue
6
Publish Date
1990
Start Page
1313
End Page
1319

HUMAN MACROPHAGE-COLONY STIMULATING FACTOR (M-CSF) LEVELS - A COMPARISON BETWEEN PLASMA AND PERITONEAL-FLUID LEVELS AND THEIR RELATION TO PERITONEAL-FLUID MACROPHAGE CONTENT

Authors
WEINBERG, JB; HANEY, AF; XU, FJ; RAMAKRISHNAN, S
MLA Citation
WEINBERG, JB, HANEY, AF, XU, FJ, and RAMAKRISHNAN, S. "HUMAN MACROPHAGE-COLONY STIMULATING FACTOR (M-CSF) LEVELS - A COMPARISON BETWEEN PLASMA AND PERITONEAL-FLUID LEVELS AND THEIR RELATION TO PERITONEAL-FLUID MACROPHAGE CONTENT." 1990.
Source
wos-lite
Published In
PHYSIOLOGICAL AND PATHOLOGICAL EFFECTS OF CYTOKINES
Volume
10
Publish Date
1990
Start Page
159
End Page
163

Sphingosine inhibits monocyte tissue factor-initiated coagulation by altering factor VII binding.

Tissue factor is a lipoprotein, expressed on the surface of cells, which binds coagulation Factor VII or VIIa, leading to activation of Factors X and IX with subsequent fibrin generation. Cellular tissue factor activity is important in pathophysiologic processes such as inflammation and disseminated intravascular coagulation. In this study, the long-chain base sphingosine inhibited coagulation initiated by lipopolysaccharide-stimulated intact human monocytes. Sphingosine (5-100 microM) also profoundly inhibited thromboplastin-initiated coagulation (greater than 90% decrease in thromboplastin activity). This inhibition was dose- and time-dependent. Sphingosine inhibited neither the intrinsic pathway of coagulation nor thrombin generation of fibrin. The sphingosine analogues sphingomyelin, ceramide, or N-acetylsphingosine did not affect thromboplastin activity, suggesting that the polar head of sphingosine was necessary for interaction of the molecule with the coagulation system. Investigation of the biochemical mechanism revealed that sphingosine (5-50 microM), but neither sphingomyelin nor ceramide, inhibited specific binding of radiolabeled Factor VII to lipopolysaccharide-stimulated intact monocytes. The results suggest that sphingosine may regulate monocyte tissue factor-initiated coagulation by modulating Factor VII binding to tissue factor. Sphingosine may represent a new class of inhibitors of hemostasis.

Authors
Conkling, PR; Patton, KL; Hannun, YA; Greenberg, CS; Weinberg, JB
MLA Citation
Conkling, PR, Patton, KL, Hannun, YA, Greenberg, CS, and Weinberg, JB. "Sphingosine inhibits monocyte tissue factor-initiated coagulation by altering factor VII binding." J Biol Chem 264.31 (November 5, 1989): 18440-18444.
PMID
2808383
Source
pubmed
Published In
The Journal of biological chemistry
Volume
264
Issue
31
Publish Date
1989
Start Page
18440
End Page
18444

Chemotactic peptide receptor-cytoskeletal interactions and functional correlations in differentiated HL-60 cells and human polymorphonuclear leukocytes.

We studied the chemotactic peptide receptor/cytoskeletal interactions in HL-60 cells induced to differentiate with different agents and attempted to correlate these observations with the acquisition of different functional responses. Dibutyryl cyclic AMP-treated cells showed rapid superoxide anion production in response to N-formyl-methionyl-leucyl-phenylalanine (FMLP) and slow, sustained response to phorbol myristate acetate (PMA). Retinoic acid-induced cells showed a slow, sustained response to both FMLP and PMA. Interferon-gamma-treated cells produced no superoxide anion on stimulation with FMLP, whereas tumor necrosis factor (TNF)-treated cells showed a slight response. Chemotactic peptide receptor association was the same in the HL-60 cells treated with different agents, despite marked differences in the superoxide anion generation and actin polymerization responses to FMLP and PMA in these cells. In mature neutrophils chemotactic peptide receptor association with the cytoskeleton was not affected by either pertussis or cholera toxin. However, both toxins inhibited FMLP-induced actin polymerization and superoxide anion generation. This suggested involvement of a G-protein similar to Gt, rather than Gi or Gs. Neither toxin had any effect on PMA-induced superoxide anion generation. These observations indicate that receptor association with the cytoskeleton may not have a significant role in affecting signal recognition and response. Among the several possible roles suggested, clearance of the occupied receptors may be the most important role of the cytoskeletal association. HL-60 cells induced to differentiate with different agents (because of their varied functional responses) might prove very useful in dissecting the molecular mechanisms regulating stimulus-induced activation of neutrophils.

Authors
Rao, KM; Currie, MS; Cohen, HJ; Weinberg, JB
MLA Citation
Rao, KM, Currie, MS, Cohen, HJ, and Weinberg, JB. "Chemotactic peptide receptor-cytoskeletal interactions and functional correlations in differentiated HL-60 cells and human polymorphonuclear leukocytes." J Cell Physiol 141.1 (October 1989): 119-125.
PMID
2550479
Source
pubmed
Published In
Journal of Cellular Physiology
Volume
141
Issue
1
Publish Date
1989
Start Page
119
End Page
125
DOI
10.1002/jcp.1041410118

Monocytoid differentiation of freshly isolated human myeloid leukemia cells and HL-60 cells induced by the glutamine antagonist acivicin.

Previously we showed that starvation of HL-60 promyelocytic leukemia cells for a single essential amino acid induced irreversible differentiation into more mature monocyte-like cells. Although not an essential amino acid, glutamine is important in the growth of normal and neoplastic cells. The glutamine analogue, alpha S,5S-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (acivicin) inhibits several glutamine-utilizing enzymes and therefore depletes cells of certain metabolic end products. The current study was designed to examine in vitro the effects of acivicin on growth and differentiation of several established human myeloid leukemia cell lines, including the HL-60 cell line, and of freshly isolated cells from patients with acute nonlymphocytic leukemia (ANLL). Four-day culture of HL-60 cells with acivicin at concentrations of 0.1 to 10.0 micrograms/mL (0.56 to 56 nmol/L) decreased cell growth by 33% to 88% as compared with untreated control cells. Viability of cells was greater than 92% for untreated cells and 93% to 41% for acivicin-treated cells. Cells treated with acivicin differentiated along a monocytic pathway as shown by increased H2O2 production and alpha-naphthyl butyrate esterase (NSE) content. Differentiation was time and dose dependent, and was irreversible. Changes in H2O2 production and NSE content were partially abrogated by co-culture with 10 mmol/L exogenous cytidine and guanosine but not by co-culture with other nucleosides or glutamine. At these concentrations of acivicin, differentiation was associated with expression of the N-formyl-methyl-leucyl-phenylalanine-receptor (FMLP-R) on 8% to 29% of cells as compared with 8% for control cells. Acivicin potentiated the differentiating effects of interferon-gamma, tumor necrosis factor, dihydroxyvitamin D3, dimethylsulfoxide, and retinoic acid. Culture of cells from the U937 (monoblastic), K562 (erythroleukemia), and KG-1 (myeloblastic) cell lines resulted in decreased growth and viability, but not consistently in differentiation. Acivicin decreased survival of freshly isolated ANLL cells and increased their H2O2 production and NSE content. These results suggest that the glutamine analogue acivicin may be useful as a differentiating agent with antileukemia activity in patients with ANLL.

Authors
Nichols, KE; Chitneni, SR; Moore, JO; Weinberg, JB
MLA Citation
Nichols, KE, Chitneni, SR, Moore, JO, and Weinberg, JB. "Monocytoid differentiation of freshly isolated human myeloid leukemia cells and HL-60 cells induced by the glutamine antagonist acivicin." Blood 74.5 (October 1989): 1728-1737.
PMID
2790198
Source
pubmed
Published In
Blood
Volume
74
Issue
5
Publish Date
1989
Start Page
1728
End Page
1737

EXTRAVASCULAR COAGULATION IN HUMANS - MACROPHAGE CONTENT AND FIBRIN D-DIMER LEVELS IN PERITONEAL-FLUID AND PLASMA IN NORMAL AND INFERTILE WOMEN WITH INFLAMMATORY PERITONEAL DISORDERS

Authors
WEINBERG, JB; HANEY, AF; WORTHAM, TS; DOTY, E
MLA Citation
WEINBERG, JB, HANEY, AF, WORTHAM, TS, and DOTY, E. "EXTRAVASCULAR COAGULATION IN HUMANS - MACROPHAGE CONTENT AND FIBRIN D-DIMER LEVELS IN PERITONEAL-FLUID AND PLASMA IN NORMAL AND INFERTILE WOMEN WITH INFLAMMATORY PERITONEAL DISORDERS." JOURNAL OF LEUKOCYTE BIOLOGY 46.4 (October 1989): 303-304.
Source
wos-lite
Published In
Journal of leukocyte biology
Volume
46
Issue
4
Publish Date
1989
Start Page
303
End Page
304

GLUCOCORTICOID MODULATION OF CYTOKINE-MEDIATED MACROPHAGE FIBROBLAST INTERACTIONS

Authors
BACHUS, KE; WEINBERG, JB; DOTY, E; HANEY, AF
MLA Citation
BACHUS, KE, WEINBERG, JB, DOTY, E, and HANEY, AF. "GLUCOCORTICOID MODULATION OF CYTOKINE-MEDIATED MACROPHAGE FIBROBLAST INTERACTIONS." JOURNAL OF LEUKOCYTE BIOLOGY 46.4 (October 1989): 293-293.
Source
wos-lite
Published In
Journal of leukocyte biology
Volume
46
Issue
4
Publish Date
1989
Start Page
293
End Page
293

Human mononuclear phagocyte transglutaminase activity cross-links fibrin.

The physiologic function of the monocyte transglutaminases is not known. In this study, we detected Factor XIII A-subunit antigen and "tissue" transglutaminase antigen in human monocytes by polyacrylamide gel electrophoresis and immunoblotting techniques. Flow cytometric analysis demonstrated that 27% and 49% of the total Factor XIII antigen in monocytes and human peritoneal macrophages, respectively, are expressed on the surface of the cells. Monocytes maintained in culture for 8 days had a 4-fold increase in Factor XIIIa activity and a 3.2-fold increase in the amount of Factor XIII antigen/mg cell protein. However, there was no increase in the "tissue" transglutaminase activity or antigen levels in cultured monocytes. In addition, we identified a Factor XIII deficient individual who does not express Factor XIII activity or antigen in plasma, platelets, monocytes, lymphocytes or erythrocytes. Intact monocytes from normal donors were able to cross-link fibrin formed in the plasma from the Factor XIII deficient individual. This suggests that transglutaminase activity expressed by peripheral blood monocytes may play a physiologic role in cross-linking fibrin during blood clotting or inflammation.

Authors
Conkling, PR; Achyuthan, KE; Greenberg, CS; Newcomb, TF; Weinberg, JB
MLA Citation
Conkling, PR, Achyuthan, KE, Greenberg, CS, Newcomb, TF, and Weinberg, JB. "Human mononuclear phagocyte transglutaminase activity cross-links fibrin." Thromb Res 55.1 (July 1, 1989): 57-68.
PMID
2571199
Source
pubmed
Published In
Thrombosis Research
Volume
55
Issue
1
Publish Date
1989
Start Page
57
End Page
68

Sequential development of polycythemia vera and chronic myelocytic leukemia in a patient following radiation exposure from nuclear weapons tests.

Authors
Weinberg, JB
MLA Citation
Weinberg, JB. "Sequential development of polycythemia vera and chronic myelocytic leukemia in a patient following radiation exposure from nuclear weapons tests." Am J Med 87.1 (July 1989): 121-123.
PMID
2741974
Source
pubmed
Published In
The American Journal of Medicine
Volume
87
Issue
1
Publish Date
1989
Start Page
121
End Page
123

Essential amino acid deprivation induces monocytic differentiation of the human HL-60 myeloid leukemia cell line.

In this study we examine the effects of amino acid deprivation on the growth and differentiation of the human HL-60 myeloid leukemia cell line. The HL-60 cell line was chosen for study because of its ability to differentiate along either a granulocytic or monocytic pathway under appropriate culture conditions. Differentiation was determined by changes in cell morphology, nonspecific esterase (NSE) content, hydrogen peroxide (H2O2) production, and expression of the cell surface differentiation antigens LeuM3 (CD14) and OKM1 (CD11). Using a model system in which HL-60 cells were cultured in medium that selectively lacked one amino acid (AA), it was seen that deprivation of HL-60 cells for essential (but not nonessential) AAs results in decreased cell growth and viability and in differentiation of 30% to 60% of the surviving population of cells specifically along the monocytic pathway. This differentiation is irreversible as well as time- and dose-dependent. Culture of HL-60 cells in essential AA-deficient medium potentiated the differentiative effects of recombinant human interferon-gamma (IFN-gamma), recombinant human tumor necrosis factor (TNF), and dihydroxyvitamin D3 (D3), all of which have previously been shown to induce monocytic differentiation of HL-60 cells. Differentiated cells had decreased DNA and RNA synthesis, but protein synthesis was unchanged compared with control cells. The protein synthesis inhibitor cycloheximide prevented differentiation, indicating the necessity of protein synthesis in this process. Cell cycle analysis revealed that an increased proportion of cells cultured in AA-deficient medium was arrested in G0-G1 (80% and 50% for AA-deficient and control cells, respectively). These results suggest that alterations of AA metabolism and subsequent perturbations in DNA and RNA synthesis may be important in initiating differentiation or in augmenting cytokine-induced differentiation of HL-60 cells into more mature, nonreplicating, monocyte-like cells.

Authors
Nichols, KE; Weinberg, JB
MLA Citation
Nichols, KE, and Weinberg, JB. "Essential amino acid deprivation induces monocytic differentiation of the human HL-60 myeloid leukemia cell line." Blood 73.5 (April 1989): 1298-1306.
PMID
2467706
Source
pubmed
Published In
Blood
Volume
73
Issue
5
Publish Date
1989
Start Page
1298
End Page
1306

EXTRAVASCULAR COAGULATION IN HUMANS - FIBRIN D-DIMER LEVELS AND MACROPHAGE CONTENT IN PERITONEAL-FLUID AND PLASMA IN NORMAL AND DISEASE STATES

Authors
WEINBERG, JB; HANEY, AF; DOTY, E
MLA Citation
WEINBERG, JB, HANEY, AF, and DOTY, E. "EXTRAVASCULAR COAGULATION IN HUMANS - FIBRIN D-DIMER LEVELS AND MACROPHAGE CONTENT IN PERITONEAL-FLUID AND PLASMA IN NORMAL AND DISEASE STATES." CLINICAL RESEARCH 37.2 (April 1989): A551-A551.
Source
wos-lite
Published In
Clinical Research
Volume
37
Issue
2
Publish Date
1989
Start Page
A551
End Page
A551

ACIVICIN-INDUCED MONOCYTIC DIFFERENTIATION OF HUMAN-LEUKEMIA CELLS CORRELATION OF DIFFERENTIATION EFFECTS WITH ALTERATIONS IN GENE-EXPRESSION

Authors
NICHOLS, KE; MASON, SN; WEINBERG, JB
MLA Citation
NICHOLS, KE, MASON, SN, and WEINBERG, JB. "ACIVICIN-INDUCED MONOCYTIC DIFFERENTIATION OF HUMAN-LEUKEMIA CELLS CORRELATION OF DIFFERENTIATION EFFECTS WITH ALTERATIONS IN GENE-EXPRESSION." CLINICAL RESEARCH 37.2 (April 1989): A384-A384.
Source
wos-lite
Published In
Clinical Research
Volume
37
Issue
2
Publish Date
1989
Start Page
A384
End Page
A384

Alpha 2 macroglobulin-proteinase complexes stimulate prostaglandin E2 synthesis by peritoneal macrophages.

alpha 2-Macroglobulin is a proteinase inhibitor which is converted from its native form into an electrophoretically "fast" form by reaction with a proteinase or methylamine. All alpha 2M "fast" forms bind to a specific high-affinity receptor on macrophages. alpha 2M "fast" forms inhibit the interferon-gamma (IFN)-induced increase in macrophage Ia expression. This study examined whether alpha 2M-proteinase complexes alter prostaglandin (PG) E2 synthesis, and whether PGE2 mediates alpha 2M "fast" forms effects on macrophage Ia expression. Culture with alpha 2M "fast" forms increased PGE2 accumulation in the medium over control values in a dose-dependent manner. Culture with IFN alone did not increase PGE2 levels, but potentiated the effect of alpha 2M-proteinase complexes on PGE2 levels. Inhibition of PGE2 synthesis did not alter the inhibitory effect of alpha 2M-proteinase complexes on IFN-induced Ia expression. However, exogenous PGE2 did suppress IFN-induced Ia expression. Thus, alpha 2M-proteinase complexes increase macrophage PGE2 synthesis, but increased synthesis of PGE2 or other cyclooxygenase products is not the mediator of antagonism of IFN-induced Ia expression by alpha 2M-proteinase complexes.

Authors
Hoffman, M; Pizzo, SV; Weinberg, JB
MLA Citation
Hoffman, M, Pizzo, SV, and Weinberg, JB. "Alpha 2 macroglobulin-proteinase complexes stimulate prostaglandin E2 synthesis by peritoneal macrophages." Agents Actions 25.3-4 (December 1988): 360-367.
PMID
2464277
Source
pubmed
Published In
Agents and Actions
Volume
25
Issue
3-4
Publish Date
1988
Start Page
360
End Page
367

HEMATOLOGIC AND SURGICAL-MANAGEMENT OF THE DENTAL PATIENT WITH PLASMINOGEN-ACTIVATOR DEFICIENCY

Authors
SCHEITLER, LE; HART, N; PHILLIPS, G; WEINBERG, JB
MLA Citation
SCHEITLER, LE, HART, N, PHILLIPS, G, and WEINBERG, JB. "HEMATOLOGIC AND SURGICAL-MANAGEMENT OF THE DENTAL PATIENT WITH PLASMINOGEN-ACTIVATOR DEFICIENCY." ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY AND ENDODONTICS 66.6 (December 1988): 680-682.
PMID
2974525
Source
wos-lite
Published In
Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology
Volume
66
Issue
6
Publish Date
1988
Start Page
680
End Page
682
DOI
10.1016/0030-4220(88)90317-9

Clinical trials with human tumor necrosis factor: in vivo and in vitro effects on human mononuclear phagocyte function.

The purpose of this investigation was to understand the biological effects of recombinant human tumor necrosis factor used as therapy for cancer. We studied changes in mononuclear phagocyte function following exposure to this cytokine in vitro or in vivo. Tumor necrosis factor increased phorbol myristate acetate-induced hydrogen peroxide production 8- to 20-fold in peripheral blood monocytes and peritoneal macrophages in vitro in a dose-dependent manner. Similarly, tumor necrosis factor increased phorbol myristate acetate-induced peroxide production 2.3-fold in monocytes isolated from nine patients following an i.v. infusion of this cytokine (40 to 200 micrograms/m2). In addition, tumor necrosis factor induced a 2.3-fold increase in tissue factor-like activity in mononuclear phagocytes in vitro. In vivo, tumor necrosis factor induced a trend toward higher procoagulant activity in monocytes, although this change was not statistically significant. We also noted a trend toward increased activated partial thromboplastin times and the presence of fibrin D-dimer in patients treated with tumor necrosis factor, demonstrating activation of the coagulation and fibrinolytic systems. Thus, in vivo treatment of humans with i.v. recombinant human tumor necrosis factor induced functional changes in mononuclear phagocytes similar to those noted with in vitro treatment.

Authors
Conkling, PR; Chua, CC; Nadler, P; Greenberg, CS; Doty, E; Misukonis, MA; Haney, AF; Bast, RC; Weinberg, JB
MLA Citation
Conkling, PR, Chua, CC, Nadler, P, Greenberg, CS, Doty, E, Misukonis, MA, Haney, AF, Bast, RC, and Weinberg, JB. "Clinical trials with human tumor necrosis factor: in vivo and in vitro effects on human mononuclear phagocyte function." Cancer Res 48.19 (October 1, 1988): 5604-5609.
PMID
3046744
Source
pubmed
Published In
Cancer Research
Volume
48
Issue
19
Publish Date
1988
Start Page
5604
End Page
5609

SYNOVIAL TISSUE MACROPHAGES IN HUMAN RHEUMATOID-ARTHRITIS AND OSTEO-ARTHRITIS

Authors
CHITNENI, SR; PATTON, KL; WEINBERG, JB
MLA Citation
CHITNENI, SR, PATTON, KL, and WEINBERG, JB. "SYNOVIAL TISSUE MACROPHAGES IN HUMAN RHEUMATOID-ARTHRITIS AND OSTEO-ARTHRITIS." JOURNAL OF LEUKOCYTE BIOLOGY 44.4 (October 1988): 302-303.
Source
wos-lite
Published In
Journal of leukocyte biology
Volume
44
Issue
4
Publish Date
1988
Start Page
302
End Page
303

α2Macroglobulin-proteinase complexes stimulate prostaglandin E2 synthesis by peritoneal macrophages

α 2 Macroglobulin is a proteinase inhibitor which is converted from its native form into an electrophoretically "fast" form by reaction with a proteinase or methylamine. All α 2 M "fast" forms bind to a specific high-affinity receptor on macrophages. α 2 M "fast" forms inhibit the interferon-γ (IFN)-induced increase in macrophage Ia expression. This study examined whether α 2 M-proteinase complexes alter prostaglandin (PG) E 2 synthesis, and whether PGE 2 mediates α 2 M "fast" forms effects on macrophage Ia expression. Culture with α 2 M "fast" forms increased PGE 2 accumulation in the medium over control values in a dose-dependent manner. Culture with IFN alone did not increase PGE 2 levels, but potentiated the effect of α 2 M-proteinase complexes on PGE 2 levels. Inhibition of PGE 2 synthesis did not alter the PGE 2 did suppress IFN-induced Ia expression. Thus, α 2 M-proteinase complexes increase macrophage PGE 2 synthesis, but increased synthesis of PGE 2 or other cyclooxygenase products is not the mediator of antagonism of IFN-induced Ia expression by α 2 M-proteinase complexes. © 1988 Birkhäusver Verlag.

Authors
Hoffman, M; Pizzo, SV; Weinberg, JB
MLA Citation
Hoffman, M, Pizzo, SV, and Weinberg, JB. 2Macroglobulin-proteinase complexes stimulate prostaglandin E2 synthesis by peritoneal macrophages." Agents and Actions 25.3-4 (September 1, 1988): 360-367.
Source
scopus
Published In
Agents and Actions
Volume
25
Issue
3-4
Publish Date
1988
Start Page
360
End Page
367
DOI
10.1007/BF01965043

Reduction of the intraperitoneal inflammation associated with endometriosis by treatment with medroxyprogesterone acetate.

An intraperitoneal inflammatory exudate has been repeatedly observed in infertile women without mechanical compromise of the pelvic viscera, particularly with endometriosis. This is manifested by increases in the peritoneal fluid volume, leukocyte number, and proteolytic enzyme concentrations. We tested the hypothesis that the stimulus responsible for eliciting this intraperitoneal inflammation is retrograde menstruation by measuring the peritoneal fluid volume and leukocyte count in 16 infertile women with endometriosis before and after ovulation suppression with medroxyprogesterone acetate, 30 mg/day for 4 months. Medroxyprogesterone acetate therapy significantly reduced the peritoneal fluid volume (22.5 +/- 4.1 versus 6.8 +/- 0.9 ml mean +/- SE, p less than 0.0001), the peritoneal fluid leukocyte count (30.7 +/- 6.5 versus 7.1 +/- 0.7 x 10(6) cells per patient, p less than 0.0001), and American Fertility Society score (23.2 +/- 5.1 versus 15.4 +/- 4.1, p less than 0.0002). We conclude that medroxyprogesterone acetate treatment reduces the intraperitoneal exudate associated with endometriosis. These results support the contention that the stimulus eliciting the intraperitoneal inflammation in infertile women with endometriosis is retrograde menstruation.

Authors
Haney, AF; Weinberg, JB
MLA Citation
Haney, AF, and Weinberg, JB. "Reduction of the intraperitoneal inflammation associated with endometriosis by treatment with medroxyprogesterone acetate." Am J Obstet Gynecol 159.2 (August 1988): 450-454.
PMID
3407705
Source
pubmed
Published In
American Journal of Obstetrics & Gynecology
Volume
159
Issue
2
Publish Date
1988
Start Page
450
End Page
454

Reduced trypsin-binding capacity of alpha 2-macroglobulin in the peritoneal fluid of women with endometriosis: possible relevance to alterations in macrophase function.

Alpha 2-macroglobulin (alpha 2M) is a plasma protein with proteinase inhibitor and immune modulatory capabilities. The amounts of alpha 2M in peritoneal fluid (PF) from women with endometriosis and women with noninflammatory gynecologic conditions were analyzed by functional (trypsin binding) and immunologic assays. The most important finding of this study was that a significant amount of the alpha 2M in the peritoneal fluid of patients with endometriosis had been inactivated by an as yet undetermined mechanism. The concentration and total amount of immunologically reactive alpha 2M in the samples varied widely and was not significantly different between the groups. However, women with endometriosis had significantly lower amounts of functional alpha 2M than did women without endometriosis. There was no significant difference between functional and immunologic measurements of alpha 2M in samples from women without endometriosis. Women with endometriosis, however, had less functional than immunologically reactive alpha 2M. This discrepancy was not due to inactivation of alpha 2M by having previously bound proteinase. Alpha 2M-proteinase complexes can down-regulate macrophase functions. It is possible that decreased proteinase-binding ability of alpha 2M may play a role in the pathogenesis of endometriosis and associated infertility by decreasing negative feedback control of macrophage activities.

Authors
Hoffman, M; Haney, AF; Weinberg, JB
MLA Citation
Hoffman, M, Haney, AF, and Weinberg, JB. "Reduced trypsin-binding capacity of alpha 2-macroglobulin in the peritoneal fluid of women with endometriosis: possible relevance to alterations in macrophase function." Fertil Steril 50.1 (July 1988): 39-47.
PMID
2454848
Source
pubmed
Published In
Fertility and Sterility
Volume
50
Issue
1
Publish Date
1988
Start Page
39
End Page
47

Tumor necrosis factor induces tissue factor-like activity in human leukemia cell line U937 and peripheral blood monocytes.

The induction of procoagulant activity (PCA) by human recombinant tumor necrosis factor (rTNF) was studied in human monoblastic leukemia cell line U937 and human peripheral blood monocytes. Using a one-step recalcificating clotting assay, PCA in cell lysates or whole cell preparations was measured by comparison to a rabbit brain thromboplastin standard. There was a dose- and time-dependent increase in PCA when U937 cells were cultured with rTNF. The effect of rTNF was not enhanced by recombinant human interferon-gamma (rIFN gamma). Cycloheximide inhibited the expression of PCA by U937 cells, showing that protein synthesis was necessary to mediate the effects of rTNF. Whole cell preparations demonstrated that greater than 80% of the PCA was expressed on the surface of the cells. The PCA functioned as a tissue factor-like substance, since it required coagulation factor VII and factor X. rTNF also increased PCA in human monocytes in a dose- and time-dependent manner. This effect was abrogated by boiling the rTNF for ten minutes, and was not inhibited by adding polymyxin-B to the cultures, making it unlikely that endotoxin accounted for the observed effects. These results suggest that TNF-induced expression of tissue factor by mononuclear phagocytes may modulate immunologic, inflammatory, and hemostatic processes.

Authors
Conkling, PR; Greenberg, CS; Weinberg, JB
MLA Citation
Conkling, PR, Greenberg, CS, and Weinberg, JB. "Tumor necrosis factor induces tissue factor-like activity in human leukemia cell line U937 and peripheral blood monocytes." Blood 72.1 (July 1988): 128-133.
PMID
3134064
Source
pubmed
Published In
Blood
Volume
72
Issue
1
Publish Date
1988
Start Page
128
End Page
133

Human T-cell lymphotropic virus I and adult T-cell leukemia: report of a cluster in North Carolina.

PURPOSE: Human adult T-cell leukemia-lymphoma is a malignant, proliferative disease of CD4+ lymphocytes associated with infection with human T-cell lymphotropic virus type I (HTLV-I). Following the presentation of a patient who was infected with the virus, we undertook a study of his family members and sexual contacts to see if a cluster of infected persons could be identified. CASE REPORT: A black heterosexual North Carolina native with a history of drug abuse presented with jaundice, and pancytopenia subsequently developed. He then became hypercalcemic and leukemic, with high numbers of circulating, morphologically abnormal CD4+ lymphocytes. RESULTS: As determined by radioimmunoassay and immunoblot analyses, the serum of the index case contained antibodies against core proteins (p19 and p24) of HTLV-I. When cultured in vitro with interleukin-2, the lymphocytes expressed HTLV-I specific core proteins. The virus recovered from these T cells was transmitted to cord blood T cells, which became immortalized for continuous growth in vitro, expressed HTLV-I p19 protein, and displayed characteristic C-type particles by electron microscopy. Studies of family members and sexual contacts, all of whom were black, heterosexual central North Carolina natives, revealed five of 28 whose serum had anti-HTLV-I antibodies as determined by radioimmunoassay and immunoblot. Neither the patient nor the seropositive family/contacts had antibodies against human immunodeficiency virus proteins. Four of the six people with HTLV-I infection had no history of intravenous drug abuse. Three of the five seropositive family/contacts had circulating, morphologically abnormal lymphocytes suggestive of "preleukemic" or "smoldering" human adult T-cell leukemia-lymphoma.

Authors
Weinberg, JB; Spiegel, RA; Blazey, DL; Janssen, RS; Kaplan, JE; Robert-Guroff, M; Popovic, M; Matthews, TJ; Haynes, BF; Palker, TJ
MLA Citation
Weinberg, JB, Spiegel, RA, Blazey, DL, Janssen, RS, Kaplan, JE, Robert-Guroff, M, Popovic, M, Matthews, TJ, Haynes, BF, and Palker, TJ. "Human T-cell lymphotropic virus I and adult T-cell leukemia: report of a cluster in North Carolina." Am J Med 85.1 (July 1988): 51-58.
PMID
2898891
Source
pubmed
Published In
The American Journal of Medicine
Volume
85
Issue
1
Publish Date
1988
Start Page
51
End Page
58

Cooperative effect of tumor necrosis factor and gamma-interferon on chemotactic peptide receptor expression and stimulus-induced actin polymerization in HL-60 cells.

We studied the effect of tumor necrosis factor (TNF) and gamma interferon (IFN-gamma), alone and in combination, on the expression of chemotactic peptide receptors, stimulus-induced actin polymerization, hydrogen peroxide production (H2O2), and expression of nonspecific esterase (NSE) positivity in human promyelocytic leukemic cell line HL-60. These parameters were analyzed following a five-day culture with the cytokines. Chemotactic peptide receptor expression was studied using the fluoresceinated hexapeptide, formyl-norleucyl-leucyl-phenylalanyl-norleucyl-tyrosyl-lysine and flow cytometry. Actin polymerization, an important event required for chemotaxis and phagocytosis, was studied using NBD-phallacidin labeling, following stimulation with the chemotactic peptide formyl-methionyl-leucyl-phenylalanine (FMLP) or phorbol myristate acetate (PMA). TNF increased the expression of chemotactic peptide receptors in a dose-dependent fashion, and there was good correlation between the receptor expression, stimulus-induced actin polymerization, H2O2 production, and NSE positivity. IFN-gamma was less potent in inducing all the parameters studied but exerted a positive cooperative effect when combined with TNF. IFN-gamma at high concentrations induced chemotactic peptide receptors comparable in magnitude to that seen with TNF but failed to prime these cells to undergo actin polymerization in response to FMLP or PMA. Undifferentiated HL-60 cells showed a decrease in F-actin content on stimulation with PMA. This suggests that protein kinase C might have a negative regulatory role in stimulus-induced actin polymerization. The observations reported here indicate that appropriate combinations of different inducing agents with different modes of action might be necessary to duplicate the functional abilities of mature phagocytic cells.

Authors
Rao, KM; Misukonis, MA; Cohen, HJ; Weinberg, JB
MLA Citation
Rao, KM, Misukonis, MA, Cohen, HJ, and Weinberg, JB. "Cooperative effect of tumor necrosis factor and gamma-interferon on chemotactic peptide receptor expression and stimulus-induced actin polymerization in HL-60 cells." Blood 71.4 (April 1988): 1062-1067.
PMID
3128345
Source
pubmed
Published In
Blood
Volume
71
Issue
4
Publish Date
1988
Start Page
1062
End Page
1067

Erythrocyte anisocytosis. Visual inspection of blood films vs automated analysis of red blood cell distribution width.

An improved anemia classification may be available by combining measures of red blood cell size variability with mean corpuscular volume. Visual inspection of the peripheral blood film allows semiquantitative description of anisocytosis while quantitative measures are determined from electronic cell counter analyzers' red blood cell distribution width. We evaluated correlations between semiquantitative and quantitative measures of anisocytosis for different groups of observers. Hematologists', medical students', and medical residents' semiquantitative assessment of anisocytosis correlated with the quantitative red blood cell distribution width. The interobserver variability demonstrated that all observers correlated with each other, while the intraobserver variability of semiquantitative anisocytosis demonstrated that observers were more precise than could be predicted by chance. However, the extreme precision of the red blood cell distribution width strongly suggests that it should be the "gold standard" for measuring red blood cell size variability.

Authors
Simel, DL; DeLong, ER; Feussner, JR; Weinberg, JB; Crawford, J
MLA Citation
Simel, DL, DeLong, ER, Feussner, JR, Weinberg, JB, and Crawford, J. "Erythrocyte anisocytosis. Visual inspection of blood films vs automated analysis of red blood cell distribution width." Arch Intern Med 148.4 (April 1988): 822-824.
PMID
3355302
Source
pubmed
Published In
Archives of internal medicine
Volume
148
Issue
4
Publish Date
1988
Start Page
822
End Page
824

AMINO-ACID DEPRIVATION INDUCES MONOCYTIC DIFFERENTIATION OF HUMAN HL-60 PROMYELOCYTIC LEUKEMIA-CELLS

Authors
NICHOLS, KE; GRANGER, DL; WEINBERG, JB
MLA Citation
NICHOLS, KE, GRANGER, DL, and WEINBERG, JB. "AMINO-ACID DEPRIVATION INDUCES MONOCYTIC DIFFERENTIATION OF HUMAN HL-60 PROMYELOCYTIC LEUKEMIA-CELLS." CLINICAL RESEARCH 36.3 (April 1988): A568-A568.
Source
wos-lite
Published In
Clinical Research
Volume
36
Issue
3
Publish Date
1988
Start Page
A568
End Page
A568

INVIVO EFFECTS OF TUMOR NECROSIS FACTOR (TNF), AND INTERLEUKIN-1 (IL1) ON MURINE PERITONEAL MACROPHAGE (MP) FUNCTIONS

Authors
HOFFMAN, M; CHITNENI, S; WEINBERG, JB; KURLANDER, R
MLA Citation
HOFFMAN, M, CHITNENI, S, WEINBERG, JB, and KURLANDER, R. "INVIVO EFFECTS OF TUMOR NECROSIS FACTOR (TNF), AND INTERLEUKIN-1 (IL1) ON MURINE PERITONEAL MACROPHAGE (MP) FUNCTIONS." FASEB JOURNAL 2.6 (March 25, 1988): A1600-A1600.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
2
Issue
6
Publish Date
1988
Start Page
A1600
End Page
A1600

Transcription interruption may be a common mechanism of c-myc regulation during HL-60 differentiation.

Human promyelocytic leukemia cells (HL-60) differentiate along a monocytoid pathway in response to recombinant human tumor necrosis factor or recombinant human interferon gamma. Together, these agents act synergistically to induce phenotypic differentiation. Since reduced expression of mRNA for the proto-oncogene c-myc correlates with differentiation of HL-60 cells induced by other agents, we tested the abilities of tumor necrosis factor and interferon gamma to regulate expression of c-myc mRNA. Tumor necrosis factor rapidly and effectively reduced c-myc mRNA levels. In contrast, interferon gamma did not affect c-myc mRNA levels, nor did it show synergy with tumor necrosis factor in reducing c-myc. Transcription run-on studies confirmed that tumor necrosis factor caused interruption of c-myc transcription after exon 1. Phorbol diesters also caused interruption of transcription of c-myc. Thus, interruption of transcription may be a common mode of regulation of c-myc during induced differentiation of HL-60 cells.

Authors
McCachren, SS; Salehi, Z; Weinberg, JB; Niedel, JE
MLA Citation
McCachren, SS, Salehi, Z, Weinberg, JB, and Niedel, JE. "Transcription interruption may be a common mechanism of c-myc regulation during HL-60 differentiation." Biochem Biophys Res Commun 151.1 (February 29, 1988): 574-582.
PMID
3126739
Source
pubmed
Published In
Biochemical and Biophysical Research Communications
Volume
151
Issue
1
Publish Date
1988
Start Page
574
End Page
582

α2Macroglobulin-proteinase complexes stimulate prostaglandin E2 synthesis by peritoneal macrophages

α2Macroglobulin is a proteinase inhibitor which is converted from its native form into an electrophoretically "fast" form by reaction with a proteinase or methylamine. All α2M "fast" forms bind to a specific high-affinity receptor on macrophages. α2M "fast" forms inhibit the interferon-γ (IFN)-induced increase in macrophage Ia expression. This study examined whether α2M-proteinase complexes alter prostaglandin (PG) E2 synthesis, and whether PGE2 mediates α2M "fast" forms effects on macrophage Ia expression. Culture with α2M "fast" forms increased PGE2 accumulation in the medium over control values in a dose-dependent manner. Culture with IFN alone did not increase PGE2 levels, but potentiated the effect of α2M-proteinase complexes on PGE2 levels. Inhibition of PGE2 synthesis did not alter the PGE2 did suppress IFN-induced Ia expression. Thus, α2M-proteinase complexes increase macrophage PGE2 synthesis, but increased synthesis of PGE2 or other cyclooxygenase products is not the mediator of antagonism of IFN-induced Ia expression by α2M-proteinase complexes. © 1988 Birkhäusver Verlag.

Authors
Hoffman, M; Pizzo, SV; Weinberg, JB
MLA Citation
Hoffman, M, Pizzo, SV, and Weinberg, JB. 2Macroglobulin-proteinase complexes stimulate prostaglandin E2 synthesis by peritoneal macrophages." Agents and Actions 25.3-4 (1988): 360-367.
Source
scival
Published In
Agents and Actions
Volume
25
Issue
3-4
Publish Date
1988
Start Page
360
End Page
367
DOI
10.1007/BF01965043

SPHINGOSINE INHIBITS TISSUE FACTOR-INDUCED BLOOD-CLOTTING

Authors
CONKLING, PR; PATTON, KL; HANNUN, YA; GREENBERG, CS; WEINBERG, JB
MLA Citation
CONKLING, PR, PATTON, KL, HANNUN, YA, GREENBERG, CS, and WEINBERG, JB. "SPHINGOSINE INHIBITS TISSUE FACTOR-INDUCED BLOOD-CLOTTING." ARTERIOSCLEROSIS 8.5 (1988): A664-A664.
Source
wos-lite
Published In
Arteriosclerosis
Volume
8
Issue
5
Publish Date
1988
Start Page
A664
End Page
A664

Sperm-macrophage interaction in the mouse: a quantitative assay in vitro using 111indium oxine-labeled sperm.

The role of reproductive tract macrophages in contraception and reproductive failure has become widely recognized. However, in vitro analysis of sperm phagocytosis by macrophages has relied upon a semi-quantitative method of sperm counting that is of limited accuracy and reproducibility. We have developed an assay using murine sperm labeled with 111indium oxine, and results indicate the labeling to be rapid and efficient. Incorporation of 111indium into sperm increased the dose and sperm concentration and reached 90% maximal uptake after 15 min incubation, with maximal uptake occurring at 30 min. No decrease in sperm motility was noted with levels of oxine in excess of those required for significant labeling. Maximal labeling efficiency occurred in phosphate-buffered saline (PBS), with Dulbecco's modified Eagle's medium (DMEM) + 10% adult bovine serum (ABS) producing significantly less uptake. Label dissociation was detectable in PBS at room temperature, but at 37 degrees C in DMEM + 10% ABS, loss of label occurred at a rate of 23.5%/h. Addition of labeled sperm to murine macrophage monolayers under optimal conditions resulted in uptake of 111indium by macrophages, while free label was unincorporated. Results indicated assay specificity for macrophage-limited uptake, with insignificant label uptake by nonphagocytic murine fibroblasts and better sensitivity than sperm counting. Macrophages from Bacillus Calmette-Guerin (BCG)-infected mice resulted in a decrease in sperm uptake. Female macrophages showed greater capacity for sperm uptake than those of the male mouse. These initial studies demonstrated the utility of this model system in enhancing the understanding of sperm-macrophage interaction in the female reproductive tract.

Authors
Olive, DL; Weinberg, JB; Haney, AF
MLA Citation
Olive, DL, Weinberg, JB, and Haney, AF. "Sperm-macrophage interaction in the mouse: a quantitative assay in vitro using 111indium oxine-labeled sperm." Biol Reprod 37.5 (December 1987): 1170-1178.
PMID
3442695
Source
pubmed
Published In
Biology of Reproduction
Volume
37
Issue
5
Publish Date
1987
Start Page
1170
End Page
1178

Tumor necrosis factor-alpha induces increased hydrogen peroxide production and Fc receptor expression, but not increased Ia antigen expression by peritoneal macrophages.

It has recently been shown that tumor necrosis factor (TNF) induces increased Ia antigen expression on a malignant murine macrophage cell line, and that TNF is synergistic with gamma interferon (IFN) in inducing Ia expression. This finding raises the possibility that TNF serves as a non-interferon macrophage activating factor in vivo. Since it is known that TNF has different effects on malignant and benign cells, we chose to evaluate the effects of recombinant TNF on primary cultures of murine peritoneal macrophages (MP). Neither human nor murine TNF increased the proportion of MP which expressed Ia antigen, and TNF actually partially prevented the IFN-induced increase in Ia. However, culture with TNF activated MP for increased hydrogen peroxide production in response to phorbol myristate acetate (PMA) and antagonized the IFN-induced decrease in the proportion of the MP bearing receptors for the Fc region of IgG2b. TNF and IFN were additive in increasing peroxide production. Both human and murine TNF had the same effects on MP, and MP from C3H/HeN (endotoxin sensitive) and C3H/HeJ (endotoxin resistant) mice responded comparably to TNF and IFN. Our results support the hypothesis that TNF has some macrophage-activating activity, but its effects are selective and not identical with those of IFN.

Authors
Hoffman, M; Weinberg, JB
MLA Citation
Hoffman, M, and Weinberg, JB. "Tumor necrosis factor-alpha induces increased hydrogen peroxide production and Fc receptor expression, but not increased Ia antigen expression by peritoneal macrophages." J Leukoc Biol 42.6 (December 1987): 704-707.
PMID
3316463
Source
pubmed
Published In
Journal of leukocyte biology
Volume
42
Issue
6
Publish Date
1987
Start Page
704
End Page
707

The nature of the intraperitoneal exudate associated with infertility: peritoneal fluid and serum lysozyme activity.

An intraperitoneal inflammatory process has been associated with infertility in women without anatomic distortion of the pelvic viscera, particularly with endometriosis. This phenomenon was investigated by measuring peritoneal fluid (PF) and serum levels of a major secretory product of the macrophage, lysozyme, in fertile and infertile women undergoing laparoscopy. Serum lysozyme levels were in the normal range and did not correlate with total PF lysozyme. Regression analysis revealed a negative correlation between adnexal adhesions and PF volume (P less than 0.05), PF leukocyte number (P less than 0.05), and total PF lysozyme (P less than 0.05). Significant correlations were found between total PF lysozyme and PF volume (r = 0.72, P less than 0.0001) and leukocyte number (r = 0.67, P less than 0.0001). These results suggest that a localized intraperitoneal inflammatory reaction is associated with infertility in the absence of anatomic distortion of the pelvic viscera.

Authors
Olive, DL; Haney, AF; Weinberg, JB
MLA Citation
Olive, DL, Haney, AF, and Weinberg, JB. "The nature of the intraperitoneal exudate associated with infertility: peritoneal fluid and serum lysozyme activity." Fertil Steril 48.5 (November 1987): 802-806.
PMID
3666182
Source
pubmed
Published In
Fertility and Sterility
Volume
48
Issue
5
Publish Date
1987
Start Page
802
End Page
806

1 alpha,25 Dihydroxyvitamin D3 and mononuclear phagocytes: enhancement of mouse macrophage and human monocyte hydrogen peroxide production without alteration of tumor cytolysis.

1 alpha,25 dihydroxyvitamin D3 (1,25 D3) is known to interact with hematopoietic cells. The purpose of this study was to determine the effect of 1,25 D3 on hydrogen peroxide (H2O2) production and tumor cell killing by mouse peritoneal macrophages and human blood monocytes. Enhanced monocyte and macrophages phorbol myristate acetate (PMA)-stimulated H2O2 production was observed at concentrations of 0.13 to 130 nM 1,25 D3 and and was maximal at 1.3 nM. At concentrations of 100 U/ml, gamma interferon (IFN-gamma) alone had a similar effect but, in combination with 1,25 D3, there was no cooperative effect. At concentrations ranging from 0.13 to 130 nM, 1,25 D3 failed to augment tumor cell lysis by macrophages from peptone-injected normal or bacillus Calmette-Guerin (BCG)-infected mice, or by blood monocytes from normal humans. Our results indicate that 1,25 D3 can activate the monocyte and macrophage for H2O2 secretion without concomitant activation for tumor cell killing.

Authors
Gluck, WL; Weinberg, JB
MLA Citation
Gluck, WL, and Weinberg, JB. "1 alpha,25 Dihydroxyvitamin D3 and mononuclear phagocytes: enhancement of mouse macrophage and human monocyte hydrogen peroxide production without alteration of tumor cytolysis." J Leukoc Biol 42.5 (November 1987): 498-503.
PMID
3119753
Source
pubmed
Published In
Journal of leukocyte biology
Volume
42
Issue
5
Publish Date
1987
Start Page
498
End Page
503

TUMOR-NECROSIS-FACTOR-ALPHA (TNF) STIMULATES PEROXIDE PRODUCTION AND EXPRESSION OF FC-RECEPTORS FOR IGG2B/1A (FCR), BUT DOES NOT INDUCE IA EXPRESSION ON MURINE PERITONEAL-MACROPHAGES (MP)

Authors
HOFFMAN, M; WEINBERG, JB
MLA Citation
HOFFMAN, M, and WEINBERG, JB. "TUMOR-NECROSIS-FACTOR-ALPHA (TNF) STIMULATES PEROXIDE PRODUCTION AND EXPRESSION OF FC-RECEPTORS FOR IGG2B/1A (FCR), BUT DOES NOT INDUCE IA EXPRESSION ON MURINE PERITONEAL-MACROPHAGES (MP)." JOURNAL OF LEUKOCYTE BIOLOGY 42.5 (November 1987): 609-609.
Source
wos-lite
Published In
Journal of leukocyte biology
Volume
42
Issue
5
Publish Date
1987
Start Page
609
End Page
609

Receptor-mediated monocytoid differentiation of human promyelocytic cells by tumor necrosis factor: synergistic actions with interferon-gamma and 1,25-dihydroxyvitamin D3.

Human myeloid leukemia cells respond to various signals by differentiating to more mature cells. This study was designed to evaluate the effects of a mononuclear phagocyte-derived factor, tumor necrosis factor/cachectin (TNF), on the proliferation and differentiation of the human cell lines HL-60 (promyelocytic) and U937 (monoblastic), and to characterize TNF receptors on these cells. TNF had no effect on HL-60 cell growth or thymidine incorporation, but it markedly inhibited that of U937 cells. HL-60 cells treated with TNF formed osteoclast-like polykaryons and developed nonspecific esterase positivity. In a dose-dependent fashion, TNF enhanced HL-60 cell nonspecific esterase activity, H2O2 production, NBT reduction, and acid phosphatase content. Together, TNF and interferon-gamma (IFN-gamma) additively and synergistically caused increases in these activities as well as the expression of HLA-DR and the monocyte antigens LeuM3 (CDw14) and OKM1 (CD11). TNF also synergistically enhanced the differentiating effects of 1,25-dihydroxyvitamin D3. The potentiating actions of D3 of IFN-gamma on the TNF effect were maximal when the two agents were present together throughout the incubation, and pretreatment with TNF augmented the subsequent response to D3, but not IFN-gamma. HL-60 and U937 cells bound 125I-labeled TNF specifically, rapidly, and reversibly with binding constants of 227 and 333 pmol/L and receptors per cell of 4,435 and 6,806 for HL-60 and U937, respectively. Scatchard plots were linear, which suggested single classes of receptors. HL-60 TNF receptors were not changed by a three-day treatment with IFN-gamma or D3. U937 and HL-60 cells internalized and degraded 125I-labeled TNF to comparable degrees. TNF has differing effects on HL-60 and U937 cells that are apparently mediated through comparable high-affinity TNF receptors. The unique responses of different cell types to TNF may be due to postreceptor factors.

Authors
Weinberg, JB; Larrick, JW
MLA Citation
Weinberg, JB, and Larrick, JW. "Receptor-mediated monocytoid differentiation of human promyelocytic cells by tumor necrosis factor: synergistic actions with interferon-gamma and 1,25-dihydroxyvitamin D3." Blood 70.4 (October 1987): 994-1002.
PMID
2820533
Source
pubmed
Published In
Blood
Volume
70
Issue
4
Publish Date
1987
Start Page
994
End Page
1002

Modulation of mouse peritoneal macrophage Ia and human peritoneal macrophage HLA-DR expression by alpha 2-macroglobulin "fast" forms.

alpha 2-Macroglobulin (alpha 2M) is converted from its native form into electrophoretically "fast" forms by reaction with proteinases or with methylamine. The "fast" forms both bind to specific receptors on macrophages (MP). We have previously shown that alpha 2M "fast" forms modulate effector functions of murine peritoneal MP. In the present study, alpha 2M "fast" forms antagonized the increase in MP HLA-DR and Ia expression induced in vitro by interferon-gamma (IFN-gamma). This effect was observed with human peritoneal MP, as well as MP from peptone-injected and bacillus Calmette-Guérin-infected mice of three strains. alpha 2M-trypsin, which had been reacted with aprotinin and alpha 2M-methylamine, both of which lack proteolytic activity, also antagonized interferon-induced Ia expression. alpha 2M "fast" forms also reduced the ability of MP to serve as accessory cells for lectin-induced lymphocyte proliferation. alpha 2M "fast" form is an immune modulator of human and murine MP function, probably through a specific receptor-mediated mechanism.

Authors
Hoffman, MR; Pizzo, SV; Weinberg, JB
MLA Citation
Hoffman, MR, Pizzo, SV, and Weinberg, JB. "Modulation of mouse peritoneal macrophage Ia and human peritoneal macrophage HLA-DR expression by alpha 2-macroglobulin "fast" forms." J Immunol 139.6 (September 15, 1987): 1885-1890.
PMID
2442259
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
139
Issue
6
Publish Date
1987
Start Page
1885
End Page
1890

EFFECTS OF TUMOR-NECROSIS-FACTOR AND INTERFERON-GAMMA ON EXPRESSION OF C-MYC

Authors
MCCACHREN, SS; NIEDEL, JE; WEINBERG, JB
MLA Citation
MCCACHREN, SS, NIEDEL, JE, and WEINBERG, JB. "EFFECTS OF TUMOR-NECROSIS-FACTOR AND INTERFERON-GAMMA ON EXPRESSION OF C-MYC." CLINICAL RESEARCH 35.3 (April 1987): A428-A428.
Source
wos-lite
Published In
Clinical Research
Volume
35
Issue
3
Publish Date
1987
Start Page
A428
End Page
A428

Functional alterations of macrophages in autoimmune MRL-lpr/lpr mice.

To assess the role of macrophages (MAC) in the pathogenesis of systemic lupus erythematosus, we investigated functional aspects of peritoneal MAC obtained from autoimmune MRL/MpJ-lpr/lpr (MRL-lpr) mice. MRL-lpr and control C3H/HeN MAC were obtained from untreated mice or mice injected i.p. with 1 ml of 10% sterile peptone 3 days before cell harvest. MRL-lpr mice had significantly more peritoneal cells (MAC and lymphocytes) than did control mice. In endotoxin-free conditions, MRL-lpr MAC were similar to C3H/HeN MAC in their baseline, and IFN-gamma and/or LPS enhanced cytolysis of 3T12 fibrosarcoma tumor cells. Compared with C3H/HeN MAC, MRL-lpr MAC had a significant increase in antibody-dependent cellular cytotoxicity activity against sheep erythrocytes. This enhanced activity was not accompanied by a similar increase in adherence and/or phagocytosis of the same targets. Finally, in response to phorbol myristate acetate stimulation, both resident and peptone-induced MAC from MRL-lpr mice produced significantly more hydrogen peroxide than did those from control mice. These results indicate that MAC from MRL-lpr mice display features of selective "activation", and suggest that MAC or their products may play a role in the pathogenesis of inflammatory disorders seen in autoimmune diseases.

Authors
Dang-Vu, AP; Pisetsky, DS; Weinberg, JB
MLA Citation
Dang-Vu, AP, Pisetsky, DS, and Weinberg, JB. "Functional alterations of macrophages in autoimmune MRL-lpr/lpr mice." J Immunol 138.6 (March 15, 1987): 1757-1761.
PMID
3102599
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
138
Issue
6
Publish Date
1987
Start Page
1757
End Page
1761

TUMOR-NECROSIS-FACTOR INDUCES TISSUE FACTOR ACTIVITY IN HUMAN-LEUKEMIA CELL-LINE U937

Authors
CONKLING, PR; GREENBERG, CS; WEINBERG, JB
MLA Citation
CONKLING, PR, GREENBERG, CS, and WEINBERG, JB. "TUMOR-NECROSIS-FACTOR INDUCES TISSUE FACTOR ACTIVITY IN HUMAN-LEUKEMIA CELL-LINE U937." PROCEEDINGS OF THE AMERICAN ASSOCIATION FOR CANCER RESEARCH 28 (March 1987): 400-400.
Source
wos-lite
Published In
Proceedings of the Annual Meeting- American Association for Cancer Research
Volume
28
Publish Date
1987
Start Page
400
End Page
400

MODULATION OF PERITONEAL MACROPHAGE (MP) MEMBRANE-ANTIGENS BY ALPHA2-MACROGLOBULIN TRYPSIN (A2M-T) COMPLEXES

Authors
HOFFMAN, M; PIZZO, SV; WEINBERG, JB
MLA Citation
HOFFMAN, M, PIZZO, SV, and WEINBERG, JB. "MODULATION OF PERITONEAL MACROPHAGE (MP) MEMBRANE-ANTIGENS BY ALPHA2-MACROGLOBULIN TRYPSIN (A2M-T) COMPLEXES." PROCEEDINGS OF THE AMERICAN ASSOCIATION FOR CANCER RESEARCH 28 (March 1987): 343-343.
Source
wos-lite
Published In
Proceedings of the Annual Meeting- American Association for Cancer Research
Volume
28
Publish Date
1987
Start Page
343
End Page
343

Antibodies to granulocyte precursors in selective myeloid hypoplasia and other suspected autoimmune neutropenias: use of HL-60 cells as targets.

Patients with syndromes of autoantibody-mediated hematocytopenias may manifest signs of increased cell destruction and/or decreased cell production, depending on the maturity of the target cell and the effects of antibody binding. The purpose of this study was to use a cultured human cell line of hematopoietic origin for in vitro assays of antibody binding to overcome the relative inaccessibility of natural human marrow progenitor cells. This report describes the detection, using radioiodinated staphylococcal protein A (SPA), of antibodies binding to a human promyelocytic cell line (HL-60) in sera from three patients with chronic idiopathic granulocytic hypoplasia ("pure white cell aplasia," PWCA) and 22 patients with other syndromes of suspected immune neutropenia. Bone marrow from patients with increased IgG binding to HL-60 cells showed less than 15% granulocytic lineage cellularity in 11 of 17 cases. In vitro differentiation of HL-60 cells by retinoic acid resulted in increased IgG binding for sera that had shown increased IgG binding to mature granulocytes but not undifferentiated HL-60 cells; in contrast, for sera with antibodies to untreated HL-60 cells and for normal serum, in vitro differentiation had little effect on IgG binding. Antibodies eluted from mature granulocytes were similar to the parent serum regarding the ratio of IgG binding to mature cells v HL-60 cells. No sera from 19 patients with febrile transfusion reactions showed increased IgG binding to HL-60 cells in the absence of increased IgG binding to mature granulocytes, although two sera had antibodies to both cell types. The use of HL-60 cells as targets may permit measurement of serum antibodies associated with granulocytic hypoplasia. In combination with assays to detect antibody binding to mature granulocytes, these techniques may discriminate among autoantibody specificities for antigens that are gained, conserved, or lost during myeloid maturation.

Authors
Currie, MS; Weinberg, JB; Rustagi, PK; Logue, GL
MLA Citation
Currie, MS, Weinberg, JB, Rustagi, PK, and Logue, GL. "Antibodies to granulocyte precursors in selective myeloid hypoplasia and other suspected autoimmune neutropenias: use of HL-60 cells as targets." Blood 69.2 (February 1987): 529-536.
PMID
3801668
Source
pubmed
Published In
Blood
Volume
69
Issue
2
Publish Date
1987
Start Page
529
End Page
536

Acute myeloblastic leukemia in paroxysmal nocturnal hemoglobinuria. Evidence of evolution from the abnormal paroxysmal nocturnal hemoglobinuria clone.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell disorder in which the blood cells demonstrate aberrant interactions with serum complement. In part, this is due to the absence of the complement regulatory protein, decay accelerating factor (DAF). A small number of patients with PNH have gone on to develop acute nonlymphocytic leukemia, which is thought to arise from the injured marrow as a second hematopoietic disorder. We have studied a patient with PNH who developed acute myeloblastic leukemia (AML); the blasts from this patient were found to lack DAF as measured by polyclonal antibody binding and fluorescence flow cytometry as well as by immunoblotting. The blasts from 11 other patients with AML bound anti-DAF antibody in amounts similar to normal mononuclear cells from healthy donors. Cells of the human leukemia cell lines HL-60, K562, U937, and HEL also bound anti-DAF antibody. In addition to DAF deficiency, blasts from the PNH patient had undetectable alkaline phosphatase activity, in contrast to human leukemia cell lines. These data suggest that the leukemic cells of the PNH patient arose out of the PNH clone and that AML in the setting of PNH is not a separate disorder.

Authors
Devine, DV; Gluck, WL; Rosse, WF; Weinberg, JB
MLA Citation
Devine, DV, Gluck, WL, Rosse, WF, and Weinberg, JB. "Acute myeloblastic leukemia in paroxysmal nocturnal hemoglobinuria. Evidence of evolution from the abnormal paroxysmal nocturnal hemoglobinuria clone." J Clin Invest 79.1 (January 1987): 314-317.
PMID
2432090
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
79
Issue
1
Publish Date
1987
Start Page
314
End Page
317
DOI
10.1172/JCI112802

PERIPHERAL-BLOOD FILM INTERPRETATION OF ANISOCYTOSIS VERSUS QUANTITATIVE ASSESSMENT BY RDW

Authors
SIMEL, DL; DELONG, ER; FEUSSNER, JR; CRAWFORD, J; WEINBERG, JB
MLA Citation
SIMEL, DL, DELONG, ER, FEUSSNER, JR, CRAWFORD, J, and WEINBERG, JB. "PERIPHERAL-BLOOD FILM INTERPRETATION OF ANISOCYTOSIS VERSUS QUANTITATIVE ASSESSMENT BY RDW." CLINICAL RESEARCH 35.1 (January 1987): A92-A92.
Source
wos-lite
Published In
Clinical Research
Volume
35
Issue
1
Publish Date
1987
Start Page
A92
End Page
A92

Metastatic hemangiopericytoma with prolonged survival

A case of a hemangiopericytoma tumor metastatic to the lung from a central nervous system primary tumor in the posterior fossa is reported. The tumor was not responsive to treatment with cyclophosphamide. Adriamycin (doxorubicin), vincristine, DTIC (CYVADIC), high-dose methotrexate with citrovorum factor rescue, aziridinobenzoquinone (AZQ), or dibromodulcitol. However, the patient has had a prolonged survival, lasting for more than 26 years from original diagnosis, despite extensive recurrent primary disease and massive pulmonary metastases. Clinical and pathologic characteristics of these tumors are reviewed, with emphasis on the potential for long-term survival.

Authors
Hart, LL; Weinberg, JB
MLA Citation
Hart, LL, and Weinberg, JB. "Metastatic hemangiopericytoma with prolonged survival." Cancer 60.4 (1987): 916-920.
PMID
3594410
Source
scival
Published In
Cancer
Volume
60
Issue
4
Publish Date
1987
Start Page
916
End Page
920

1α,25 dihydroxyvitamin D3 and mononuclear phagocytes: Enhancement of mouse macrophage and human monocyte hydrogen peroxide production without alteration of tumor cytolysis

1α,25 dihydroxyvitamin D3 (1,25 D3) is known to interact with hematopoietic cells. The purpose of this study was to determine the effect of 1,25 D3 on hydrogen peroxide (H2O2) production and tumor cell killing by mouse peritoneal macrophages and human blood monocytes. Enhanced monocyte and macrophage phorbol myristate acetate (PMA)-stimulated H2O2 production was observed at concentrations of 0.13 to 130 nM 1,25 D3 and was maximal at 1.3 nM. At concentrations of 100 U/ml, gamma interferon (IFN-γ) alone had a similar effect but, in combination with 1,25 D3, there was no cooperative effect. At concentrations ranging from 0.13 to 130 nM, 1,25 D3 failed to augment tumor cell lysis by macrophages from peptone-injected normal or bacillus Calmette-Guerin (BCG)-infected mice, or by blood monocytes from normal humans. Our results indicate that 1,25 D3 can activate the monocyte and macrophage for H2O2 secretion without concomitant activation for tumor cell killing.

Authors
Gluck, WL; Weinberg, JB
MLA Citation
Gluck, WL, and Weinberg, JB. "1α,25 dihydroxyvitamin D3 and mononuclear phagocytes: Enhancement of mouse macrophage and human monocyte hydrogen peroxide production without alteration of tumor cytolysis." Journal of Leukocyte Biology 42.5 (1987): 498-503.
Source
scival
Published In
Journal of Leukocyte Biology
Volume
42
Issue
5
Publish Date
1987
Start Page
498
End Page
503

In vitro function of indium-111 oxine-labeled human monocytes.

Mononuclear phagocytes (monocytes and macrophages) are widely distributed throughout the body. Indium-111 (111In) oxine has been a useful radioactive label in studies of in vivo cellular kinetics and distribution. In preparation for in vivo monocyte investigations in humans, this study was designed to determine the effects of labeling human blood monocytes with 111In on their function in vitro. The monocytes labeled with an efficiency of 57.9 +/- 14.2% (range of 47-95%). The 111In eluted from the cells at a rate of 0.25%/h over 48 h in vitro. The labeled monocytes had a slight, but statistically significant, reduction in their ability to phagocytize or mediate antibody-dependent cellular cytotoxicity of antibody-coated sheep erythrocytes. The labeled cells were not different than control monocytes with respect to viability (trypan blue exclusion and lactate dehydrogenase release), adherence to plastic, hydrogen peroxide production, chemotaxis to N-formyl methionylleucylphenylalanine, and antibody-independent lysis of the tumor cells U937 and HeLa. 111In-labeled human monocytes should be useful for in vivo studies of mononuclear phagocyte kinetics and distribution in normal and diseased subjects.

Authors
Weinberg, JB; Blinder, RA; Coleman, RE
MLA Citation
Weinberg, JB, Blinder, RA, and Coleman, RE. "In vitro function of indium-111 oxine-labeled human monocytes." J Immunol Methods 95.1 (December 4, 1986): 9-14.
PMID
3782827
Source
pubmed
Published In
Journal of Immunological Methods
Volume
95
Issue
1
Publish Date
1986
Start Page
9
End Page
14

CHARACTERIZATION OF COAGULATION-FACTOR XIII (FXIII) IN PERITONEAL-MACROPHAGES AND MONOCYTES FROM NORMAL AND FXIII-DEFICIENT HUMANS

Authors
CONKLING, PR; GREENBERG, CS; NEWCOMB, TF; WEINBERG, JB
MLA Citation
CONKLING, PR, GREENBERG, CS, NEWCOMB, TF, and WEINBERG, JB. "CHARACTERIZATION OF COAGULATION-FACTOR XIII (FXIII) IN PERITONEAL-MACROPHAGES AND MONOCYTES FROM NORMAL AND FXIII-DEFICIENT HUMANS." JOURNAL OF LEUKOCYTE BIOLOGY 40.3 (September 1986): 267-268.
Source
wos-lite
Published In
Journal of leukocyte biology
Volume
40
Issue
3
Publish Date
1986
Start Page
267
End Page
268

ALPHA-2 MACROGLOBULIN-PROTEASE COMPLEXES (ALPHA-2-M-P) DECREASE PERITONEAL MACROPHAGE (MAC) IA EXPRESSION

Authors
HOFFMAN, M; PIZZO, SV; WEINBERG, JB
MLA Citation
HOFFMAN, M, PIZZO, SV, and WEINBERG, JB. "ALPHA-2 MACROGLOBULIN-PROTEASE COMPLEXES (ALPHA-2-M-P) DECREASE PERITONEAL MACROPHAGE (MAC) IA EXPRESSION." JOURNAL OF LEUKOCYTE BIOLOGY 40.3 (September 1986): 291-291.
Source
wos-lite
Published In
Journal of leukocyte biology
Volume
40
Issue
3
Publish Date
1986
Start Page
291
End Page
291

IN-111 OXINE LABELED MONOCYTE STUDIES IN HUMANS - INVITRO FUNCTION, AND INVIVO KINETICS AND DISTRIBUTION

Authors
WEINBERG, JB; BLINDER, RA; BEYTAS, EM; COLEMAN, RE
MLA Citation
WEINBERG, JB, BLINDER, RA, BEYTAS, EM, and COLEMAN, RE. "IN-111 OXINE LABELED MONOCYTE STUDIES IN HUMANS - INVITRO FUNCTION, AND INVIVO KINETICS AND DISTRIBUTION." CLINICAL RESEARCH 34.2 (April 1986): A665-A665.
Source
wos-lite
Published In
Clinical Research
Volume
34
Issue
2
Publish Date
1986
Start Page
A665
End Page
A665

ENHANCED HYDROGEN-PEROXIDE SECRETION BY MACROPHAGES FROM AUTOIMMUNE MRL-1PR MICE

Authors
DANGVU, AP; PISETSKY, DS; WEINBERG, JB
MLA Citation
DANGVU, AP, PISETSKY, DS, and WEINBERG, JB. "ENHANCED HYDROGEN-PEROXIDE SECRETION BY MACROPHAGES FROM AUTOIMMUNE MRL-1PR MICE." CLINICAL RESEARCH 34.2 (April 1986): A616-A616.
Source
wos-lite
Published In
Clinical Research
Volume
34
Issue
2
Publish Date
1986
Start Page
A616
End Page
A616

Cooperative effects of gamma interferon and 1-alpha,25-dihydroxyvitamin D3 in inducing differentiation of human promyelocytic leukemia (HL-60) cells.

Various agents induce differentiation of human leukemia cells in vitro. Most of these agents cause myeloid differentiation, but phorbol diesters, 1-alpha,25-dihydroxyvitamin D3 (1,25[OH2]D3), and certain lymphokines cause differentiation to monocyte-like cells. The purpose of this study was to determine the cooperative effects of 1,25(OH2)D3 and the lymphokine gamma interferon (IFN-gamma) on HL-60 cell differentiation. The recombinant human IFN-gamma or 1,25(OH2)D3 caused a slight reduction in the proliferation of the HL-60 cells (30%-40% reduction at doses of 100-200 U/ml [0.25-0.50 nM] IFN-gamma, or 5-25 nM 1,25[OH2]D3). HL-60 cells treated with 100 U/ml IFN-G had an eightfold increase in expression of nonspecific esterase (NSE) and a twofold increase in H2O2 production in response to phorbol myristate acetate (PMA). 1,25(OH2)D3 enhanced NSE expression eight- to 30-fold and H2O2 secretion twofold in response to PMA. There was also enhanced expression of HLA-DR and the receptor for C3bi. The 1,25(OH2)D3- and IFN-gamma-differentiating effects appeared to be additive or synergistic. Populations of IFN-gamma-treated HL-60 cells (but not the 1,25[OH2]D3-treated cells) had multinucleated giant cells. The polykaryons had NSE activity and had some properties of macrophage polykaryons or osteoclasts. 1,25(OH2)D3 did not augment the IFN-gamma-induced polykaryon formation.

Authors
Weinberg, JB; Misukonis, MA; Hobbs, MM; Borowitz, MJ
MLA Citation
Weinberg, JB, Misukonis, MA, Hobbs, MM, and Borowitz, MJ. "Cooperative effects of gamma interferon and 1-alpha,25-dihydroxyvitamin D3 in inducing differentiation of human promyelocytic leukemia (HL-60) cells." Exp Hematol 14.2 (February 1986): 138-142.
PMID
3080326
Source
pubmed
Published In
Experimental Hematology
Volume
14
Issue
2
Publish Date
1986
Start Page
138
End Page
142

Phenotypic characterization of gamma interferon-induced human monocyte polykaryons.

Multinucleated giant cells of mononuclear phagocyte origin (monocyte or macrophage polykaryons [MPs] ) are seen in numerous different normal and pathologic states. We have previously shown that gamma interferon (IFN-gamma) induces fusion of uninuclear monocytes (UMs) to form MPs. This study was designed to characterize these IFN-gamma-induced MPs. Control and IFN-gamma-treated UMs and MPs did not have peroxidase activity, but they stained intensely for nonspecific esterase and acid phosphatase. The esterase of UMs and MPs was abolished by fluoride, but the acid phosphatase of UMs and MPs was only minimally decreased by tartrate. The phagocytosis of polystyrene spheres and glutaraldehyde-fixed erythrocytes by MPs was moderately depressed as compared with control or treated UMs, whereas the phagocytosis of IgG-coated erythrocytes was markedly depressed. Populations of control monocytes produced less H2O2 in response to 200 nmol/L of phorbol myristate acetate than did IFN-gamma-treated monocytes (37 +/- 7 v 199 +/- 29 nmol/h per milligram of cell protein). However, when examined microscopically, individual MPs had less ability to reduce NBT (18% +/- 5% positive for MP, 91% +/- 3% for treated UMs, and 67% +/- 3% for control UMs). The surface membrane antigens Leu M3, OKM1 (C3bi receptor), DU-HL60-3, DU-HL60-4, TE5, and V1 were not expressed or were expressed poorly in MPs; they were expressed normally in control and treated UMs. However, HLA-DR expression was increased in treated UMs and MPs. The binding of the lectins RCA, Con A, WGA, DBA, UEA, and PNA was equivalent in all cells. Thus, MPs formed by fusion of UMs in vitro after culture with IFN-gamma differ in several features from UMs.

Authors
Weinberg, JB; Hobbs, MM; Misukonis, MA
MLA Citation
Weinberg, JB, Hobbs, MM, and Misukonis, MA. "Phenotypic characterization of gamma interferon-induced human monocyte polykaryons." Blood 66.6 (December 1985): 1241-1246.
PMID
3933591
Source
pubmed
Published In
Blood
Volume
66
Issue
6
Publish Date
1985
Start Page
1241
End Page
1246

Peritoneal macrophages and infertility: the association between cell number and pelvic pathology.

Increased numbers of peritoneal macrophages have been repeatedly associated with infertility. Because the factors contributing to this intraperitoneal exudate are unknown, this study was carried out to determine which anatomic or endocrinologic abnormalities in infertile women might be associated with an increase in leukocyte numbers. The peritoneal fluid from 103 women was analyzed. Nonparametric data analysis demonstrated significantly greater cell counts in infertile women with endometriosis, compared with other infertile women (P less than 0.01) or fertile control subjects (P less than 0.005). Multiple regression analysis was then used to determine the relationship of individual variables to cell number without the influence of confounding factors. These data demonstrate that the best correlation with elevated macrophage number is in women who have infertility and no mechanical fertility factors (of which mild endometriosis is a subgroup). Thus, an increase in peritoneal macrophage number is not restricted to women with endometriosis but, rather, is seen in a subset of infertile women generally without mechanical or endocrinologic infertility factors.

Authors
Olive, DL; Weinberg, JB; Haney, AF
MLA Citation
Olive, DL, Weinberg, JB, and Haney, AF. "Peritoneal macrophages and infertility: the association between cell number and pelvic pathology." Fertil Steril 44.6 (December 1985): 772-777.
PMID
4076434
Source
pubmed
Published In
Fertility and Sterility
Volume
44
Issue
6
Publish Date
1985
Start Page
772
End Page
777

Leukemic ascites complicating acute myelomonoblastic leukemia.

We describe a patient with acute myelomonoblastic leukemia, jaundice, and ascites. The ascitic fluid contained leukemic cells comparable with those of the blood and bone marrow. Treatment with cytarabine (cytosine arabinoside) caused a decrease in the peripheral blood blast cell count and the serum bilirubin level, but the leukemic ascites did not change. Ascites in patients with acute leukemia must be examined to differentiate leukemic infiltration from other causes such as infection.

Authors
Simel, DL; Weinberg, JB
MLA Citation
Simel, DL, and Weinberg, JB. "Leukemic ascites complicating acute myelomonoblastic leukemia." Arch Pathol Lab Med 109.4 (April 1985): 365-367.
PMID
3857025
Source
pubmed
Published In
Archives of Pathology and Laboratory Medicine
Volume
109
Issue
4
Publish Date
1985
Start Page
365
End Page
367

Macrophages and infertility: enhancement of human macrophage-mediated sperm killing by antisperm antibodies.

The mechanism by which antisperm antibodies inhibit fertility is not completely understood. Macrophages may play a role in mediating infertility by interacting with sperm and destroying gametes. Experiments were conducted evaluating the effect of antisperm antibody on the phagocytosis and lysis of sperm by human peritoneal macrophages in vitro. Sperm from a fertile man treated with sera from normal men and women or medium alone had 5 to 280 molecules of IgG/sperm, as determined by a 125I-labeled anti-human IgG monoclonal antibody assay. By contrast, sperm treated with sera containing antisperm antibodies had 310 to 1240 molecules of IgG/sperm. Peritoneal macrophages harvested from infertile women with tubal/adhesive problems mediated phagocytosis and lysis of 111In-labeled sperm which was enhanced by treatment of the sperm with sera containing antisperm antibodies (39.0% +/- 1.5% versus 76.3% +/- 3.2% phagocytosis, and 3.3% +/- 0.3% versus 23.3% +/- 2.3% lysis of sperm [control versus antibody-treated]). The likelihood of fertilization in couples with antisperm antibody may be determined not only by the antibody but also by the presence of genital tract macrophages capable of destroying the antibody-coated sperm.

Authors
London, SN; Haney, AF; Weinberg, JB
MLA Citation
London, SN, Haney, AF, and Weinberg, JB. "Macrophages and infertility: enhancement of human macrophage-mediated sperm killing by antisperm antibodies." Fertil Steril 43.2 (February 1985): 274-278.
PMID
3967786
Source
pubmed
Published In
Fertility and Sterility
Volume
43
Issue
2
Publish Date
1985
Start Page
274
End Page
278

Treatment of red cell aplasia with antithymocyte globulin: Repeated inductions of complete remissions in two patients

Two patients with red cel aplasia unresponsive to prednisone and cyclophosphamide were treated with antithymocyte globulin (ATG). Both patients developed reticulocytosis within 2-4 days after ATG treatment and had complete remissions. Within 4-6 months, they relapsed, and after retreatment with ATG both again developed reticulocytosis and remission. ATG should be considered for the treatment of patients with red cell aplasia who fail to respond to glucocorticoid/alkylator treatment.

Authors
Harris, SI; Weinberg, JB
MLA Citation
Harris, SI, and Weinberg, JB. "Treatment of red cell aplasia with antithymocyte globulin: Repeated inductions of complete remissions in two patients." American Journal of Hematology 20.2 (1985): 183-186.
PMID
3929597
Source
scival
Published In
American Journal of Hematology
Volume
20
Issue
2
Publish Date
1985
Start Page
183
End Page
186

DIFFERING PHENOTYPES OF HUMAN-MONOCYTES AND GAMMA-INTERFERON-INDUCED MONOCYTE POLYKARYONS

Authors
WEINBERG, JB
MLA Citation
WEINBERG, JB. "DIFFERING PHENOTYPES OF HUMAN-MONOCYTES AND GAMMA-INTERFERON-INDUCED MONOCYTE POLYKARYONS." JOURNAL OF LEUKOCYTE BIOLOGY 38.1 (1985): 105-105.
Source
wos-lite
Published In
Journal of leukocyte biology
Volume
38
Issue
1
Publish Date
1985
Start Page
105
End Page
105

Microassay for the photometric quantitation of cell-associated plasminogen activator using a chromogenic tripeptide substrate.

Plasminogen activator (PA), a neutral protease whose primary function is to convert plasminogen to plasmin, is produced by various cells including macrophages, monocytes, endothelial cells, and tumor cells. This study reports the use of the chromogenic tripeptide substrate D-Val-Leu-Lys-p-nitroanilide (S-2251) and an automated microtiter plate reader spectrophotometer for the determination of PA activity in cells and fluids. There was a linear relationship between the time of incubation at 37 degrees C and the square root of the absorbance measured at 405 nm when urokinase was incubated with the substrate in the presence of plasminogen. There was no activity in the absence of plasminogen. The slopes of the lines (square root A 405/time) were directly related to the concentrations of urokinase, up through 0.05 CTA units. Using this assay, we determined the cellular activity of PA in human promyelocytic cells HL-60 (1.33 +/- 0.12 CTA units/mg), human monocytoid cells U937 (1.27 +/- 0.12 CTA units/mg), mouse myeloid leukemia cells RFM/UN (0.70 +/- 0.07 CTA units/mg), freshly isolated normal human monocytes (0.00 +/- 0.00 CTA units/mg), and human monocytes after 7 days in culture (5.66 +/- 0.38 CTA units/mg). There was a variable amount of activity expressed in freshly isolated cells or cell lysates of peritoneal macrophages from normal mice, or mice that had gotten intraperitoneal injections of peptone, thioglycollate, or NaIO4, but after 24 or 48 h of culture, these activities, in general, increased. Using this assay, PA levels in the euglobulin precipitates from human plasma prepared without venous occlusion (0.03 +/- 0.02 CTA units/mg protein) or after 5 min of venous occlusion of the arm (0.18 +/- 0.01 CTA units/mg) were comparable to those reported by others using different assays. Thus, this represents a simple, rapid, accurate assay of PA that should be useful to those in immunology, cell biology, and clinical medicine.

Authors
Weinberg, JB; Hobbs, MM; Pizzo, SV
MLA Citation
Weinberg, JB, Hobbs, MM, and Pizzo, SV. "Microassay for the photometric quantitation of cell-associated plasminogen activator using a chromogenic tripeptide substrate." J Immunol Methods 75.2 (December 31, 1984): 289-294.
PMID
6596319
Source
pubmed
Published In
Journal of Immunological Methods
Volume
75
Issue
2
Publish Date
1984
Start Page
289
End Page
294

Comparison of in vitro and in vivo differentiation of myeloblastic leukemia of the RFM/Un mouse.

Various human and mouse myeloid leukemia cell lines can differentiate to mature myeloid or monocytoid cells in response to different agents. The myeloblastic leukemia of the RFM/Un mouse (the RF.AML line) was studied here to determine its ability to differentiate after in vitro and in vivo treatment. The RF.AML cells were passed in vivo by i.v. or i.p. injection of freshly harvested leukemic spleen cells or in vitro-passaged leukemia cells. The cells proliferated in the spleen and peritoneal cavity. The RF.AML cells had the appearance of myeloblasts or myelomonoblasts on Wright's stain, had slight positivity for peroxidase, and lacked staining for nonspecific esterase. The cells grew in suspension in vitro with a doubling time of 48 hr. Various phorbol diester tumor promotors inhibited proliferation and incorporation of thymidine into the RF.AML cells. Phorbol myristate acetate (10 to 100 nM) caused the cells to adhere to plastic, and enhanced the phagocytic ability of the cells for Candida albicans. The RF.AML cells had specific receptors for phorbol dibutyrate, binding 0.37 +/- 0.03 (S.E.) pmol of [3H]phorbol dibutyrate/10(6) cells after a 2-hr incubation at 4 degrees with 50 nM [3H]phorbol dibutyrate. Thirty-three to 300 nM dexamethasone caused 19 to 37% of the cells to become nonspecific esterase positive and enhanced their phagocytosis of C. albicans. Likewise, 0.5 or 1.0 microM 13-cis-retinoic acid, or 0.6 or 1.2% dimethyl sulfoxide enhanced the phagocytic ability of the RF.AML cells but had no effect on the adherence, proliferation, or nonspecific esterase activity. None of the treatments induced lysozyme activity in the cells or rendered the RF.AML cells able to produce H2O2 in response to phorbol myristate acetate treatment in vitro. In vivo treatment of mice with RF.AML present with phorbol myristate acetate or dexamethasone did not induce differentiation of the RF.AML cells or alter the survival of the animals. Thus, although the RF.AML cells differentiate in vitro in response to various agents, in vivo differentiation was not seen in this model.

Authors
Weinberg, JB; Misukonis, MA
MLA Citation
Weinberg, JB, and Misukonis, MA. "Comparison of in vitro and in vivo differentiation of myeloblastic leukemia of the RFM/Un mouse." Cancer research 44.12 Pt 1 (December 1984): 5594-5598. (Academic Article)
Source
manual
Published In
Cancer Research
Volume
44
Issue
12 Pt 1
Publish Date
1984
Start Page
5594
End Page
5598

Recombinant human gamma-interferon induces human monocyte polykaryon formation.

Monocyte or macrophage polykaryons (MP) are seen in different tissues in various inflammatory states and in normal bone (osteoclasts). The factors controlling the formation and the function of MP are not completely understood. This study was designed to evaluate the effects of the lymphokine gamma-interferon (IFN-gamma) on human monocyte function in vitro. Purified recombinant IFN-gamma [20-200 units/ml (0.1-1.0 nM)] caused the appearance of MP in cultures of normal human monocytes cultured in 10% unheated autologous serum. The MP were noted by as early as 36 hr of culture with fusion indices of 40%-60% and up to 160 nuclei per cell. The effect was seen with both recombinant IFN-gamma and natural IFN-gamma produced by Staphylococcal enterotoxin A-stimulated lymphocytes, but IFN-alpha (leukocyte-derived and recombinant) and IFN-beta did not induce MP formation. The activity of the IFN-gamma was destroyed by heating at 56 degrees C for 4 hr, incubating at pH 2 for 3 hr, or incubating with antibody against IFN-gamma. Populations of monocytes incubated 3 days with 100 units of IFN-gamma per ml (0.5 nM) had enhanced capacity to produce H2O2 in response to phorbol 12-myristate 13-acetate and increased content of acid phosphatase and plasminogen activator. As determined by autoradiography, the MP did not incorporate [3H]dThd into their nuclei. Thus, the IFN-gamma appears to induce MP formation by a process of monocyte fusion, and to "activate" monocytes, as judged by various parameters.

Authors
Weinberg, JB; Hobbs, MM; Misukonis, MA
MLA Citation
Weinberg, JB, Hobbs, MM, and Misukonis, MA. "Recombinant human gamma-interferon induces human monocyte polykaryon formation." Proc Natl Acad Sci U S A 81.14 (July 1984): 4554-4557.
PMID
6431409
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
81
Issue
14
Publish Date
1984
Start Page
4554
End Page
4557

Diverse humoral and cell-mediated effects of antisperm antibodies on reproduction.

No single test to detect the presence of antisperm antibodies has correlated precisely with subsequent fertility. The purpose of this study was to determine whether heterogeneous effects of antibodies could potentially explain this observation. The effects of serum on sperm motility, complement-mediated sperm lysis, mouse macrophage-mediated sperm phagocytosis, and sperm IgG opsonization were assessed in several patients with known antisperm antibodies. Each patient's serum produced its own unique profile. Motility ranged from normal (70% to 85%) to 10% using different subjects' serum. Antibody-dependent complement-mediated sperm lysis ranged from 35% to 65%. Normal sperm incubated with normal serum had approximately 200 molecules of IgG per sperm, whereas normal sperm incubated with patient sera had 546 to 900 molecules of IgG per sperm. In all cases where serum enhanced IgG sperm opsonization, there was enhanced mouse macrophage-mediated phagocytosis of the opsonized sperm (a three- to fourfold increase). These data suggest that antisperm antibodies may affect reproduction by different mechanisms, including direct humoral effects (immunoglobulin and/or complement) and indirect cell-mediated effects (macrophage-mediated sperm phagocytosis). However, the mechanism(s) involved are unique to each individual's antibody. The heterogeneity of these potential mechanisms may explain why the presence of antisperm antibodies as measured by a single assay correlate poorly with infertility.

Authors
London, SN; Haney, AF; Weinberg, JB
MLA Citation
London, SN, Haney, AF, and Weinberg, JB. "Diverse humoral and cell-mediated effects of antisperm antibodies on reproduction." Fertil Steril 41.6 (June 1984): 907-912.
PMID
6724002
Source
pubmed
Published In
Fertility and Sterility
Volume
41
Issue
6
Publish Date
1984
Start Page
907
End Page
912

Human leukemia cell lines with comparable receptor binding characteristics but different phenotypic responses to phorbol diesters.

Phorbol diester (PDE) tumor promoters have differing effects on normal and neoplastic hematopoietic cells in vitro. The effects of PDEs on cells are apparently mediated by specific cellular receptors for these ligands. The purpose of this study was to determine if the different phenotypic responses of cells of different human leukemia cell lines were due to differences in the PDE receptors in these cells. All cells of the different lines studied [HL-60 (promyelocytic), HL-60Bll (undifferentiated blastic), U-937 (monoblastic), H-SB2 (T-lymphoblastoid), and SB (B-lymphoblastoid) bound the [20-3H]phorbol-12,13-dibutyrate in a specific manner. The ligand bound to the cells rapidly, reaching a maximum by 10 to 20 min at 37 degrees or by 60 min at 4 degrees. The bound [20-3H]phorbol-12,13-dibutyrate could be fully dissociated from the cells by adding unlabeled phorbol-12,13-dibutyrate; the kinetics of this dissociation paralleled association kinetics. Scatchard analysis of the binding data, derived from experiments done at 4 degrees, revealed linear plots, indicating, most likely, that only single classes of receptors existed on all of these lines. The dissociation constants for binding were all comparable (46 to 152 nM), and the calculated numbers of binding sites were comparable (4.8 to 8.1 X 10(5)/cell). None of the cells could degrade [20-3H]phorbol-12-myristate-13-acetate or [20-3H]phorbol-12,13-dibutyrate as determined by thin-layer chromatographic analysis of cells or supernatants of the cell cultures. PDEs inhibited the proliferation of U-937 and HL-60 cells but not that of the HL-60Bll, SB, or H-SB2 cells. The incorporation of tritiated thymidine into HL-60 cells (but not HL-60Bll cells) was dramatically inhibited by various PDEs, and the potency in causing this inhibition paralleled that known for the potency of the phorbol analogues to cause tumor promotion in vivo or to elicit other in vitro responses from hematopoietic cells. [20-3H]Phorbol-12-myristate-13-acetate caused the HL-60 and U-937 cells to adhere to the plastic, spread, and develop vacuoles, but the other cells displayed no changes. These results suggest that the differing phenotypic responses to PDEs are most likely related to postreceptor factors.

Authors
Weinberg, JB; Misukonis, MA; Goodwin, BJ
MLA Citation
Weinberg, JB, Misukonis, MA, and Goodwin, BJ. "Human leukemia cell lines with comparable receptor binding characteristics but different phenotypic responses to phorbol diesters." Cancer Res 44.3 (March 1984): 976-980.
PMID
6318990
Source
pubmed
Published In
Cancer Research
Volume
44
Issue
3
Publish Date
1984
Start Page
976
End Page
980

Specific receptors for phorbol diesters on freshly isolated human myeloid and lymphoid leukemia cells: comparable binding characteristics despite different cellular responses.

Freshly isolated human leukemia cells have been shown in the past to display varying in vitro responses to phorbol diesters, depending on their cell type. Specific receptors for the phorbol diesters have been demonstrated on numerous different cells. This study was designed to characterize the receptors for phorbol diesters on leukemia cells freshly isolated from patients with different kinds of leukemia and to determine if differences in binding characteristics for tritium-labeled phorbol 12,13-dibutyrate (3H-PDBu) accounted for the different cellular responses elicited in vitro by phorbol diesters. Cells from 26 patients with different kinds of leukemia were studied. PDBu or phorbol 12-myristate 13-acetate (PMA) caused cells from patients with acute myeloblastic leukemia (AML), acute promyelocytic (APML), acute myelomonocytic (AMML), acute monocytic (AMoL), acute erythroleukemia (AEL), chronic myelocytic leukemia (CML) in blast crisis (myeloid), acute undifferentiated leukemia (AUL), and hairy cell leukemia (HCL) (n = 15) to adhere to plastic and spread. However, they caused no adherence or spreading and only slight aggregation of cells from patients with acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), or CML-blast crisis (lymphoid) (n = 11). All leukemia cells studied, irrespective of cellular type, displayed specific receptors for 3H-PDBu. The time courses for binding by all leukemia types were similar, with peak binding at 5-10 min at 37 degrees C and 120 min at 4 degrees C. The binding affinities were similar for patients with ALL (96 +/- 32 nM, n = 4), CLL (126 +/- 32 nM, n = 6), and acute nonlymphoid leukemia (73 +/- 14 nM, n = 11). Likewise, the numbers of specific binding sites/cell were comparable for the patients with ALL (6.2 +/- 1.3 X 10(5) sites/cell, n = 4), CLL (5.0 +/- 2.0 X 10(5) sites/cell, n = 6), and acute nonlymphoid leukemia (4.4 +/- 1.9 X 10(5) sites/cell, n = 11). Thus, the differing responses to phorbol diesters of various types of freshly isolated leukemia cells appear to be due to differences other than initial ligand-receptor binding.

Authors
Goodwin, BJ; Moore, JO; Weinberg, JB
MLA Citation
Goodwin, BJ, Moore, JO, and Weinberg, JB. "Specific receptors for phorbol diesters on freshly isolated human myeloid and lymphoid leukemia cells: comparable binding characteristics despite different cellular responses." Blood 63.2 (February 1984): 298-304.
PMID
6318866
Source
pubmed
Published In
Blood
Volume
63
Issue
2
Publish Date
1984
Start Page
298
End Page
304

Extramedullary recurrence of acute lymphoblastic leukemia 15 years after initial diagnosis

We describe a 19-year-old man with recurrence of a lymphoid malignancy involving the ethmoid sinus 15 years following diagnosis and 10 years after discontinuation of therapy for childhood acute lymphoblastic leukemia (ALL). The cytologic appearance and immunologic phenotype of the tumor cells suggest that this malignancy represents a recurrence of his original tumor. Initial relapse of ALL is unusual after 4 years of continuous remission off therapy. This case illustrates that late relapse can occur and may present with unusual sites of involvement.

Authors
Burton, GV; Weinberg, JB; Borowitz, MJ
MLA Citation
Burton, GV, Weinberg, JB, and Borowitz, MJ. "Extramedullary recurrence of acute lymphoblastic leukemia 15 years after initial diagnosis." Medical and Pediatric Oncology 12.4 (1984): 255-257.
PMID
6589464
Source
scival
Published In
Medical and Pediatric Oncology
Volume
12
Issue
4
Publish Date
1984
Start Page
255
End Page
257

Peritoneal fluid prolactin in infertile women with endometriosis: Lack of evidence of secretory activity by endometrial implants

To evaluate the functional status of endometriotic implants, a luteal secretory product of endometrium, PRL, was measured in the PF of 27 infertile women with endometriosis, 13 infertile women without endometriosis, and 11 fertile women undergoing elective sterilization. PF PRL concentrations and PF/plasma PRL ratios were similar in all the groups and did not vary with the menstrual cycle or the stage of endometriosis. These data demonstrate that the ectopic endometrium in infertile women with endometriosis does not secrete PRL in amounts sufficient to elevate PF concentrations and suggest that the infertility observed in these women is probably not dependent upon the secretory activity of endometriotic implants.

Authors
Haney, AF; Handwerger, S; Weinberg, JB
MLA Citation
Haney, AF, Handwerger, S, and Weinberg, JB. "Peritoneal fluid prolactin in infertile women with endometriosis: Lack of evidence of secretory activity by endometrial implants." Fertility and Sterility 42.6 (1984): 935-938.
PMID
6500083
Source
scival
Published In
Fertility and Sterility
Volume
42
Issue
6
Publish Date
1984
Start Page
935
End Page
938

Comparison of in vitro and in vivo differentiation of myeloblastic leukemia of the RFM/Un mouse

Various human and mouse myeloid leukemia cell lines can differentiate to mature myeloid or monocytoid cells in response to different agents. The myeloblastic leukemia of the RFM/Un mouse (the RF.AML line) was studied here to determine its ability to differentiate after in vitro and in vivo treatment. The RF.AML cells were passed in vivo by i.v. or i.p. injection of freshly harvested leukemic spleen cells or in vitro-passaged leukemia cells. The cells proliferated in the spleen and peritoneal cavity. The RF.AML cells had the appearance of myeloblasts or myelomonoblasts on Wright's stain, had slight positivity for peroxidase, and lacked staining for nonspecific esterase. The cells grew in suspension in vitro with a doubling time of 48 hr. Various phorbol diester tumor promotors inhibited proliferation and incorporation of thymidine into the RF.AML cells. Phorbol myristate acetate (10 to 100 nM) caused the cells to adhere to plastic, and enhanced the phagocytic ability of the cells for Candida albicans. The RF.AML cells had specific receptors for phorbol dibutyrate, binding 0.37 ± 0.03 (S.E.) pmol of [3H]phorbol dibutyrate/106 cells after a 2-hr incubation at 4° with 50 nM [3H]phorbol dibutyrate. Thirty-three to 300 nM dexamethasone caused 19 to 37% of the cell to become nonspecific esterase positive and enhanced their phagocytosis of C. albicans. Likewise, 0.5 or 1.0 μM 13-cis-retinoic acid, or 0.6 or 1.2% dimethyl sulfoxide enhanced the phagocytic ability of the RF.AML cells but had no effect on the adherence, proliferation, or nonspecific esterase activity. None of the treatments induced lysozyme activity in the cells or rendered the RF.AML cells able to produce H2O2 in response to phorbol myristate acetate treatment in vitro. In vivo treatment of mice with RF.AML present with phorbol myristate acetate or dexamethasone did not induce differentiation of the RF.AML cells or alter the survival of the animals. Thus, although the RF.AML cells differentiate in vitro in response to various agents, in vivo differentiation was not seen in this model.

Authors
Weinberg, JB; Misukonis, MA
MLA Citation
Weinberg, JB, and Misukonis, MA. "Comparison of in vitro and in vivo differentiation of myeloblastic leukemia of the RFM/Un mouse." Cancer Research 44.12 I (1984): 5594-5598.
Source
scival
Published In
Cancer Research
Volume
44
Issue
12 I
Publish Date
1984
Start Page
5594
End Page
5598

Recombinant human γ-interferon induces human monocyte polykaryon formation

Monocyte or macrophage polykaryons (MP) are seen in different tissues in various inflammatory states and in normal bone (osteoclasts). The factors controlling the formation and the function of MP are not completely understood. This study was designed to evaluate the effects of the lymphokine γ-interferon (IFN-γ) on human monocyte function in vitro. Purified recombinant IFN-γ [20-200 units/ml (0.1-1.0 nM)] caused the appearance of MP in cultures of normal human monocytes cultured in 10% unheated autologous serum. The MP were noted by as early as 36 hr of culture with fusion indices of 40-60% and up to 160 nuclei per cell. The effect was seen with both recombinant IFN-γ and natural IFN-γ produced by Staphylococcus enterotoxin A-stimulated lymphocytes, but IFN-α (leukocyte-derived and recombinant) and IFN-β did not induce MP formation. The activity of the IFN-γ was destroyed by heating at 56° C for 4 hr, incubating at pH 2 for 3 hr, or incubating with antibody against IFN-γ. Populations of monocytes incubated 3 days with 100 units of IFN-γ per ml (0.5 nM) had enhanced capacity to produce H2O2 in response to phorbol 12-myristate 13-acetate and increased content of acid phosphatase and plasminogen activator. As determined by autoradiography, the MP did not incorporate [3H]dThd into their nuclei. Thus, the IFN-γ apears to induce MP formation by a process of monocyte fusion, and to 'activate' monocytes, as judged by various parameters.

Authors
Weinberg, JB; Hobbs, MM; Misukonis, MA
MLA Citation
Weinberg, JB, Hobbs, MM, and Misukonis, MA. "Recombinant human γ-interferon induces human monocyte polykaryon formation." Proceedings of the National Academy of Sciences of the United States of America 81.14 I (1984): 4554-4557.
Source
scival
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
81
Issue
14 I
Publish Date
1984
Start Page
4554
End Page
4557

IMAGING OF HUMANS WITH LABELED MONOCYTES - INVITRO FUNCTION OF IN-111 OXINE LABELED MONOCYTES

Authors
BLINDER, RA; COLEMAN, RE; WEINBERG, JB
MLA Citation
BLINDER, RA, COLEMAN, RE, and WEINBERG, JB. "IMAGING OF HUMANS WITH LABELED MONOCYTES - INVITRO FUNCTION OF IN-111 OXINE LABELED MONOCYTES." JOURNAL OF LEUKOCYTE BIOLOGY 36.3 (1984): 432-432.
Source
wos-lite
Published In
Journal of leukocyte biology
Volume
36
Issue
3
Publish Date
1984
Start Page
432
End Page
432

PHENOTYPIC CHARACTERIZATION OF GAMMA-INTERFERON-INDUCED HUMAN MONOCYTE POLYKARYONS (MP)

Authors
WEINBERG, JB; MISUKONIS, MA; HOBBS, MM
MLA Citation
WEINBERG, JB, MISUKONIS, MA, and HOBBS, MM. "PHENOTYPIC CHARACTERIZATION OF GAMMA-INTERFERON-INDUCED HUMAN MONOCYTE POLYKARYONS (MP)." JOURNAL OF LEUKOCYTE BIOLOGY 36.2 (1984): 203-204.
Source
wos-lite
Published In
Journal of leukocyte biology
Volume
36
Issue
2
Publish Date
1984
Start Page
203
End Page
204

RECOMBINANT GAMMA INTERFERON (IFN-GAMMA) INDUCES HUMAN MONOCYTE ACTIVATION AND POLYKARYON FORMATION

Authors
WEINBERG, JB; HOBBS, MM; MISUKONIS, MA
MLA Citation
WEINBERG, JB, HOBBS, MM, and MISUKONIS, MA. "RECOMBINANT GAMMA INTERFERON (IFN-GAMMA) INDUCES HUMAN MONOCYTE ACTIVATION AND POLYKARYON FORMATION." PROCEEDINGS OF THE AMERICAN ASSOCIATION FOR CANCER RESEARCH 25.MAR (1984): 267-267.
Source
wos-lite
Published In
Proceedings of the Annual Meeting- American Association for Cancer Research
Volume
25
Issue
MAR
Publish Date
1984
Start Page
267
End Page
267

LACK OF EVIDENCE OF REACTIVE OXYGEN SPECIES AS MEDIATORS IN HUMAN AND MOUSE MONONUCLEAR PHAGOCYTE TUMOR-CELL KILLING

Authors
WEINBERG, JB
MLA Citation
WEINBERG, JB. "LACK OF EVIDENCE OF REACTIVE OXYGEN SPECIES AS MEDIATORS IN HUMAN AND MOUSE MONONUCLEAR PHAGOCYTE TUMOR-CELL KILLING." JOURNAL OF LEUKOCYTE BIOLOGY 36.5 (1984): 674-674.
Source
wos-lite
Published In
Journal of leukocyte biology
Volume
36
Issue
5
Publish Date
1984
Start Page
674
End Page
674

RECOMBINANT GAMMA INTERFERON (IFN-GAMMA) AND 1,25 DIHYDROXY VITAMIN-D3 (D3) INDUCE MONOCYTOID DIFFERENTIATION AND POLYKARYON FORMATION OF HUMAN-LEUKEMIA (HL-60) CELLS-INVITRO

Authors
WEINBERG, JB; MISUKONIS, MA; HOBBS, MM
MLA Citation
WEINBERG, JB, MISUKONIS, MA, and HOBBS, MM. "RECOMBINANT GAMMA INTERFERON (IFN-GAMMA) AND 1,25 DIHYDROXY VITAMIN-D3 (D3) INDUCE MONOCYTOID DIFFERENTIATION AND POLYKARYON FORMATION OF HUMAN-LEUKEMIA (HL-60) CELLS-INVITRO." PROCEEDINGS OF THE AMERICAN ASSOCIATION FOR CANCER RESEARCH 25.MAR (1984): 44-44.
Source
wos-lite
Published In
Proceedings of the Annual Meeting- American Association for Cancer Research
Volume
25
Issue
MAR
Publish Date
1984
Start Page
44
End Page
44

COMPARISON OF INVITRO AND INVIVO DIFFERENTIATION OF MYELOBLASTIC-LEUKEMIA OF THE RFM/UN MOUSE

Authors
WEINBERG, JB; MISUKONIS, MA
MLA Citation
WEINBERG, JB, and MISUKONIS, MA. "COMPARISON OF INVITRO AND INVIVO DIFFERENTIATION OF MYELOBLASTIC-LEUKEMIA OF THE RFM/UN MOUSE." CANCER RESEARCH 44.12 (1984): 5594-5598.
PMID
6594193
Source
wos-lite
Published In
Cancer Research
Volume
44
Issue
12
Publish Date
1984
Start Page
5594
End Page
5598

Spontaneous tumor cell killing by human blood monocytes and human peritoneal macrophages: lack of alteration by endotoxin or quenchers of reactive oxygen species.

Human mononuclear phagocytes (monocytes and macrophages) act as effectors in the destruction of tumor cells. Peritoneal macrophages from normal or infertile women killed a variety of tumor cells in vitro more efficiently than did blood monocytes from the same subjects. Lysis depended on the effector-to-target cell ratio and was neither reproduced by supernatants from nor lysates of the mononuclear phagocytes. Normal fibroblasts were not lysed. Lipopolysaccharide (10(1)-10(4) ng/ml) did not alter the monocyte- or macrophage-mediated tumor cell killing. The monocytes and macrophages had equivalent basal and phorbol 12,13-myristate acetate-stimulated H2O2 and O-2 production, and the reactive oxygen species scavengers or quenchers catalase, superoxide dismutase, mannitol, and L-histidine did not diminish the killing. These observations suggest that the spontaneous tumor cell killing by human mononuclear phagocytes was not mediated by reactive oxygen species.

Authors
Weinberg, JB; Haney, AF
MLA Citation
Weinberg, JB, and Haney, AF. "Spontaneous tumor cell killing by human blood monocytes and human peritoneal macrophages: lack of alteration by endotoxin or quenchers of reactive oxygen species." J Natl Cancer Inst 70.6 (June 1983): 1005-1010.
PMID
6574267
Source
pubmed
Published In
Journal of the National Cancer Institute
Volume
70
Issue
6
Publish Date
1983
Start Page
1005
End Page
1010

Macrophages and infertility: oviductal macrophages as potential mediators of infertility.

Human peritoneal macrophages have previously been shown to phagocytize normal sperm. We had hypothesized that if macrophages were present in the distal oviducts, they could interfere with fertilization by phagocytizing sperm in vivo. The present study was designed to determine whether functional macrophages are present in the human oviducts, and to determine the relationship between oviductal and peritoneal macrophages. Forty patients undergoing laparotomy for sterilization or evaluation of infertility or other gynecologic factors were studied. Infertile patients with endometriosis had more peritoneal macrophages than did fertile normal women or infertile women with distal or proximal tubal obstruction. Oviductal macrophages were observed in all patients. The oviductal macrophages were indistinguishable from the peritoneal macrophages, as judged by similar morphologic features, adherence to plastic, phagocytosis of polystyrene spheres and IgG-coated erythrocytes, and presence of peroxidase and alpha-naphthylbutyrate esterase. Patients with endometriosis had the highest numbers of oviductal macrophages, while those patients with distal tubal obstruction had extremely few oviductal macrophages. The results suggest that oviductal macrophages may arise from peritoneal macrophages that migrate into the oviducts.

Authors
Haney, AF; Misukonis, MA; Weinberg, JB
MLA Citation
Haney, AF, Misukonis, MA, and Weinberg, JB. "Macrophages and infertility: oviductal macrophages as potential mediators of infertility." Fertil Steril 39.3 (March 1983): 310-315.
PMID
6681781
Source
pubmed
Published In
Fertility and Sterility
Volume
39
Issue
3
Publish Date
1983
Start Page
310
End Page
315

Macrophage polykaryon formation in vitro by peritoneal cells from mice given injections of sodium periodate.

Peritoneal macrophages from mice that have received two separate intraperitoneal injections of the sterile, soluble oxidant NaIO4 form macrophage polykaryons (MPs) in vitro, but peritoneal macrophage from untreated, peptone-treated, or mice infected with bacille Calmette-Guerin (BCG) do not. The polykaryons are noted after 18-24 hours of culture and continue to form over a 60-72-hour period. The MPs do not form if the macrophage density is less than 4 x 10(3)/sq mm. The polykaryons appear in vitro only in cultures with less than or equal to 1-5 ng/ml lipopolysaccharide (LPS) (amounts of LPS that commonly contaminate culture medium and serum). Hydrocortisone hemisuccinate (2.6 x 10(-9) M) inhibits MP formation in vitro. Lymphocytes do not influence the polykaryon formation, and supernatants from MP cultures do not cause fusion of other macrophages. Microcinephotography demonstrates fusion of the macrophages to form the large polykaryons, which are less motile than uninuclear macrophages. The polykaryons assume different forms; generally, the nuclei (mean, 16.8 nuclei/MP; range, 2-137 nuclei/MP) are centrally located, and the nuclear chromatin of all nuclei appears similar. The MPs phagocytize polystyrene spheres and glutaraldehyde-treated erythrocytes to the same degree as do uninuclear macrophages when determined as particles per nucleus (phagocytic index), but their phagocytic index of IgG-coated erythrocytes is decreased. Peritoneal macrophages from mice given double injections of NaIO4 are nontumoricidal in the absence of LPS, but LPS, in amounts sufficient to inhibit polykaryon formation, renders the macrophages tumoricidal. Populations of macrophages containing MPs formed over 3 days of cultures also respond to LPS or macrophage activating factor (MAF) to demonstrate enhanced tumoricidal activity.

Authors
Weinberg, JB
MLA Citation
Weinberg, JB. "Macrophage polykaryon formation in vitro by peritoneal cells from mice given injections of sodium periodate." Am J Pathol 110.2 (February 1983): 182-192.
PMID
6297306
Source
pubmed
Published In
The American journal of pathology
Volume
110
Issue
2
Publish Date
1983
Start Page
182
End Page
192

Sperm phagocytosis by human peritoneal macrophages: A possible cause of infertility in endometriosis

Authors
Muscato, JJ; Haney, AF; Weinberg, JB
MLA Citation
Muscato, JJ, Haney, AF, and Weinberg, JB. "Sperm phagocytosis by human peritoneal macrophages: A possible cause of infertility in endometriosis." Obstetrical and Gynecological Survey 38.3 (January 1, 1983): 177-179.
Source
scopus
Published In
Obstetrical and Gynecological Survey
Volume
38
Issue
3
Publish Date
1983
Start Page
177
End Page
179

Phorbol diester-induced H2O2 production by peritoneal macrophages. Different H2O2 production by macrophages from normal and BCG-infected mice despite comparable phorbol diester receptors

Mouse peritoneal macrophages respond to environmental stimuli in different ways depending on their state of differentiation. Macrophages from mice with bacillus Calmette-Guerin (BCG) infection produced large amounts of H2O2 in response to phorbol diesters (PDEs), while those from noninfected mice produced little or no H2O2. The effects of PDEs on cells are mediated by specific cellular receptors for these ligands. The purpose of this study was to determine if the varying responses of macrophages from different groups of mice were caused by differences in their receptors for the PDE ligands. By all parameters studied, the binding of [20-3H]phorbol 12,13-dibutyrate ([3H]PDBu) was similar in all macrophages irrespective of their ability to produce H2O2 in response to PDEs. Binding of [3H]PDBu was rapid at 23°C reaching a maximum at 10-20 min with a subsequent decline to 50-60% of maximum by 30-60 min. Binding was slower at 0 °C reaching a maximum at 90-120 min. The binding was reversible, with dissociation kinetics paralleling association kinetics. The binding was saturable; the Kd's (45 to 91 nM) and number of binding sites (about 7-14 × 105/cell or 11-12 pmol/mg protein) were essentially the same for the different classes of macrophages. The binding was specific, and analogs of PDBu inhibited [3H]PDBu binding to macrophages with potencies comparable to their potencies in causing in vivo tumor promotion and elicitation of other cellular responses in vitro. The ligands [3H]PDBu and [3H]PMA were degraded to comparable degrees by macrophages from normal or BCG-infected mice. Macrophages from C3H/HeJ and C3H/HeN mice, although known to differ in their abilities to respond to stimuli such as lymphokines and LPS, did not differ in their ability to produce H2O2 in response to PDEs or in their receptors for PDEs. Results of this study suggest that in vivo "activation" of macrophages in mice infected with BCG is not associated with a change in the cells' receptors for PDEs, but may be associated with "postreceptor" changes such as linkage of the PDE receptor with NAD(P)H oxidase, a change in NAD(P)H oxidase, or induction of synthesis of NAD(P)H oxidase. © 1983.

Authors
Weinberg, JB; Misukonis, MA
MLA Citation
Weinberg, JB, and Misukonis, MA. "Phorbol diester-induced H2O2 production by peritoneal macrophages. Different H2O2 production by macrophages from normal and BCG-infected mice despite comparable phorbol diester receptors." Cellular Immunology 80.2 (1983): 405-415.
PMID
6309416
Source
scival
Published In
Cellular Immunology
Volume
80
Issue
2
Publish Date
1983
Start Page
405
End Page
415

Enhancement of macrophage-mediated tumor cell killing by bacterial outer membrane proteins (porins)

Various microbial products are known to influence the function of mouse peritoneal macrophages. Lipopolysaccharide (LPS) and certain lipid A-associated proteins are known to enhance the tumoricidal effects of macrophages. The purpose of this study was to determine whether porins (outer membrane proteins) of Salmonella typhimurium G30/C21 would influence the activity of macrophages from lipid A-responsive and -unresponsive mice. Porins, extracted by a combined sodium dodecyl sulfate-EDTA method from cell walls, were free of LPS as determined by Limulus amebocyte lysate assay and appeared as a band at approximately 36,000 molecular weight on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In tumor cell killing assays done under LPS-free conditions, the porins in doses of 1 to 10 ng/ml enhanced the tumoricidal effect of macrophages from bacillus Calmette-Guerin-infected C3H/HeN or C3H/HeJ mice. Protein-free LPS enhanced the tumoricidal activity of macrophages from bacillus Calmette-Guerin-infected C3H/HeN but not C3H/HeH mice. The tumoricidal-enhancing activity of protein-free LPS was blocked by the lipid A-binding antibiotic polymyxin B sulfate, but the effects of porins were not altered by the polymyxin B sulfate. These results suggest that porins, proteins known to alter membrane function, may alter macrophage function by interaction with macrophage membranes.

Authors
Weinberg, JB; Ribi, E; Wheat, RW
MLA Citation
Weinberg, JB, Ribi, E, and Wheat, RW. "Enhancement of macrophage-mediated tumor cell killing by bacterial outer membrane proteins (porins)." Infection and Immunity 42.1 (1983): 219-223.
PMID
6311745
Source
scival
Published In
Infection and Immunity
Volume
42
Issue
1
Publish Date
1983
Start Page
219
End Page
223

Sperm phagocytosis by human peritoneal macrophages: a possible cause of infertility in endometriosis.

The mechanism of infertility in women with endometriosis is unknown, but it is independent of mechanical factors that affect fallopian tube function. Increased numbers of peritoneal macrophages are present in women with endometriosis and have access to the female reproductive tract via the oviducts. To determine whether peritoneal macrophages might phagocytize sperm and thereby contribute to infertility in women with endometriosis, we examined peritoneal macrophages from 32 fertile and infertile women; the infertile group was separated into those with and those without visible endometriosis. Peritoneal macrophages from infertile patients with endometriosis phagocytized more normal sperm in vitro (84% +/- 4%) than did those from fertile women (43% +/- 4%) or infertile women without endometriosis (46% +/- 8%) (p less than 0.002). The sperm phagocytosis occurred rapidly and reached a peak by approximately 6 hours. Incubation at 0 degrees C, lysing the macrophages by freezing and thawing, or fixing the macrophages with glutaraldehyde inhibited the sperm uptake by macrophages. The process occurred in cultures with or without serum, thereby indicating that the sperm phagocytosis was not dependent on sperm opsonization with a serum factor. Electron microscopy showed internalization of the spermatozoa into phagosomes with subsequent intravacuolar degradation. These data demonstrate that: (1) peritoneal macrophages phagocytize and degrade sperm in vitro and (2) peritoneal macrophages isolated from women with endometriosis exhibit greater phagocytosis in vitro than do macrophages from fertile women or infertile women without endometriosis. These results suggest that, if peritoneal macrophages from women with endometriosis enter the reproductive tract via the oviducts, they might adversely influence fertilization by phagocytizing sperm.

Authors
Muscato, JJ; Haney, AF; Weinberg, JB
MLA Citation
Muscato, JJ, Haney, AF, and Weinberg, JB. "Sperm phagocytosis by human peritoneal macrophages: a possible cause of infertility in endometriosis." Am J Obstet Gynecol 144.5 (November 1, 1982): 503-510.
PMID
6753586
Source
pubmed
Published In
American Journal of Obstetrics & Gynecology
Volume
144
Issue
5
Publish Date
1982
Start Page
503
End Page
510

Receptor-mediated modulation of human monocyte, neutrophil, lymphocyte, and platelet function by phorbol diesters.

The tumor promoting phorbol diesters elicit a variety of responses from normal and leukemic blood cells in vitro by apparently interacting with cellular receptors. The biologically active ligand [20-(3)H] phorbol 12,13-dibutyrate ([(3)H]PDBu) bound specifically to intact human lymphocytes, monocytes, polymorphonuclear leukocytes (PMN), and platelets, but not to erythrocytes. Binding, which was comparable for all four blood cell types, occurred rapidly at 23 degrees and 37 degrees C, reaching a maximum by 20-30 min usually followed by a 30-40% decrease in cell associated radioactivity over the next 30-60 min. The time course for binding was temperature dependent with equilibrium binding occurring after 120-150 min at 4 degrees C, with no subsequent loss of cell-associated radioactivity at this temperature. Bound [(3)H]PDBu could be eluted by addition of unlabeled PDBu. Scatchard analysis of data from 4 degrees C binding studies revealed linear plots with high affinity receptors in these cell types with dissociation constants and receptors per cell of 60 nM and 7.8 x 10(5)/cell for lymphocytes, 51 nM and 15.5 x 10(5)/cell for monocytes, 38 nM and 4.0 x 10(5)/cell for PMN, and 19 nM and 2.9 x 10(4)/cell for platelets. Structure-activity studies using unlabeled phorbol-related compounds demonstrated a close correlation between their abilities to inhibit binding of [(3)H]PDBu to cells and their abilities to induce cellular responses (monocyte and PMN H(2)O(2) secretion, lymphocyte (3)HTdR incorporation, and platelet tritiated serotonin release); phorbol and 4-alpha phorbol were inactive while phorbol 12-myristate 13-acetate (PMA), PDBu, mezerein, and phorbol 12,13-diacetate (in decreasing order of potency) inhibited [(3)H]PDBu binding and elicited the various responses. Thus, these high affinity, specific receptors for the phorbol diesters, present on monocytes, lymphocytes, PMN, and platelets, mediate the pleiotypic effects induced by these ligands.

Authors
Goodwin, BJ; Weinberg, JB
MLA Citation
Goodwin, BJ, and Weinberg, JB. "Receptor-mediated modulation of human monocyte, neutrophil, lymphocyte, and platelet function by phorbol diesters." J Clin Invest 70.4 (October 1982): 699-706.
PMID
6956584
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
70
Issue
4
Publish Date
1982
Start Page
699
End Page
706

Specific phorbol diester receptors on normal and leukemic blood-cells: Relationships of binding to cellular responses

Authors
Goodwin, BJ; Weinberg, JB
MLA Citation
Goodwin, BJ, and Weinberg, JB. "Specific phorbol diester receptors on normal and leukemic blood-cells: Relationships of binding to cellular responses." Proceedings of the American Association for Cancer Research Vol. 23 (1982): 402--.
Source
scival
Published In
Proceedings of the American Association for Cancer Research
Volume
Vol. 23
Publish Date
1982
Start Page
402-

Macrophage receptors for phorbol diesters: Comparable receptors in normal and 'activated' cells despite different cellular responses

Authors
Weinberg, JB
MLA Citation
Weinberg, JB. "Macrophage receptors for phorbol diesters: Comparable receptors in normal and 'activated' cells despite different cellular responses." RES Journal of the Reticuloendothelial Society 32.1 (1982): 63--.
Source
scival
Published In
RES Journal of the Reticuloendothelial Society
Volume
32
Issue
1
Publish Date
1982
Start Page
63-

HUMAN OVIDUCTAL (OM) AND PERITONEAL-MACROPHAGES (PM) AS CELLULAR MEDIATORS OF INFERTILITY

Authors
HANEY, AF; WEINBERG, JB
MLA Citation
HANEY, AF, and WEINBERG, JB. "HUMAN OVIDUCTAL (OM) AND PERITONEAL-MACROPHAGES (PM) AS CELLULAR MEDIATORS OF INFERTILITY." JOURNAL OF THE RETICULOENDOTHELIAL SOCIETY 32.1 (1982): 51-52.
Source
wos-lite
Published In
RES Journal of the Reticuloendothelial Society
Volume
32
Issue
1
Publish Date
1982
Start Page
51
End Page
52

RECEPTOR-BINDING AND SIGNAL TRANSMISSION IN CGD NEUTROPHILS

Authors
LYNN, WS; WEINBERG, JB
MLA Citation
LYNN, WS, and WEINBERG, JB. "RECEPTOR-BINDING AND SIGNAL TRANSMISSION IN CGD NEUTROPHILS." CLINICAL RESEARCH 30.2 (1982): A570-A570.
Source
wos-lite
Published In
Clinical Research
Volume
30
Issue
2
Publish Date
1982
Start Page
A570
End Page
A570

ENDOTOXIN-INDUCED, MACROPHAGE-MEDIATED KILLING OF TUMOR-CELLS - COMPARISON OF BACTERIAL LIPOPOLYSACCHARIDE AND MYCOPLASMAL LIPOGLYCANS

Authors
WEINBERG, JB; SMITH, PF; KAHANE, I
MLA Citation
WEINBERG, JB, SMITH, PF, and KAHANE, I. "ENDOTOXIN-INDUCED, MACROPHAGE-MEDIATED KILLING OF TUMOR-CELLS - COMPARISON OF BACTERIAL LIPOPOLYSACCHARIDE AND MYCOPLASMAL LIPOGLYCANS." REVIEWS OF INFECTIOUS DISEASES 4 (1982): S270-S270.
Source
wos-lite
Published In
Reviews of Infectious Diseases
Volume
4
Publish Date
1982
Start Page
S270
End Page
S270

SPECIFIC PHORBOL DIESTER RECEPTORS ON NORMAL AND LEUKEMIC BLOOD-CELLS - RELATIONSHIPS OF BINDING TO CELLULAR-RESPONSES

Authors
GOODWIN, BJ; WEINBERG, JB
MLA Citation
GOODWIN, BJ, and WEINBERG, JB. "SPECIFIC PHORBOL DIESTER RECEPTORS ON NORMAL AND LEUKEMIC BLOOD-CELLS - RELATIONSHIPS OF BINDING TO CELLULAR-RESPONSES." PROCEEDINGS OF THE AMERICAN ASSOCIATION FOR CANCER RESEARCH 23.MAR (1982): 102-102.
Source
wos-lite
Published In
Proceedings of the Annual Meeting- American Association for Cancer Research
Volume
23
Issue
MAR
Publish Date
1982
Start Page
102
End Page
102

Tumor cell killing by phorbol ester--differentiated human leukemia cells.

The tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate causes differentiation of cells of the human leukemia cell line HL60 to nondividing macrophage-like cells. These differentiated cells are cytotoxic for tumor cells (including parent, untreated HL60 cells) in vitro. Agents that induce this desirable differentiation to nondividing, antitumor effector cells may be useful in the experimental treatment of leukemia.

Authors
Weinberg, JB
MLA Citation
Weinberg, JB. "Tumor cell killing by phorbol ester--differentiated human leukemia cells." Science 213.4508 (August 7, 1981): 655-657.
PMID
7196085
Source
pubmed
Published In
Science
Volume
213
Issue
4508
Publish Date
1981
Start Page
655
End Page
657

Peritoneal fluid cell populations in infertility patients.

Authors
Haney, AF; Muscato, JJ; Weinberg, JB
MLA Citation
Haney, AF, Muscato, JJ, and Weinberg, JB. "Peritoneal fluid cell populations in infertility patients." Fertil Steril 35.6 (June 1981): 696-698.
PMID
7195828
Source
pubmed
Published In
Fertility and Sterility
Volume
35
Issue
6
Publish Date
1981
Start Page
696
End Page
698

In vivo modulation of macrophage tumoricidal activity: enhanced tumor cell killing by peritoneal macrophages from mice given injections of sodium periodate.

Sodium periodate (NaIO4) administered ip to mice was nontoxic and enhanced the in vitro tumoricidal activity of their peritoneal macrophages. The injection ip of 1 ml of 5 mM NaIO4 caused an influx of polymorphonuclear leukocytes (PMN) at 5-24 hours followed by an accumulation of macrophages and disappearance of the PMN at 48-72 hours. These peritoneal macrophages from mice given injections of NaIO4 were noncytotoxic and nontumoricidal in the absence of lipopolysaccharide (LPS), but in the presence of 5-25 ng/ml or more LPS in vitro, they became markedly cytotoxic and cytocidal for tumor cells. Peritoneal macrophages from mice given injections of phosphate-buffered saline became cytotoxic or cytocidal only with amounts of LPS exceeding 100-500 ng/ml in vitro. Like the peritoneal macrophages from BCG-infected mice that demonstrated selective tumor cytotoxicity, macrophages from mice given injections of NaIO4 had minimal lytic activity for nontransformed normal embryo fibroblasts. Thus when given ip to mice, the simple chemical NaIO4, much like complex and heterogeneous biologic preparations such as BCG, caused differentiation of peritoneal macrophages toward the tumoricidal state.

Authors
Weinberg, JB
MLA Citation
Weinberg, JB. "In vivo modulation of macrophage tumoricidal activity: enhanced tumor cell killing by peritoneal macrophages from mice given injections of sodium periodate." J Natl Cancer Inst 66.3 (March 1981): 529-533.
PMID
6259399
Source
pubmed
Published In
Journal of the National Cancer Institute
Volume
66
Issue
3
Publish Date
1981
Start Page
529
End Page
533

Monocyte chemotactic peptide receptor. Functional characteristics and ligand-induced regulation

Monocytes, macrophages, and neutrophils will demonstrate several important cellular functions in response to synthetic formylated oligopeptides. N-formyl-norleucyl-leucyl-phenylalanyl-norleucyl-tyrosyl-lysine (fNLPNTL) was a potent chemoattractant for human blood monocytes; a 1.0-nM concentration induced a maximal chemotactic response. Binding of 125I-labeled fNLPNTL to the monocyte formyl peptide receptor was rapid, specific, and saturable at 4, 24, or 37°C. At 4°C, monocytes from several different donors demonstrated between 10,000 and 18,000 receptors/cell with a dissociation constant [K(d)] of 1.7-2.7 nM. The association of the 125I peptide with the cells was irreversible at the elevated temperatures and exceeded the amount of surface receptor by approximately four-fold, suggesting receptor-mediated peptide endocytosis. Processing of rhodamine-labeled fNLPNTL by monocytes was observed directly by video intensification microscopy. At 37°C, diffuse membrane fluorescence was seen initially, followed by rapid aggregation and internalization of the peptide. Monocytes incubated with fNLPNTL displayed a temperature-dependent loss of surface binding capacity (receptor down-regulation). This decrease was due to a decrease in surface receptor number rather than to a decrease in receptor affinity. A dose-response curve for peptide-induced receptor down-regulation correlated with a dose-response curve for 125I-labeled fNLPNTL uptake, suggesting that each uptake event led to the loss of one surface receptor. Surface receptor replenishment following down-regulation was rapid and not dependent on new protein synthesis, but was inversely related to both the time and peptide concentration used to induce down-regulation. An exact correlation between receptor down-regulation and functional deactivation of the chemotactic response could not be demonstrated.

Authors
Weinberg, JB; Muscato, JJ; Niedel, JE
MLA Citation
Weinberg, JB, Muscato, JJ, and Niedel, JE. "Monocyte chemotactic peptide receptor. Functional characteristics and ligand-induced regulation." Journal of Clinical Investigation 68.3 (1981): 621-630.
PMID
6268661
Source
scival
Published In
Journal of Clinical Investigation
Volume
68
Issue
3
Publish Date
1981
Start Page
621
End Page
630
DOI
10.1172/JCI110296

HUMAN MONONUCLEAR PHAGOCYTES - INVIVO DIFFERENTIATION OF BLOOD MONOCYTES TO PERITONEAL-MACROPHAGES WITH ENHANCED TUMORICIDAL ACTIVITY

Authors
WEINBERG, JB; MUSCATO, JJ; HANEY, AF
MLA Citation
WEINBERG, JB, MUSCATO, JJ, and HANEY, AF. "HUMAN MONONUCLEAR PHAGOCYTES - INVIVO DIFFERENTIATION OF BLOOD MONOCYTES TO PERITONEAL-MACROPHAGES WITH ENHANCED TUMORICIDAL ACTIVITY." PROCEEDINGS OF THE AMERICAN ASSOCIATION FOR CANCER RESEARCH 22.MAR (1981): 309-309.
Source
wos-lite
Published In
Proceedings of the Annual Meeting- American Association for Cancer Research
Volume
22
Issue
MAR
Publish Date
1981
Start Page
309
End Page
309

ENHANCEMENT OF MACROPHAGE TUMOR-CELL KILLING BY BACTERIAL OUTER-MEMBRANE PROTEINS (PORINS)

Authors
WEINBERG, JB; NARAMORE, MA; CAPEL, WD; WHEAT, RW
MLA Citation
WEINBERG, JB, NARAMORE, MA, CAPEL, WD, and WHEAT, RW. "ENHANCEMENT OF MACROPHAGE TUMOR-CELL KILLING BY BACTERIAL OUTER-MEMBRANE PROTEINS (PORINS)." FEDERATION PROCEEDINGS 40.3 (1981): 1160-1160.
Source
wos-lite
Published In
The FASEB Journal
Volume
40
Issue
3
Publish Date
1981
Start Page
1160
End Page
1160

Analysis of a large pedigree with elliptocytosis, multiple lipomatosis, and biological false-positive serological test for syphilis.

Elliptocytosis, multiple lipomatosis, and biological false-postive serological test for syphilis (BFPSTS) were found in a single individual. One hundred eighty relatives were tested for the three diseases: 74 were typed for seven blood group antigens, and 58 were typed for four electrophoretic enzyme markers. Likelihood analysis of the pedigree data confirmed independent dominant inheritance for elliptocytosis and lipomatosis. BFPSTS appears dominant, but the analysis was inconclusive. No linkages were found between any disease gene and any marker gene. Two female pedigree members with BFPSTS developed systemic lupus erythematosus, a finding in agreement with the previously described association. The analysis did not lead to any conclusions about the causal relationship between the two traits.

Authors
Weinberg, JB; Hasstedt, SJ; Skolnick, MH; Kimberling, WJ; Baty, B
MLA Citation
Weinberg, JB, Hasstedt, SJ, Skolnick, MH, Kimberling, WJ, and Baty, B. "Analysis of a large pedigree with elliptocytosis, multiple lipomatosis, and biological false-positive serological test for syphilis." Am J Med Genet 5.1 (1980): 57-67.
PMID
7395901
Source
pubmed
Published In
American Journal of Medical Genetics Part A
Volume
5
Issue
1
Publish Date
1980
Start Page
57
End Page
67
DOI
10.1002/ajmg.1320050108

Bacterial lipopolysaccharides and mycoplasmal lipoglycans: A comparison between their abilities to induce macrophage-mediated tumor cell killing and Limulus amebocyte lysate clotting

The ability of various bacterial lipopolysaccharides and mycoplasmal lipopolysaccharides (lipoglycans) to induce macrophage-mediated tumor cell killing and Limulus amebocyte lysate clotting was determined. Lipoglycans from the mycoplasma Acholeplasma axantum or Acholeplasma granularum had no activity or 104 to 105 less activity than lipopolysaccharides from Escherichia coli 0128:B12, Escherichia coli K235, or Salmonella minnesota R595 in causing Limulus lysate clotting and tumor cell killing by peritoneal macrophages from normal or bacillus Calmette-Guerin-infected mice. Previous studies have shown that the lipid A portion of bacterial lipopolysaccharide is responsible for the effects on macrophage-mediated tumor cell killing and Limulus lysate clotting. The known differences in the lipid structures of bacterial lipopolysaccharides and mycoplasmal lipopolysaccharides may account for the noted differences in the biologic potencies observed here.

Authors
Weinberg, JB; Smith, PF; Kahane, I
MLA Citation
Weinberg, JB, Smith, PF, and Kahane, I. "Bacterial lipopolysaccharides and mycoplasmal lipoglycans: A comparison between their abilities to induce macrophage-mediated tumor cell killing and Limulus amebocyte lysate clotting." Biochemical and Biophysical Research Communications 97.2 (1980): 493-499.
PMID
7008788
Source
scival
Published In
Biochemical and Biophysical Research Communications
Volume
97
Issue
2
Publish Date
1980
Start Page
493
End Page
499

Plasma thrombopoietic activity in humans with normal and abnormal platelet counts

Although much experimental evidence suggests the presence of a humoral stimulator of thrombopoiesis, relatively few human studies have been done to determine the presence of such a stimulator in disorders of thrombopoiesis. Human plasma fractions from patients with normal and abnormal platelet counts were tested for thrombopoietic stimulatory or inhibitory activity in a mouse bioassay system by measuring the incorporation of 75Se-methionine into platelets of mice injected with plasma fractions. Twenty-two patients with normal platelet counts had no evidence of stimulatory activity in plasma, except for one postoperative patient. Fifty-three percent of 17 patients with thrombocytosis had increased stimulatory activity, and 33% of patients with thrombocytopenia had such activity in plasma. Inhibitory activity in plasma was found in 4 patients with normal platelet counts, 7 with thrombocytopenia, and none with thrombocytosis. A hypothesis based on the presence of both stimulatory and inhibitory factors in plasma is advanced to explain the humoral control mechanisms in normal patients and in patients with abnormal platelet counts of diverse etiology.

Authors
Shreiner, DP; Weinberg, J; Enoch, D
MLA Citation
Shreiner, DP, Weinberg, J, and Enoch, D. "Plasma thrombopoietic activity in humans with normal and abnormal platelet counts." Blood 56.2 (1980): 183-188.
PMID
7397376
Source
scival
Published In
Blood
Volume
56
Issue
2
Publish Date
1980
Start Page
183
End Page
188

In vitro modulation of macrophage tumoricidal activity - Enhanced tumor cell killing by sodium periodate-treated peritoneal macrophages or sodium periodate-treated cloned macrophages

NaIO4 treatment of mouse adherent peritoneal cells or lymphocyte-free cloned macrophages enhances their cytotoxic and tumoricidal activity. 5×10-3 M NaIO4 treatment of nontumoricidal BCG-activated macrophages renders them completely tumoricidal, whereas the same treatment of stimulated (peptone-normal) macrophages renders them weakly tumoricidal. Addition of LPS in nanogram quantities too low to enhance tumor cell killing by untreated peptone-normal macrophages causes NaIO4-treated peptone-normal macrophages to be maximally tumoricidal. The activating action of NaIO4, MAF, or LPS can be potently, but inconsistently, blocked or reversed by the reducing agent NaBH4 or the aldehyde-reacting agent dimedone. NaIO4 treatment of lymphocyte-free macrophage colonies does not make them cytotoxic, but NaIO4-treated colony macrophages are cytotoxic for tumor cells when cultured in 10 ng/ml LPS (an amount of LPS inadequate to render untreated colony macrophages cytotoxic). Supernatants of NaIO4-treated adherent peritoneal cells contain MAF activity. Thus, the NaIO4-induced enhancement of peritoneal cell tumoricidal activity may result from both direct NaIO4 activating effects on macrophages and indirect NaIO4 effects through NaIO4-induced MAF production. © 1980 Springer-Verlag.

Authors
Weinberg, JB; Jr, JBH
MLA Citation
Weinberg, JB, and Jr, JBH. "In vitro modulation of macrophage tumoricidal activity - Enhanced tumor cell killing by sodium periodate-treated peritoneal macrophages or sodium periodate-treated cloned macrophages." Cancer Immunology Immunotherapy 7.4 (1980): 225-233.
Source
scival
Published In
Cancer Immunology, Immunotherapy
Volume
7
Issue
4
Publish Date
1980
Start Page
225
End Page
233
DOI
10.1007/BF00205471

Enhanced macrophage tumoricidal activity and tumor suppression or regression caused by heat-killed Candida albicans.

The growth of line-10 hepatoma in male Sewall Wright strain 2 guinea pigs was totally suppressed when tumor cells were mixed with heat-killed Candida albicans. In a significant number of animals, injection of C. albicans into established tumors 10-12 mm in diameter caused complete, rapid tumor regression. Guinea pigs whose tumors regressed or were suppressed as a result of injection of C. albicans rejected subsequent challenges at distant sites with the line-10 hepatoma, which indicated the development of systemic immunity to the tumor. Untreated control guinea pigs had positive delayed hypersensitivity reactions to intradermally injected C. albicans, which suggested prior natural exposure of the animals to C. albicans antigens. Peritoneal macrophages from mice that had received ip injections of phosphate-buffered saline (PBS) or C. albicans were not cytocidal for mouse 3T12 tumor cells in vitro. However, macrophages from the mice given injections of C. albicans, unlike those from mice given PBS, were markedly tumoricidal in the presence of 1 ng or more endotoxin/ml in vitro. These results demonstrated that heat-killed C. albicans, when inoculated into the peritoneal cavity, increased the tumoricidal potential of peritoneal macrophages.

Authors
Weinberg, JB; Hibbs, JB
MLA Citation
Weinberg, JB, and Hibbs, JB. "Enhanced macrophage tumoricidal activity and tumor suppression or regression caused by heat-killed Candida albicans." J Natl Cancer Inst 63.5 (November 1979): 1273-1278.
PMID
388016
Source
pubmed
Published In
Journal of the National Cancer Institute
Volume
63
Issue
5
Publish Date
1979
Start Page
1273
End Page
1278

In vitro modulation of macrophage tumoricidal activity: partial characterization of a macrophage-activating factor(s) in supernatants of NaIO4-treated peritoneal cells.

Authors
Weinberg, JB; Hibbs, JB
MLA Citation
Weinberg, JB, and Hibbs, JB. "In vitro modulation of macrophage tumoricidal activity: partial characterization of a macrophage-activating factor(s) in supernatants of NaIO4-treated peritoneal cells." J Reticuloendothel Soc 26.3 (September 1979): 283-293.
PMID
228037
Source
pubmed
Published In
RES Journal of the Reticuloendothelial Society
Volume
26
Issue
3
Publish Date
1979
Start Page
283
End Page
293

Modulation of the tumoricidal function of activated macrophages by bacterial endotoxin and mammalian macrophage activation factor (s).

Authors
Hibbs, JB; Weinberg, JB; Chapman, HA
MLA Citation
Hibbs, JB, Weinberg, JB, and Chapman, HA. "Modulation of the tumoricidal function of activated macrophages by bacterial endotoxin and mammalian macrophage activation factor (s)." Adv Exp Med Biol 121B (1979): 433-453.
PMID
232620
Source
pubmed
Published In
Advances in experimental medicine and biology
Volume
121B
Publish Date
1979
Start Page
433
End Page
453

Blast cell leukemia with IgM monoclonal gammopathy and intracytoplasmic vacuoles and Auer-body-like inclusions

A patient with acute leukemia and an IgM, kappa (IgMκ) monoclonal gammopathy, Bence-Jones proteinuria, and blasts containing intracytoplasmic vacuoles with peroxidase-positive inclusions is discussed. Special stains, immunofluorescence, and electron microscopy suggested that the vacuoles were autophagosomes containing Auer-body-like inclusions, and that the blast cells did not synthesize tha paraprotein. Chemotherapy with cyclophosphamide, vincristine, and prednisone resulted in transient improvement of the leukemia, but the level of the paraprotein was unchaged. Other case reports involving monoclonal gammopathy in association with acute leukemia are reviewed and contrasted with this case.

Authors
Weinberg, JB; Hammar, SP
MLA Citation
Weinberg, JB, and Hammar, SP. "Blast cell leukemia with IgM monoclonal gammopathy and intracytoplasmic vacuoles and Auer-body-like inclusions." American Journal of Clinical Pathology 71.2 (1979): 151-157.
PMID
218443
Source
scival
Published In
American Journal of Clinical Pathology
Volume
71
Issue
2
Publish Date
1979
Start Page
151
End Page
157

The macrophage as an antineoplastic surveillance cell: biological perspectives.

Authors
Hibbs, JB; Chapman, HA; Weinberg, JB
MLA Citation
Hibbs, JB, Chapman, HA, and Weinberg, JB. "The macrophage as an antineoplastic surveillance cell: biological perspectives." J Reticuloendothel Soc 24.5 (November 1978): 549-570. (Review)
PMID
104035
Source
pubmed
Published In
RES Journal of the Reticuloendothelial Society
Volume
24
Issue
5
Publish Date
1978
Start Page
549
End Page
570

Characterization of the effects of endotoxin on macrophage tumor cell killing.

Authors
Weinberg, JB; Chapman, HA; Hibbs, JB
MLA Citation
Weinberg, JB, Chapman, HA, and Hibbs, JB. "Characterization of the effects of endotoxin on macrophage tumor cell killing." J Immunol 121.1 (July 1978): 72-80.
PMID
27559
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
121
Issue
1
Publish Date
1978
Start Page
72
End Page
80

In vivo administered NaIO4 causes macrophage polykaryon formation in vitro and enhances macrophage tumoricidal activity

Authors
Weinberg, JB; Jr, JBH
MLA Citation
Weinberg, JB, and Jr, JBH. "In vivo administered NaIO4 causes macrophage polykaryon formation in vitro and enhances macrophage tumoricidal activity." RES Journal of the Reticuloendothelial Society 24.suppl. (1978): No.-99.
Source
scival
Published In
RES Journal of the Reticuloendothelial Society
Volume
24
Issue
suppl.
Publish Date
1978
Start Page
No.
End Page
99

INVIVO ADMINISTERED NAIO4 CAUSES MACROPHAGE POLYKARYON FORMATION INVITRO AND ENHANCES MACROPHAGE TUMORICIDAL ACTIVITY

Authors
WEINBERG, JB; HIBBS, JB
MLA Citation
WEINBERG, JB, and HIBBS, JB. "INVIVO ADMINISTERED NAIO4 CAUSES MACROPHAGE POLYKARYON FORMATION INVITRO AND ENHANCES MACROPHAGE TUMORICIDAL ACTIVITY." JOURNAL OF THE RETICULOENDOTHELIAL SOCIETY 24.DEC (1978): A50-A50.
Source
wos-lite
Published In
RES Journal of the Reticuloendothelial Society
Volume
24
Issue
DEC
Publish Date
1978
Start Page
A50
End Page
A50

Endocytosis of red blood cells or haemoglobin by activated macrophages inhibits their tumoricidal effect.

Authors
Weinberg, JB; Hibbs, JB
MLA Citation
Weinberg, JB, and Hibbs, JB. "Endocytosis of red blood cells or haemoglobin by activated macrophages inhibits their tumoricidal effect." Nature 269.5625 (September 15, 1977): 245-247.
PMID
563513
Source
pubmed
Published In
Nature
Volume
269
Issue
5625
Publish Date
1977
Start Page
245
End Page
247

Macrophage tumor killing: influence of the local environment.

Tumor killing by activated macrophages is not a highly determined biologic event, but a relative capability influenced by the local environment. An intrinsic macrophage cytotoxic effector system is modulated by serum and other environmental factors that can either enhance or suppress tumor killing. Activated macrophages kill tumor cells only when a regulating threshold drops to a critically low level.

Authors
Hibbs, JB; Taintor, RR; Chapman, HA; Weinberg, JB
MLA Citation
Hibbs, JB, Taintor, RR, Chapman, HA, and Weinberg, JB. "Macrophage tumor killing: influence of the local environment." Science 197.4300 (July 15, 1977): 279-282.
PMID
327547
Source
pubmed
Published In
Science
Volume
197
Issue
4300
Publish Date
1977
Start Page
279
End Page
282

The role of endotoxin in activated macrophage tumor cell killing

Authors
Weinberg, JB; Jr, HAC; Jr, JBH
MLA Citation
Weinberg, JB, Jr, HAC, and Jr, JBH. "The role of endotoxin in activated macrophage tumor cell killing." RES Journal of the Reticuloendothelial Society 22.Suppl. (1977): 23a-.
Source
scival
Published In
RES Journal of the Reticuloendothelial Society
Volume
22
Issue
Suppl.
Publish Date
1977
Start Page
23a

USE OF POLYMER D-LACTIC ACID (PDLA) OR EQUIVALENTS THEREOF TO INHIBIT GROWTH OF CANCER CELLS AND DIAGNOSE CANCER

Authors
Goldberg, JS; weinberg, JB
MLA Citation
Goldberg, JS, and weinberg, JB. "USE OF POLYMER D-LACTIC ACID (PDLA) OR EQUIVALENTS THEREOF TO INHIBIT GROWTH OF CANCER CELLS AND DIAGNOSE CANCER." (Digital Edition)
Website
http://hdl.handle.net/10161/10413
Source
manual
Show More