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Dressman, Holly Kloos

Positions:

Research Professor in Molecular Genetics and Microbiology

Molecular Genetics and Microbiology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

B.S. 1988

B.S. — North Carolina State University

Ph.D. 1994

Ph.D. — Pennsylvania State University

Postdoctoral Fellow, Molecular Genetics

NIEHS

Grants:

A comprehensive research resource to define mechanisms underlying microbial regulation of host metabolism in pediatric obesity and obesity-targeted therapeutics

Administered By
Molecular Genetics and Microbiology
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
September 25, 2016
End Date
August 31, 2021

A hands-on, integrative next-generation sequencing course: design, experiment, and analysis

Administered By
Biostatistics & Bioinformatics
AwardedBy
National Institutes of Health
Role
Training Faculty
Start Date
September 22, 2016
End Date
June 30, 2019

Biodosimetry High-Throughput Test

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
AwardedBy
DxTerity Diagnostics
Role
Co Investigator
Start Date
June 30, 2017
End Date
September 29, 2018

Single cell analysis of intratumoral heterogeneity in parathyroid neoplasia

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
January 16, 2015
End Date
February 28, 2017

Point of Care Biodosimeter

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
AwardedBy
Department of Health and Human Services
Role
Co Investigator
Start Date
December 16, 2009
End Date
December 31, 2016

Alternative splicing and epithelial-mesenchymal plasticity in prostate tumors

Administered By
Molecular Genetics and Microbiology
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
December 01, 2008
End Date
November 30, 2014

Validating Molecular Signature Risk Models of NSCLC

Administered By
Surgery, Cardiovascular and Thoracic Surgery
AwardedBy
National Institutes of Health
Role
Collaborating Investigator
Start Date
August 21, 2006
End Date
July 31, 2012

Intellectual Property Challenges for the Development of Genomic Diagnostics

Administered By
University Institutes and Centers
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
April 01, 2009
End Date
March 31, 2012

Molecular mechanisms of altered calcium sensing in human parathyroid disease

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Collaborating Investigator
Start Date
June 01, 2010
End Date
January 31, 2012

Novel Zebrafish Models to Study Toxicity of PCBs and Pesticides During Pregnancy

Administered By
Biomedical Engineering
AwardedBy
National Institutes of Health
Role
Advisor
Start Date
September 28, 2007
End Date
August 31, 2011

Neurosciences Microarray Center

Administered By
Neurobiology
AwardedBy
National Institutes of Health
Role
Mircroarray Manager
Start Date
September 06, 2005
End Date
May 31, 2011

Refining and Validating Genomic Signatures in Lung Cancer

Administered By
Institutes and Centers
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
August 14, 2009
End Date
December 31, 2010

Prospective Validation of Genomic Signatures of Chemosensitivity in NSCLC

Administered By
Institutes and Centers
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
January 01, 2009
End Date
November 30, 2010

Multiscale Integrative Immunology for Adjuvant Develpmnt

Administered By
Biostatistics & Bioinformatics
AwardedBy
National Institutes of Health
Role
Researcher
Start Date
September 15, 2005
End Date
September 14, 2010

Duke-NHLBI Functional Microarray Facility

Administered By
Institutes and Centers
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 30, 2002
End Date
July 31, 2006

Neurosciences Microarray Center

Administered By
Neurobiology
AwardedBy
National Institutes of Health
Role
Mircroarray Manager
Start Date
June 01, 2002
End Date
May 31, 2005

Duke/NIDDK Functional Genomics Center

Administered By
Molecular Genetics and Microbiology
AwardedBy
National Institutes of Health
Role
Administrative Assistant
Start Date
September 30, 2000
End Date
August 31, 2003
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Publications:

Orphan Adhesion GPCR GPR64/ADGRG2 Is Overexpressed in Parathyroid Tumors and Attenuates Calcium-Sensing Receptor-Mediated Signaling.

Abnormal feedback of serum calcium to parathyroid hormone (PTH) secretion is the hallmark of primary hyperparathyroidism (PHPT). Although the molecular pathogenesis of parathyroid neoplasia in PHPT has been linked to abnormal expression of genes involved in cell growth (e.g., cyclin D1, retinoblastoma, and β-catenin), the molecular basis of abnormal calcium sensing by calcium-sensing receptor (CaSR) and PTH hypersecretion in PHPT are incompletely understood. Through gene expression profiling, we discovered that an orphan adhesion G protein-coupled receptor (GPCR), GPR64/ADGRG2, is expressed in human normal parathyroid glands and is overexpressed in parathyroid tumors from patients with PHPT. Using immunohistochemistry, Western blotting, and coimmunoprecipitation, we found that GPR64 is expressed on the cell surface of parathyroid cells, is overexpressed in parathyroid tumors, and physically interacts with the CaSR. By using reporter gene assay and GPCR second messenger readouts we identified Gαs, 3',5'-cyclic adenosine monophosphate (cAMP), protein kinase A, and cAMP response element binding protein (CREB) as the signaling cascade downstream of GPR64. Furthermore, we found that an N-terminally truncated human GPR64 is constitutively active and a 15-amino acid-long peptide C-terminal to the GPCR proteolysis site (GPS) of GPR64 activates this receptor. Functional characterization of GPR64 demonstrated its ability to increase PTH release from human parathyroid cells at a range of calcium concentrations. We discovered that the truncated constitutively active, but not the full-length GPR64 physically interacts with CaSR and attenuates the CaSR-mediated intracellular Ca2+ signaling and cAMP suppression in HEK293 cells. Our results indicate that GPR64 may be a physiologic regulator of PTH release that is dysregulated in parathyroid tumors, and suggest a role for GPR64 in pathologic calcium sensing in PHPT. © 2016 American Society for Bone and Mineral Research.

Authors
Balenga, N; Azimzadeh, P; Hogue, JA; Staats, PN; Shi, Y; Koh, J; Dressman, H; Olson, JA
MLA Citation
Balenga, N, Azimzadeh, P, Hogue, JA, Staats, PN, Shi, Y, Koh, J, Dressman, H, and Olson, JA. "Orphan Adhesion GPCR GPR64/ADGRG2 Is Overexpressed in Parathyroid Tumors and Attenuates Calcium-Sensing Receptor-Mediated Signaling." Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 32.3 (March 2017): 654-666.
PMID
27760455
Source
epmc
Published In
Journal of Bone and Mineral Research
Volume
32
Issue
3
Publish Date
2017
Start Page
654
End Page
666
DOI
10.1002/jbmr.3023

A Molecular Profile of the Endothelial Cell Response to Ionizing Radiation.

Ionizing radiation exposure can cause acute radiation sickness (ARS) by damaging the hematopoietic compartment. Radiation damages quiescent hematopoietic stem cells (HSCs) and proliferating hematopoietic cells, resulting in neutropenia, thrombocytopenia and increased risk for long-term hematopoietic dysfunction and myelodysplasia. While some aspects of the hematopoietic response to radiation injury are intrinsic to hematopoietic cells, the recovery of the HSC pool and overall hematopoiesis is also dependent on signals from bone marrow endothelial cells (BM ECs) within the HSC vascular niche. The precise mechanisms through which BM ECs regulate HSC regeneration remain unclear. Characterization of the altered EC gene expression that occurs in response to radiation could provide a roadmap to the discovery of EC-derived mechanisms that regulate hematopoietic regeneration. Here, we show that 5 Gy total-body irradiation substantially alters the expression of numerous genes in BM ECs within 24 h and this molecular response largely resolves by day 14 postirradiation. Several unique and nonannotated genes, which encode secreted proteins were upregulated and downregulated in ECs in response to radiation. These results highlight the complexity of the molecular response of BM ECs to ionizing radiation and identify several candidate mechanisms that should be prioritized for functional analysis in models of hematopoietic injury and regeneration.

Authors
Himburg, HA; Sasine, J; Yan, X; Kan, J; Dressman, H; Chute, JP
MLA Citation
Himburg, HA, Sasine, J, Yan, X, Kan, J, Dressman, H, and Chute, JP. "A Molecular Profile of the Endothelial Cell Response to Ionizing Radiation." Radiation research 186.2 (August 2016): 141-152.
PMID
27387861
Source
epmc
Published In
Radiation Research
Volume
186
Issue
2
Publish Date
2016
Start Page
141
End Page
152
DOI
10.1667/rr14444.1

Genomic profiling in locally advanced and inflammatory breast cancer and its link to DCE-MRI and overall survival.

We have previously reported that dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) perfusion patterns obtained from locally advanced breast cancer (LABC) patients prior to neoadjuvant therapy predicted pathologic clinical response. Genomic analyses were also independently conducted on the same patient population. This retrospective study was performed to test two hypotheses: (1) gene expression profiles are associated with DCE-MRI perfusion patterns, and (2) association between long-term overall survival data and gene expression profiles can lead to the identification of novel predictive biomarkers.We utilised RNA microarray and DCE-MRI data from 47 LABC patients, including 13 inflammatory breast cancer (IBC) patients. Association between gene expression profile and DCE-MRI perfusion patterns (centrifugal and centripetal) was determined by Wilcoxon rank sum test. Association between gene expression level and survival was assessed using a Cox rank score test. Additional genomic analysis of the IBC subset was conducted, with a period of follow-up of up to 11 years. Associations between gene expression and overall survival were further assessed in The Cancer Genome Atlas Data Portal.Differences in gene expression profiles were seen between centrifugal and centripetal perfusion patterns in the sulphotransferase family, cytosolic, 1 A, phenol-preferring, members 1 and 2 (SULT1A1, SULT1A2), poly (ADP-ribose) polymerase, member 6 (PARP6), and metastasis tumour antigen1 (MTA1). In the IBC subset our analyses demonstrated that differential expression of 45 genes was associated with long-term survival.Here we have demonstrated an association between DCE-MRI perfusion patterns and gene expression profiles. In addition we have reported on candidate prognostic biomarkers in IBC patients, with some of the genes being significantly associated with survival in IBC and LABC.

Authors
Siamakpour-Reihani, S; Owzar, K; Jiang, C; Scarbrough, PM; Craciunescu, OI; Horton, JK; Dressman, HK; Blackwell, KL; Dewhirst, MW
MLA Citation
Siamakpour-Reihani, S, Owzar, K, Jiang, C, Scarbrough, PM, Craciunescu, OI, Horton, JK, Dressman, HK, Blackwell, KL, and Dewhirst, MW. "Genomic profiling in locally advanced and inflammatory breast cancer and its link to DCE-MRI and overall survival." International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group 31.4 (June 2015): 386-395.
PMID
25811737
Source
epmc
Published In
International Journal of Hyperthermia (Informa)
Volume
31
Issue
4
Publish Date
2015
Start Page
386
End Page
395
DOI
10.3109/02656736.2015.1016557

Biological pathway selection through Bayesian integrative modeling.

Pathway analysis has become a central approach to understanding the underlying biology of differentially expressed genes. As large amounts of microarray data have been accumulated in public repositories, flexible methodologies are needed to extend the analysis of simple case-control studies in order to place them in context with the vast quantities of available and highly heterogeneous data sets. To address this challenge, we have developed a two-level model, consisting of 1) a joint Bayesian factor model that integrates multiple microarray experiments and ties each factor to a predefined pathway and 2) a point mass mixture distribution that infers which factors are relevant/irrelevant to each dataset. Our method can identify pathways specific to a particular experimental trait which are concurrently induced/repressed under a variety of interventions. In this paper, we describe the model in depth and provide examples of its utility in simulations as well as real data from a study of radiation exposure. Our analysis of the radiation study leads to novel insights into the molecular basis of time- and dose- dependent response to ionizing radiation in mice peripheral blood. This broadly applicable model provides a starting point for generating specific and testable hypotheses in a pathway-centric manner.

Authors
Zheng, L; Yan, X; Suchindran, S; Dressman, H; Chute, JP; Lucas, J
MLA Citation
Zheng, L, Yan, X, Suchindran, S, Dressman, H, Chute, JP, and Lucas, J. "Biological pathway selection through Bayesian integrative modeling." Statistical applications in genetics and molecular biology 13.4 (August 2014): 435-457.
PMID
24937506
Source
epmc
Published In
Statistical Applications in Genetics and Molecular Biology
Volume
13
Issue
4
Publish Date
2014
Start Page
435
End Page
457
DOI
10.1515/sagmb-2013-0043

Biological pathway selection through Bayesian integrative modeling

Authors
Zheng, L; Yan, X; Suchindran, S; Dressman, H; Chute, JP; Lucas, J
MLA Citation
Zheng, L, Yan, X, Suchindran, S, Dressman, H, Chute, JP, and Lucas, J. "Biological pathway selection through Bayesian integrative modeling." Statistical Applications in Genetics and Molecular Biology 13.6 (January 1, 2014).
Source
crossref
Published In
Statistical Applications in Genetics and Molecular Biology
Volume
13
Issue
6
Publish Date
2014
DOI
10.1515/sagmb-2014-0087

A translatable predictor of human radiation exposure.

Terrorism using radiological dirty bombs or improvised nuclear devices is recognized as a major threat to both public health and national security. In the event of a radiological or nuclear disaster, rapid and accurate biodosimetry of thousands of potentially affected individuals will be essential for effective medical management to occur. Currently, health care providers lack an accurate, high-throughput biodosimetric assay which is suitable for the triage of large numbers of radiation injury victims. Here, we describe the development of a biodosimetric assay based on the analysis of irradiated mice, ex vivo-irradiated human peripheral blood (PB) and humans treated with total body irradiation (TBI). Interestingly, a gene expression profile developed via analysis of murine PB radiation response alone was inaccurate in predicting human radiation injury. In contrast, generation of a gene expression profile which incorporated data from ex vivo irradiated human PB and human TBI patients yielded an 18-gene radiation classifier which was highly accurate at predicting human radiation status and discriminating medically relevant radiation dose levels in human samples. Although the patient population was relatively small, the accuracy of this classifier in discriminating radiation dose levels in human TBI patients was not substantially confounded by gender, diagnosis or prior exposure to chemotherapy. We have further incorporated genes from this human radiation signature into a rapid and high-throughput chemical ligation-dependent probe amplification assay (CLPA) which was able to discriminate radiation dose levels in a pilot study of ex vivo irradiated human blood and samples from human TBI patients. Our results illustrate the potential for translation of a human genetic signature for the diagnosis of human radiation exposure and suggest the basis for further testing of CLPA as a candidate biodosimetric assay.

Authors
Lucas, J; Dressman, HK; Suchindran, S; Nakamura, M; Chao, NJ; Himburg, H; Minor, K; Phillips, G; Ross, J; Abedi, M; Terbrueggen, R; Chute, JP
MLA Citation
Lucas, J, Dressman, HK, Suchindran, S, Nakamura, M, Chao, NJ, Himburg, H, Minor, K, Phillips, G, Ross, J, Abedi, M, Terbrueggen, R, and Chute, JP. "A translatable predictor of human radiation exposure." PloS one 9.9 (January 2014): e107897-.
Website
http://hdl.handle.net/10161/10977
PMID
25255453
Source
epmc
Published In
PloS one
Volume
9
Issue
9
Publish Date
2014
Start Page
e107897
DOI
10.1371/journal.pone.0107897

A methodology for utilization of predictive genomic signatures in FFPE samples.

BACKGROUND: Gene expression signatures developed to measure the activity of oncogenic signaling pathways have been used to dissect the heterogeneity of tumor samples and to predict sensitivity to various cancer drugs that target components of the relevant pathways, thus potentially identifying therapeutic options for subgroups of patients. To facilitate broad use, including in a clinical setting, the ability to generate data from formalin-fixed, paraffin-embedded (FFPE) tissues is essential. METHODS: Patterns of pathway activity in matched fresh-frozen and FFPE xenograft tumor samples were generated using the MessageAmp Premier methodology in combination with assays using Affymetrix arrays. Results generated were compared with those obtained from fresh-frozen samples using a standard Affymetrix assay. In addition, gene expression data from patient matched fresh-frozen and FFPE melanomas were also utilized to evaluate the consistency of predictions of oncogenic signaling pathway status. RESULTS: Significant correlation was observed between pathway activity predictions from paired fresh-frozen and FFPE xenograft tumor samples. In addition, significant concordance of pathway activity predictions was also observed between patient matched fresh-frozen and FFPE melanomas. CONCLUSIONS: Reliable and consistent predictions of oncogenic pathway activities can be obtained from FFPE tumor tissue samples. The ability to reliably utilize FFPE patient tumor tissue samples for genomic analyses will lead to a better understanding of the biology of disease progression and, in the clinical setting, will provide tools to guide the choice of therapeutics to those most likely to be effective in treating a patient's disease.

Authors
Freedman, JA; Augustine, CK; Selim, AM; Holshausen, KC; Wei, Z; Tsamis, KA; Hsu, DS; Dressman, HK; Barry, WT; Tyler, DS; Nevins, JR
MLA Citation
Freedman, JA, Augustine, CK, Selim, AM, Holshausen, KC, Wei, Z, Tsamis, KA, Hsu, DS, Dressman, HK, Barry, WT, Tyler, DS, and Nevins, JR. "A methodology for utilization of predictive genomic signatures in FFPE samples. (Published online)" BMC Med Genomics 4 (July 11, 2011): 58-.
PMID
21745407
Source
pubmed
Published In
BMC Medical Genomics
Volume
4
Publish Date
2011
Start Page
58
DOI
10.1186/1755-8794-4-58

Regulator of G protein signaling 5 is highly expressed in parathyroid tumors and inhibits signaling by the calcium-sensing receptor.

The molecular mechanisms responsible for aberrant calcium signaling in parathyroid disease are poorly understood. The loss of appropriate calcium-responsive modulation of PTH secretion observed in parathyroid disease is commonly attributed to decreased expression of the calcium-sensing receptor (CaSR), a G protein-coupled receptor. However, CaSR expression is highly variable in parathyroid adenomas, and the lack of correlation between CaSR abundance and calcium-responsive PTH kinetics indicates that mechanisms independent of CaSR expression may contribute to aberrant calcium sensing in parathyroid disease. To gain a better understanding of parathyroid tumors and the molecular determinants that drive parathyroid adenoma development, we performed gene expression profiling on a panel of 64 normal and neoplastic parathyroid tissues. The microarray data revealed high-level expression of genes known to be involved in parathyroid biology (PTH, VDR, CGA, CaSR, and GCM2). Moreover, our screen identified regulator of G protein signaling 5 (RGS5) as a candidate inhibitor of CaSR signaling. We confirmed RGS5 to be highly expressed in parathyroid adenomas relative to matched-pair normal glands. Transient expression of RGS5 in cells stably expressing CaSR resulted in dose-dependent abrogation of calcium-stimulated inositol trisphosphate production and ERK1/2 phosphorylation. Furthermore, we found that RGS5-nullizygous mice display reduced plasma PTH levels, an outcome consistent with attenuated opposition to CaSR activity. Collectively, these data suggest that RGS5 can act as a physiological regulator of calcium sensing by CaSR in the parathyroid gland. The abnormally elevated expression of RGS5 observed in parathyroid adenomas could thus represent a novel mechanism of CaSR desensitization in patients with primary hyperparathyroidism.

Authors
Koh, J; Dar, M; Untch, BR; Dixit, D; Shi, Y; Yang, Z; Adam, MA; Dressman, H; Wang, X; Gesty-Palmer, D; Marks, JR; Spurney, R; Druey, KM; Olson, JA
MLA Citation
Koh, J, Dar, M, Untch, BR, Dixit, D, Shi, Y, Yang, Z, Adam, MA, Dressman, H, Wang, X, Gesty-Palmer, D, Marks, JR, Spurney, R, Druey, KM, and Olson, JA. "Regulator of G protein signaling 5 is highly expressed in parathyroid tumors and inhibits signaling by the calcium-sensing receptor." Mol Endocrinol 25.5 (May 2011): 867-876.
PMID
21393447
Source
pubmed
Published In
Molecular endocrinology (Baltimore, Md.)
Volume
25
Issue
5
Publish Date
2011
Start Page
867
End Page
876
DOI
10.1210/me.2010-0277

Characterizing the developmental pathways TTF-1, NKX2-8, and PAX9 in lung cancer (Proceedings of the National Academy of Sciences of the United States of America (2009) 106, 13 (5312-5317) DOI: 10.1073/pnas.0900827106)

Authors
Hsu, DS; Acharya, CR; Balakumaran, BS; Riedel, RF; Kim, MK; Stevenson, M; Tuchman, S; Mukherjee, S; Barry, W; Dressman, HK; al, E
MLA Citation
Hsu, DS, Acharya, CR, Balakumaran, BS, Riedel, RF, Kim, MK, Stevenson, M, Tuchman, S, Mukherjee, S, Barry, W, Dressman, HK, and al, E. "Characterizing the developmental pathways TTF-1, NKX2-8, and PAX9 in lung cancer (Proceedings of the National Academy of Sciences of the United States of America (2009) 106, 13 (5312-5317) DOI: 10.1073/pnas.0900827106)." Proceedings of the National Academy of Sciences of the United States of America 108.35 (2011): 14705--.
Source
scival
Published In
Proceedings of the National Academy of Sciences of USA
Volume
108
Issue
35
Publish Date
2011
Start Page
14705-
DOI
10.1073/pnas.1111196108

An Integrated Approach to the Prediction of Chemotherapeutic Response in Patients with Breast Cancer

Background: A major challenge in oncology is the selection of the most effective chemotherapeutic agents for individual patients, while the administration of ineffective chemotherapy increases mortality and decreases quality of life in cancer patients. This emphasizes the need to evaluate every patient's probability of responding to each chemotherapeutic agent and limiting the agents used to those most likely to be effective. Methods and Results: Using gene expression data on the NCI-60 and corresponding drug sensitivity, mRNA and microRNA profiles were developed representing sensitivity to individual chemotherapeutic agents. The mRNA signatures were tested in an independent cohort of 133 breast cancer patients treated with the TFAC (paclitaxel, 5-fluorouracil, adriamycin, and cyclophosphamide) chemotherapy regimen. To further dissect the biology of resistance, we applied signatures of oncogenic pathway activation and performed hierarchical clustering. We then used mRNA signatures of chemotherapy sensitivity to identify alternative therapeutics for patients resistant to TFAC. Profiles from mRNA and microRNA expression data represent distinct biologic mechanisms of resistance to common cytotoxic agents. The individual mRNA signatures were validated in an independent dataset of breast tumors (P = 0.002, NPV = 82%). When the accuracy of the signatures was analyzed based on molecular variables, the predictive ability was found to be greater in basal-like than non basal-like patients (P = 0.03 and P = 0.06). Samples from patients with co-activated Myc and E2F represented the cohort with the lowest percentage (8%) of responders. Using mRNA signatures of sensitivity to other cytotoxic agents, we predict that TFAC non-responders are more likely to be sensitive to docetaxel (P = 0.04), representing a viable alternative therapy. Conclusions: Our results suggest that the optimal strategy for chemotherapy sensitivity prediction integrates molecular variables such as ER and HER2 status with corresponding microRNA and mRNA expression profiles. Importantly, we also present evidence to support the concept that analysis of molecular variables can present a rational strategy to identifying alternative therapeutic opportunities. © 2008 Salter et al.

Authors
Salter, KH; Acharya, CR; Walters, KS; Redman, R; Anguiano, A; Garman, KS; Anders, CK; Mukherjee, S; Dressman, HK; Barry, WT; Marcom, KP; Olson, J; Nevins, JR; Potti, A
MLA Citation
Salter, KH, Acharya, CR, Walters, KS, Redman, R, Anguiano, A, Garman, KS, Anders, CK, Mukherjee, S, Dressman, HK, Barry, WT, Marcom, KP, Olson, J, Nevins, JR, and Potti, A. "An Integrated Approach to the Prediction of Chemotherapeutic Response in Patients with Breast Cancer." PLoS ONE 6.9 (2011).
Source
scival
Published In
PloS one
Volume
6
Issue
9
Publish Date
2011
DOI
10.1371/journal.pone.0001908

Diagnosis of partial body radiation exposure in mice using peripheral blood gene expression profiles.

In the event of a terrorist-mediated attack in the United States using radiological or improvised nuclear weapons, it is expected that hundreds of thousands of people could be exposed to life-threatening levels of ionizing radiation. We have recently shown that genome-wide expression analysis of the peripheral blood (PB) can generate gene expression profiles that can predict radiation exposure and distinguish the dose level of exposure following total body irradiation (TBI). However, in the event a radiation-mass casualty scenario, many victims will have heterogeneous exposure due to partial shielding and it is unknown whether PB gene expression profiles would be useful in predicting the status of partially irradiated individuals. Here, we identified gene expression profiles in the PB that were characteristic of anterior hemibody-, posterior hemibody- and single limb-irradiation at 0.5 Gy, 2 Gy and 10 Gy in C57Bl6 mice. These PB signatures predicted the radiation status of partially irradiated mice with a high level of accuracy (range 79-100%) compared to non-irradiated mice. Interestingly, PB signatures of partial body irradiation were poorly predictive of radiation status by site of injury (range 16-43%), suggesting that the PB molecular response to partial body irradiation was anatomic site specific. Importantly, PB gene signatures generated from TBI-treated mice failed completely to predict the radiation status of partially irradiated animals or non-irradiated controls. These data demonstrate that partial body irradiation, even to a single limb, generates a characteristic PB signature of radiation injury and thus may necessitate the use of multiple signatures, both partial body and total body, to accurately assess the status of an individual exposed to radiation.

Authors
Meadows, SK; Dressman, HK; Daher, P; Himburg, H; Russell, JL; Doan, P; Chao, NJ; Lucas, J; Nevins, JR; Chute, JP
MLA Citation
Meadows, SK, Dressman, HK, Daher, P, Himburg, H, Russell, JL, Doan, P, Chao, NJ, Lucas, J, Nevins, JR, and Chute, JP. "Diagnosis of partial body radiation exposure in mice using peripheral blood gene expression profiles. (Published online)" PLoS One 5.7 (July 12, 2010): e11535-.
Website
http://hdl.handle.net/10161/4550
PMID
20634956
Source
pubmed
Published In
PloS one
Volume
5
Issue
7
Publish Date
2010
Start Page
e11535
DOI
10.1371/journal.pone.0011535

Utilization of genomic signatures for chemotherapy response in prospective clinical studies

Authors
Barry, W; Acharya, C; Datto, MB; Dressman, HK; Marcom, PK; Ready, N; Ginsburg, GS; Potti, A; Nevins, JR
MLA Citation
Barry, W, Acharya, C, Datto, MB, Dressman, HK, Marcom, PK, Ready, N, Ginsburg, GS, Potti, A, and Nevins, JR. "Utilization of genomic signatures for chemotherapy response in prospective clinical studies." JOURNAL OF CLINICAL ONCOLOGY 28.15 (May 20, 2010).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
28
Issue
15
Publish Date
2010

Intratumor heterogeneity and precision of microarray-based predictors of breast cancer biology and clinical outcome.

PURPOSE: Identifying sources of variation in expression microarray data and the effect of variance in gene expression measurements on complex predictive and diagnostic models is essential when translating microarray-based experimental approaches into clinical assays. The technical reproducibility of microarray platforms is well established. Here, we investigate the additional impact of intratumor heterogeneity, a largely unstudied component of variance, on the performance of several microarray-based assays in breast cancer. PATIENTS AND METHODS: Genome-wide expression profiling was performed on 50 core needle biopsies from 18 breast cancer patients using Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays. Global profiles of expression were characterized using unsupervised clustering methods and variance components models. Array-based measures of estrogen receptor (ER) and progesterone receptor (PR) status were compared with immunohistochemistry. The precision of genomic predictors of ER pathway status, recurrence risk, and sensitivity to chemotherapeutics was evaluated by interclass correlation. RESULTS: Global patterns of gene expression demonstrated that intratumor variation was substantially less than the total variation observed across the patient population. Nevertheless, a fraction of genes exhibited significant intratumor heterogeneity in expression. A high degree of reproducibility was observed in single-gene predictors of ER (intraclass correlation coefficient [ICC] = 0.94) and PR expression (ICC = 0.90), and in a multigene predictor of ER pathway activation (ICC = 0.98) with high concordance with immunohistochemistry. Substantial agreement was also observed for multigene signatures of cancer recurrence (ICC = 0.71) and chemotherapeutic sensitivity (ICC = 0.72 and 0.64). CONCLUSION: Intratumor heterogeneity, although present at the level of individual gene expression, does not preclude precise microarray-based predictions of tumor behavior or clinical outcome in breast cancer patients.

Authors
Barry, WT; Kernagis, DN; Dressman, HK; Griffis, RJ; Hunter, JD; Olson, JA; Marks, JR; Ginsburg, GS; Marcom, PK; Nevins, JR; Geradts, J; Datto, MB
MLA Citation
Barry, WT, Kernagis, DN, Dressman, HK, Griffis, RJ, Hunter, JD, Olson, JA, Marks, JR, Ginsburg, GS, Marcom, PK, Nevins, JR, Geradts, J, and Datto, MB. "Intratumor heterogeneity and precision of microarray-based predictors of breast cancer biology and clinical outcome." J Clin Oncol 28.13 (May 1, 2010): 2198-2206.
PMID
20368555
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
28
Issue
13
Publish Date
2010
Start Page
2198
End Page
2206
DOI
10.1200/JCO.2009.26.7245

Ovarian cancer tumor infiltrating T-regulatory (T(reg)) cells are associated with a metastatic phenotype.

OBJECTIVE: The objective of this study was to examine the clinicopathologic correlates of T-regulatory (T(reg)) cell infiltration in serous ovarian cancers and to define gene signatures associated with high T(reg)s. METHODS: Tumor infiltrating T(reg) and cytotoxic T-cells (CTLs) were quantitated in 232 primary serous ovarian cancers by immunostaining for FOXP3 and CD8. Expression microarray analysis was performed in a subset of 48 advanced cancers with the highest and lowest numbers of infiltrating T(reg)s and a genomic signature was developed using binary regression. ANOVA analysis was performed to assess the most differentially expressed genes and these genes were further assessed using Ingenuity Pathway Analysis (IPA) software. RESULTS: High T(reg) infiltration in ovarian cancers was associated with high grade (p<0.0001), advanced stage (p=0.004) and suboptimal debulking (p<0.04), but not with survival. In contrast, high tumor infiltrating CD8 CTL infiltration was associated with favorable survival (median survival 48.7 vs. 34.6 months, p=0.01). A microarray-based genomic signature for high tumor-infiltrating T(reg) cells had a 77% predictive accuracy using leave-one-out cross-validation. ANOVA of microarray data revealed the antigen presentation pathway as the most differentially expressed canonical pathway (p<0.00001) between cancers with high and low T(reg) cells. CONCLUSIONS: These data suggest that there may be an association between increased T(reg) cell infiltration in ovarian cancers and advanced stage. Increased T(reg) infiltration is characterized by a genomic signature enriched with several immunologic pathway genes. Therapeutic strategies that reduce tumor infiltrating T(reg) cells are under investigation and may prove useful in ovarian cancers with high numbers of these cells.

Authors
Barnett, JC; Bean, SM; Whitaker, RS; Kondoh, E; Baba, T; Fujii, S; Marks, JR; Dressman, HK; Murphy, SK; Berchuck, A
MLA Citation
Barnett, JC, Bean, SM, Whitaker, RS, Kondoh, E, Baba, T, Fujii, S, Marks, JR, Dressman, HK, Murphy, SK, and Berchuck, A. "Ovarian cancer tumor infiltrating T-regulatory (T(reg)) cells are associated with a metastatic phenotype." Gynecol Oncol 116.3 (March 2010): 556-562.
PMID
20006900
Source
pubmed
Published In
Gynecologic Oncology
Volume
116
Issue
3
Publish Date
2010
Start Page
556
End Page
562
DOI
10.1016/j.ygyno.2009.11.020

Pharmacogenomic strategies provide a rational approach to the treatment of cisplatin-resistant patients with advanced cancer (Journal of Clinical Oncology (2007) 25, (4350-4357))

Authors
Hsu, DS; Balakumaran, BS; Acharya, CR; Vlahovic, V; Walters, KS; Garman, K; Anders, C; Riedel, RF; Lancaster, J; Harpole, D; al, E
MLA Citation
Hsu, DS, Balakumaran, BS, Acharya, CR, Vlahovic, V, Walters, KS, Garman, K, Anders, C, Riedel, RF, Lancaster, J, Harpole, D, and al, E. "Pharmacogenomic strategies provide a rational approach to the treatment of cisplatin-resistant patients with advanced cancer (Journal of Clinical Oncology (2007) 25, (4350-4357))." Journal of Clinical Oncology 28.35 (2010): 5229--.
Source
scival
Published In
Journal of Clinical Oncology
Volume
28
Issue
35
Publish Date
2010
Start Page
5229-
DOI
10.1200/JCO.2010.33.7311

Novel tumor sampling strategies to enable microarray gene expression signatures in breast cancer: a study to determine feasibility and reproducibility in the context of clinical care.

Feasibility and reproducibility of microarray biomarkers in clinical settings are doubted because of reliance on fresh frozen tissue. We sought to develop and validate a paradigm of frozen tissue collection from early breast tumors to enable use of microarray in oncology practice. Frozen core needle biopsies (CNBx) were collected from 150 clinical stage I patients during image-guided diagnostic biopsy and/or surgery. Histology and tumor content from frozen cores were compared to diagnostic specimens. Twenty-eight patients had microarray analysis to examine accuracy and reproducibility of predictive gene signatures developed for estrogen receptor (ER) and HER2. One hundred twenty-seven (85%) of 150 patients had at least one frozen core containing cancer suitable for microarray analysis. Larger tumor size, ex vivo biopsy, and use of a new specimen device increased the likelihood of obtaining adequate specimens. Sufficient quality RNA was obtained from 90% of tumor cores. Microarray signatures predicting ER and HER2 expression were developed in training sets of up to 363 surgical samples and were applied to microarray data obtained from core samples collected in clinical settings. In these samples, prediction of ER and HER2 expression achieved a sensitivity/specificity of 94%/100%, and 82%/72%, respectively. Predictions were reproducible in 83-100% of paired samples. Frozen CNBx can be readily obtained from most breast cancers without interfering with pathologic evaluation in routine clinical settings. Collection of tumor tissue at diagnostic biopsy and/or at surgery from lumpectomy specimens using image guidance resulted in sufficient samples for array analysis from over 90% of patients. Sampling of breast cancer for microarray data is reproducible and feasible in clinical practice and can yield signatures predictive of multiple breast cancer phenotypes.

Authors
Tebbit, CL; Zhai, J; Untch, BR; Ellis, MJ; Dressman, HK; Bentley, RC; Baker, JA; Marcom, PK; Nevins, JR; Marks, JR; Olson, JA
MLA Citation
Tebbit, CL, Zhai, J, Untch, BR, Ellis, MJ, Dressman, HK, Bentley, RC, Baker, JA, Marcom, PK, Nevins, JR, Marks, JR, and Olson, JA. "Novel tumor sampling strategies to enable microarray gene expression signatures in breast cancer: a study to determine feasibility and reproducibility in the context of clinical care." Breast Cancer Res Treat 118.3 (December 2009): 635-643.
PMID
19224362
Source
pubmed
Published In
Breast Cancer Research and Treatment
Volume
118
Issue
3
Publish Date
2009
Start Page
635
End Page
643
DOI
10.1007/s10549-008-0301-1

Microarray analysis of early stage serous ovarian cancers shows profiles predictive of favorable outcome.

PURPOSE: Although few women with advanced serous ovarian cancer are cured, detection of the disease at an early stage is associated with a much higher likelihood of survival. We previously used gene expression array analysis to distinguish subsets of advanced cancers based on disease outcome. In the present study, we report on gene expression of early-stage cancers and validate our prognostic model for advanced-stage cancers. EXPERIMENTAL DESIGN: Frozen specimens from 39 stage I/II, 42 stage III/IV, and 20 low malignant potential cancers were obtained from four different sites. A linear discriminant model was used to predict survival based upon array data. RESULTS: We validated the late-stage survival model and show that three of the most differentially expressed genes continue to be predictive of outcome. Most early-stage cancers (38 of 39 invasive, 15 of 20 low malignant potential) were classified as long-term survivors (median probabilities 0.97 and 0.86). MAL, the most differentially expressed gene, was further validated at the protein level and found to be an independent predictor of poor survival in an unselected group of advanced serous cancers (P = 0.0004). CONCLUSIONS: These data suggest that serous ovarian cancers detected at an early stage generally have a favorable underlying biology similar to advanced-stage cases that are long-term survivors. Conversely, most late-stage ovarian cancers seem to have a more virulent biology. This insight suggests that if screening approaches are to succeed it will be necessary to develop approaches that are able to detect these virulent cancers at an early stage.

Authors
Berchuck, A; Iversen, ES; Luo, J; Clarke, JP; Horne, H; Levine, DA; Boyd, J; Alonso, MA; Secord, AA; Bernardini, MQ; Barnett, JC; Boren, T; Murphy, SK; Dressman, HK; Marks, JR; Lancaster, JM
MLA Citation
Berchuck, A, Iversen, ES, Luo, J, Clarke, JP, Horne, H, Levine, DA, Boyd, J, Alonso, MA, Secord, AA, Bernardini, MQ, Barnett, JC, Boren, T, Murphy, SK, Dressman, HK, Marks, JR, and Lancaster, JM. "Microarray analysis of early stage serous ovarian cancers shows profiles predictive of favorable outcome." Clin Cancer Res 15.7 (April 1, 2009): 2448-2455.
PMID
19318476
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
15
Issue
7
Publish Date
2009
Start Page
2448
End Page
2455
DOI
10.1158/1078-0432.CCR-08-2430

Characterizing the developmental pathways TTF-1, NKX2-8, and PAX9 in lung cancer.

We investigated the clinical implications of lung developmental transcription factors (TTF-1, NKX2-8, and PAX9) that we recently discovered as cooperating oncogenes activated by way of gene amplification at chromosome 14q13 in lung cancer. Using stable transfectants of human bronchial epithelial cells, RNA expression profiles (signatures) representing activation of the biological pathways defined by each of the 3 genes were determined and used to risk stratify a non-small-cell lung cancer (NSCLC) clinical data set consisting of 91 early stage tumors. Coactivation of the TTF-1 and NKX2-8 pathways identified a cluster of patients with poor survival, representing approximately 20% of patients with early stage NSCLC, whereas activation of individual pathways did not reveal significant prognostic power. Importantly, the poor prognosis associated with coactivation of TTF-1 and NKX2-8 was validated in 2 other independent clinical data sets. Furthermore, lung cancer cell lines showing coactivation of the TTF-1 and NKX2-8 pathways were shown to exhibit resistance to cisplatin, the standard of care for the treatment of NSCLC. This suggests that the cohort of patients with coactivation of TTF-1 and NKX2-8 pathways appears to be resistant to standard cisplatin therapy, suggesting the need for alternative therapies in this cohort of high-risk patients.

Authors
Hsu, DS; Acharya, CR; Balakumaran, BS; Riedel, RF; Kim, MK; Stevenson, M; Tuchman, S; Mukherjee, S; Barry, W; Dressman, HK; Nevins, JR; Powers, S; Mu, D; Potti, A
MLA Citation
Hsu, DS, Acharya, CR, Balakumaran, BS, Riedel, RF, Kim, MK, Stevenson, M, Tuchman, S, Mukherjee, S, Barry, W, Dressman, HK, Nevins, JR, Powers, S, Mu, D, and Potti, A. "Characterizing the developmental pathways TTF-1, NKX2-8, and PAX9 in lung cancer." Proc Natl Acad Sci U S A 106.13 (March 31, 2009): 5312-5317.
PMID
19279207
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
106
Issue
13
Publish Date
2009
Start Page
5312
End Page
5317
DOI
10.1073/pnas.0900827106

MicroRNAs and their target messenger RNAs associated with ovarian cancer response to chemotherapy

Objective: Few successful therapeutic options exist for patients with recurrent ovarian cancer (OVCA). This is due in part to an incomplete understanding of the molecular determinants of chemotherapy-response. Recently, it has been shown that microRNAs (miRNAs) influence messenger-RNA (mRNA) post-transcriptional control and can contribute to human carcinogenesis. The objective of the current study was to explore the role of miRNAs, and their predicted mRNA targets, in OVCA in-vitro response to chemotherapy. Methods: The expression of 335 unique miRNAs was measured in 16 OVCA cell lines. In parallel, the sensitivity of these cell lines to 6 commonly used chemotherapeutic agents (cisplatin, doxorubicin, topotecan, paclitaxel, docetaxel, and gemcitabine) was evaluated by in-vitro cell proliferation assay. MiRNAs associated with cell line drug response were identified by linear regression analysis, and their predicted mRNA targets subject to functional biologic pathway analyses. Results: Twenty-seven miRNAs were found to be associated with response to the one or more of the 6 salvage chemotherapies tested (p < 0.05). Predicted targets of these miRNAs included 52 mRNAs, previously reported to be associated with chemo-responsiveness, and which are also involved in functional biologic pathways that influence cancer cell cytotoxicity, carcinogenesis, cell mitosis, p53 signaling, and tumor cell growth and invasion. Conclusion: We have identified miRNAs and their predicted target mRNAs associated with ovarian cancer cell response to chemotherapeutic agents. Our strategy of integrating miRNA and mRNA data may aid in the characterization of important molecular pathways associated with OVCA chemo-response. © 2009 Elsevier Inc. All rights reserved.

Authors
Boren, T; Xiong, Y; Hakam, A; Wenham, R; Apte, S; Chan, G; Kamath, SG; Chen, D-T; Dressman, H; Lancaster, JM
MLA Citation
Boren, T, Xiong, Y, Hakam, A, Wenham, R, Apte, S, Chan, G, Kamath, SG, Chen, D-T, Dressman, H, and Lancaster, JM. "MicroRNAs and their target messenger RNAs associated with ovarian cancer response to chemotherapy." Gynecologic Oncology 113.2 (2009): 249-255.
PMID
19237188
Source
scival
Published In
Gynecologic Oncology
Volume
113
Issue
2
Publish Date
2009
Start Page
249
End Page
255
DOI
10.1016/j.ygyno.2009.01.014

Failure of terminal erythroid differentiation in EKLF-deficient mice is associated with cell cycle perturbation and reduced expression of E2F2.

Erythroid Krüppel-like factor (EKLF) is a Krüppel-like transcription factor identified as a transcriptional activator and chromatin modifier in erythroid cells. EKLF-deficient (Eklf(-/-)) mice die at day 14.5 of gestation from severe anemia. In this study, we demonstrate that early progenitor cells fail to undergo terminal erythroid differentiation in Eklf(-/-) embryos. To discover potential EKLF target genes responsible for the failure of erythropoiesis, transcriptional profiling was performed with RNA from wild-type and Eklf(-/-) early erythroid progenitor cells. These analyses identified significant perturbation of a network of genes involved in cell cycle regulation, with the critical regulator of the cell cycle, E2f2, at a hub. E2f2 mRNA and protein levels were markedly decreased in Eklf(-/-) early erythroid progenitor cells, which showed a delay in the G(1)-to-S-phase transition. Chromatin immunoprecipitation analysis demonstrated EKLF occupancy at the proximal E2f2 promoter in vivo. Consistent with the role of EKLF as a chromatin modifier, EKLF binding sites in the E2f2 promoter were located in a region of EKLF-dependent DNase I sensitivity in early erythroid progenitor cells. We propose a model in which EKLF-dependent activation and modification of the E2f2 locus is required for cell cycle progression preceding terminal erythroid differentiation.

Authors
Pilon, AM; Arcasoy, MO; Dressman, HK; Vayda, SE; Maksimova, YD; Sangerman, JI; Gallagher, PG; Bodine, DM
MLA Citation
Pilon, AM, Arcasoy, MO, Dressman, HK, Vayda, SE, Maksimova, YD, Sangerman, JI, Gallagher, PG, and Bodine, DM. "Failure of terminal erythroid differentiation in EKLF-deficient mice is associated with cell cycle perturbation and reduced expression of E2F2." Mol Cell Biol 28.24 (December 2008): 7394-7401.
PMID
18852285
Source
pubmed
Published In
Molecular and Cellular Biology
Volume
28
Issue
24
Publish Date
2008
Start Page
7394
End Page
7401
DOI
10.1128/MCB.01087-08

A clinicogenomic model to predict lymph node metastasis in breast cancer

Authors
Danko, ME; Untch, BR; Tebbit, CL; Zhai, J; Dressman, HK; Bentley, RC; Baker, J; Marks, JR; Nevins, JR; Jr, OJA
MLA Citation
Danko, ME, Untch, BR, Tebbit, CL, Zhai, J, Dressman, HK, Bentley, RC, Baker, J, Marks, JR, Nevins, JR, and Jr, OJA. "A clinicogenomic model to predict lymph node metastasis in breast cancer." September 2008.
Source
wos-lite
Published In
Journal of The American College of Surgeons
Volume
207
Issue
3
Publish Date
2008
Start Page
S45
End Page
S45
DOI
10.1016/j.jamcollsurg.2008.06.092

Unfolded protein response genes regulated by CED-1 are required for Caenorhabditis elegans innate immunity.

The endoplasmic reticulum stress response, also known as the unfolded protein response (UPR), has been implicated in the normal physiology of immune defense and in several disorders, including diabetes, cancer, and neurodegenerative disease. Here, we show that the apoptotic receptor CED-1 and a network of PQN/ABU proteins involved in a noncanonical UPR response are required for proper defense to pathogen infection in Caenorhabditis elegans. A full-genome microarray analysis indicates that CED-1 functions to activate the expression of pqn/abu genes. We also show that ced-1 and pqn/abu genes are required for the survival of C. elegans exposed to live Salmonella enterica, and that overexpression of pqn/abu genes confers protection against pathogen-mediated killing. The results indicate that unfolded protein response genes, regulated in a CED-1-dependent manner, are involved in the C. elegans immune response to live bacteria.

Authors
Haskins, KA; Russell, JF; Gaddis, N; Dressman, HK; Aballay, A
MLA Citation
Haskins, KA, Russell, JF, Gaddis, N, Dressman, HK, and Aballay, A. "Unfolded protein response genes regulated by CED-1 are required for Caenorhabditis elegans innate immunity." Dev Cell 15.1 (July 2008): 87-97.
Website
http://hdl.handle.net/10161/685
PMID
18606143
Source
pubmed
Published In
Developmental Cell
Volume
15
Issue
1
Publish Date
2008
Start Page
87
End Page
97
DOI
10.1016/j.devcel.2008.05.006

Gene expression determinants of ovarian cancer platinum-response in older women

Authors
Cragun, JM; Boren, T; Xiong, Y; Indermaur, M; Kamath, S; Cottrill, H; Balducci, L; Sayer, R; Dressman, HK; Berchuck, A; Lancaster, J
MLA Citation
Cragun, JM, Boren, T, Xiong, Y, Indermaur, M, Kamath, S, Cottrill, H, Balducci, L, Sayer, R, Dressman, HK, Berchuck, A, and Lancaster, J. "Gene expression determinants of ovarian cancer platinum-response in older women." JOURNAL OF CLINICAL ONCOLOGY 26.15 (May 20, 2008).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
26
Issue
15
Publish Date
2008

Use of co-activation of lung cancer specific developmental pathway genes, TTF-1, NKX2-8, and PAX9, to predict prognosis and guide therapeutic strategies

Authors
Hsu, SD; Acharya, CR; Riedel, RF; Redman, RC; Garman, KS; Dressman, HK; Ginsburg, G; Powers, S; Mu, D; Potti, A
MLA Citation
Hsu, SD, Acharya, CR, Riedel, RF, Redman, RC, Garman, KS, Dressman, HK, Ginsburg, G, Powers, S, Mu, D, and Potti, A. "Use of co-activation of lung cancer specific developmental pathway genes, TTF-1, NKX2-8, and PAX9, to predict prognosis and guide therapeutic strategies." JOURNAL OF CLINICAL ONCOLOGY 26.15 (May 20, 2008).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
26
Issue
15
Publish Date
2008

Gene expression signatures, clinicopathological features, and individualized therapy in breast cancer.

CONTEXT: Gene expression profiling may be useful for prognostic and therapeutic strategies in breast carcinoma. OBJECTIVES: To demonstrate the value in integrating genomic information with clinical and pathological risk factors, to refine prognosis, and to improve therapeutic strategies for early stage breast cancer. DESIGN, SETTING, AND PATIENTS: Retrospective study of patients with early stage breast carcinoma who were candidates for adjuvant chemotherapy; 964 clinically annotated breast tumor samples (573 in the initial discovery set and 391 in the validation cohort) with corresponding microarray data were used. All patients were assigned relapse risk scores based on their respective clinicopathological features. Signatures representing oncogenic pathway activation and tumor biology/microenvironment status were applied to these samples to obtain patterns of deregulation that correspond with relapse risk scores to refine prognosis with the clinicopathological prognostic model alone. Predictors of chemotherapeutic response were also applied to further characterize clinically relevant heterogeneity in early stage breast cancer. MAIN OUTCOME MEASURES: Gene expression signatures and clinicopathological variables in early stage breast cancer to determine a refined estimation of relapse-free survival and sensitivity to chemotherapy. RESULTS: In the initial data set of 573 patients, prognostically significant clusters representing patterns of oncogenic pathway activation and tumor biology/microenvironment states were identified within the low-risk (log-rank P = .004), intermediate-risk (log-rank P = .01), and high-risk (log-rank P = .003) model cohorts, representing clinically important genomic subphenotypes of breast cancer. As an example, in the low-risk cohort, of 6 prognostically significant clusters, patients in cluster 4 had an inferior relapse-free survival vs patients in cluster 1 (log-rank P = .004) and cluster 5 (log-rank P = .03). Median relapse-free survival for patients in cluster 4 was 16 months less than for patients in cluster 1 (95% CI, 7.5-24.5 months) and 19 months less than for patients in cluster 5 (95% CI, 10.5-27.5 months). Multivariate analyses confirmed the independent prognostic value of the genomic clusters (low risk, P = .05; high risk, P = .02). The reproducibility and validity of these patterns of pathway deregulation in predicting relapse risk was established using related but not identical clusters in the independent validation cohort. The prognostic clinicogenomic clusters also have unique sensitivity patterns to commonly used cytotoxic therapies. CONCLUSIONS: These results provide preliminary evidence that incorporation of gene expression signatures into clinical risk stratification can refine prognosis. Prospective studies are needed to determine the value of this approach for individualizing therapeutic strategies.

Authors
Acharya, CR; Hsu, DS; Anders, CK; Anguiano, A; Salter, KH; Walters, KS; Redman, RC; Tuchman, SA; Moylan, CA; Mukherjee, S; Barry, WT; Dressman, HK; Ginsburg, GS; Marcom, KP; Garman, KS; Lyman, GH; Nevins, JR; Potti, A
MLA Citation
Acharya, CR, Hsu, DS, Anders, CK, Anguiano, A, Salter, KH, Walters, KS, Redman, RC, Tuchman, SA, Moylan, CA, Mukherjee, S, Barry, WT, Dressman, HK, Ginsburg, GS, Marcom, KP, Garman, KS, Lyman, GH, Nevins, JR, and Potti, A. "Gene expression signatures, clinicopathological features, and individualized therapy in breast cancer." JAMA 299.13 (April 2, 2008): 1574-1587.
PMID
18387932
Source
pubmed
Published In
JAMA : the journal of the American Medical Association
Volume
299
Issue
13
Publish Date
2008
Start Page
1574
End Page
1587
DOI
10.1001/jama.299.13.1574

Gene expression signatures of radiation response are specific, durable and accurate in mice and humans.

BACKGROUND: Previous work has demonstrated the potential for peripheral blood (PB) gene expression profiling for the detection of disease or environmental exposures. METHODS AND FINDINGS: We have sought to determine the impact of several variables on the PB gene expression profile of an environmental exposure, ionizing radiation, and to determine the specificity of the PB signature of radiation versus other genotoxic stresses. Neither genotype differences nor the time of PB sampling caused any lessening of the accuracy of PB signatures to predict radiation exposure, but sex difference did influence the accuracy of the prediction of radiation exposure at the lowest level (50 cGy). A PB signature of sepsis was also generated and both the PB signature of radiation and the PB signature of sepsis were found to be 100% specific at distinguishing irradiated from septic animals. We also identified human PB signatures of radiation exposure and chemotherapy treatment which distinguished irradiated patients and chemotherapy-treated individuals within a heterogeneous population with accuracies of 90% and 81%, respectively. CONCLUSIONS: We conclude that PB gene expression profiles can be identified in mice and humans that are accurate in predicting medical conditions, are specific to each condition and remain highly accurate over time.

Authors
Meadows, SK; Dressman, HK; Muramoto, GG; Himburg, H; Salter, A; Wei, Z; Ginsburg, GS; Chao, NJ; Nevins, JR; Chute, JP
MLA Citation
Meadows, SK, Dressman, HK, Muramoto, GG, Himburg, H, Salter, A, Wei, Z, Ginsburg, GS, Chao, NJ, Nevins, JR, and Chute, JP. "Gene expression signatures of radiation response are specific, durable and accurate in mice and humans. (Published online)" PLoS One 3.4 (April 2, 2008): e1912-.
Website
http://hdl.handle.net/10161/13546
PMID
18382685
Source
pubmed
Published In
PloS one
Volume
3
Issue
4
Publish Date
2008
Start Page
e1912
DOI
10.1371/journal.pone.0001912

An integrated approach to the prediction of chemotherapeutic response in patients with breast cancer.

BACKGROUND: A major challenge in oncology is the selection of the most effective chemotherapeutic agents for individual patients, while the administration of ineffective chemotherapy increases mortality and decreases quality of life in cancer patients. This emphasizes the need to evaluate every patient's probability of responding to each chemotherapeutic agent and limiting the agents used to those most likely to be effective. METHODS AND RESULTS: Using gene expression data on the NCI-60 and corresponding drug sensitivity, mRNA and microRNA profiles were developed representing sensitivity to individual chemotherapeutic agents. The mRNA signatures were tested in an independent cohort of 133 breast cancer patients treated with the TFAC (paclitaxel, 5-fluorouracil, adriamycin, and cyclophosphamide) chemotherapy regimen. To further dissect the biology of resistance, we applied signatures of oncogenic pathway activation and performed hierarchical clustering. We then used mRNA signatures of chemotherapy sensitivity to identify alternative therapeutics for patients resistant to TFAC. Profiles from mRNA and microRNA expression data represent distinct biologic mechanisms of resistance to common cytotoxic agents. The individual mRNA signatures were validated in an independent dataset of breast tumors (P = 0.002, NPV = 82%). When the accuracy of the signatures was analyzed based on molecular variables, the predictive ability was found to be greater in basal-like than non basal-like patients (P = 0.03 and P = 0.06). Samples from patients with co-activated Myc and E2F represented the cohort with the lowest percentage (8%) of responders. Using mRNA signatures of sensitivity to other cytotoxic agents, we predict that TFAC non-responders are more likely to be sensitive to docetaxel (P = 0.04), representing a viable alternative therapy. CONCLUSIONS: Our results suggest that the optimal strategy for chemotherapy sensitivity prediction integrates molecular variables such as ER and HER2 status with corresponding microRNA and mRNA expression profiles. Importantly, we also present evidence to support the concept that analysis of molecular variables can present a rational strategy to identifying alternative therapeutic opportunities.

Authors
Salter, KH; Acharya, CR; Walters, KS; Redman, R; Anguiano, A; Garman, KS; Anders, CK; Mukherjee, S; Dressman, HK; Barry, WT; Marcom, KP; Olson, J; Nevins, JR; Potti, A
MLA Citation
Salter, KH, Acharya, CR, Walters, KS, Redman, R, Anguiano, A, Garman, KS, Anders, CK, Mukherjee, S, Dressman, HK, Barry, WT, Marcom, KP, Olson, J, Nevins, JR, and Potti, A. "An integrated approach to the prediction of chemotherapeutic response in patients with breast cancer. (Published online)" PLoS One 3.4 (April 2, 2008): e1908-.
Website
http://hdl.handle.net/10161/4486
PMID
18382681
Source
pubmed
Published In
PloS one
Volume
3
Issue
4
Publish Date
2008
Start Page
e1908
DOI
10.1371/journal.pone.0001908

MicroRNAs and their target messenger RNAs associated with the development of endometrial carcinoma

Authors
Boren, T; Dressman, HK; Kamath, S; Wei, ZZ; Cragun, J; Humphrey, M; Chen, N; Xiong, Y; Lancaster, JM
MLA Citation
Boren, T, Dressman, HK, Kamath, S, Wei, ZZ, Cragun, J, Humphrey, M, Chen, N, Xiong, Y, and Lancaster, JM. "MicroRNAs and their target messenger RNAs associated with the development of endometrial carcinoma." GYNECOLOGIC ONCOLOGY 108.3 (March 2008): S88-S89.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
108
Issue
3
Publish Date
2008
Start Page
S88
End Page
S89

Targeted therapy to improve endometrial cancer response to doxorubicin

Authors
Indermaur, MD; Boren, T; Kamath, SG; Wei, Z; Wenham, R; Apte, S; Dressman, HK; Lancaster, JM
MLA Citation
Indermaur, MD, Boren, T, Kamath, SG, Wei, Z, Wenham, R, Apte, S, Dressman, HK, and Lancaster, JM. "Targeted therapy to improve endometrial cancer response to doxorubicin." GYNECOLOGIC ONCOLOGY 108.3 (March 2008): S82-S82.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
108
Issue
3
Publish Date
2008
Start Page
S82
End Page
S82

Gene expression patterns in formalin-fixed, paraffin-embedded endometrial tissue associated with lymph node metastasis

Authors
Boren, T; Dressman, HK; Wei, ZZ; Martino, MA; Zhang, T; Palmer, J; Lancaster, JM
MLA Citation
Boren, T, Dressman, HK, Wei, ZZ, Martino, MA, Zhang, T, Palmer, J, and Lancaster, JM. "Gene expression patterns in formalin-fixed, paraffin-embedded endometrial tissue associated with lymph node metastasis." GYNECOLOGIC ONCOLOGY 108.3 (March 2008): S89-S90.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
108
Issue
3
Publish Date
2008
Start Page
S89
End Page
S90

Formalin-fixed, paraffin-embedded ovarian cancer gene expression signatures associated with platinum response

Authors
Indermaur, MD; Boren, T; Cragun, J; Wenham, R; Aptel, S; Chan, G; Karnath, SG; Wei, Z; Dressman, HK; Lancaster, JM
MLA Citation
Indermaur, MD, Boren, T, Cragun, J, Wenham, R, Aptel, S, Chan, G, Karnath, SG, Wei, Z, Dressman, HK, and Lancaster, JM. "Formalin-fixed, paraffin-embedded ovarian cancer gene expression signatures associated with platinum response." GYNECOLOGIC ONCOLOGY 108.3 (March 2008): S39-S39.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
108
Issue
3
Publish Date
2008
Start Page
S39
End Page
S39

MicroRNAs and their target messenger RNAs associated with endometrial carcinogenesis

Objective: Recent advances in gene expression technology have provided insights into global messenger RNA (mRNA) expression changes associated with endometrial cancer development. However, the post-transcriptional events that may also have phenotypic consequences remain to be completely delineated. MicroRNAs (miRNAs) are small non-coding RNA transcripts, that influence cell function via modulation of post-transcriptional activity of multiple target mRNA genes. Although recent reports suggest that miRNAs may influence human cancer development, their role in endometrial carcinogenesis remains to be described. Methods: We measured expression of 335 unique human miRNAs in 61 fresh-frozen endometrial specimens, including 37 endometrial cancers, 20 normal endometrium, and 4 complex atypical hyperplasia samples. In parallel, expression of 22,000 mRNA genes was analyzed using the Affymetrix Human U133A GeneChips in 29 of the endometrial samples, including 20 endometrial carcinomas and 9 normal endometrial samples. Differentially expressed mRNAs, miRNAs, and predicted miRNA-mRNA targets were integrated and evaluated for representation of relevant functional biologic pathways. Results: Thirteen miRNAs (p < 0.02) and 90 mRNAs (FDR; 0%) were identified to be associated with endometrial cancer development. Twenty-six of the 90 (29%) differentially expressed mRNAs are Sangar-database predicted mRNA targets of the 13 miRNAs. Pathway analysis demonstrates significant involvement of these 26 mRNA genes in processes including cell death, growth, proliferation, and carcinogenesis. Conclusion: We have identified miRNAs and mRNAs associated with endometrial cancer development. Further, our strategy of integrating miRNA/mRNA data may also aid in the identification of important biologic pathways and additional unique genes that have importance in endometrial pathogenesis. © 2008 Elsevier Inc. All rights reserved.

Authors
Boren, T; Xiong, Y; Hakam, A; Wenham, R; Apte, S; Wei, Z; Kamath, S; Chen, D-T; Dressman, H; al, E
MLA Citation
Boren, T, Xiong, Y, Hakam, A, Wenham, R, Apte, S, Wei, Z, Kamath, S, Chen, D-T, Dressman, H, and al, E. "MicroRNAs and their target messenger RNAs associated with endometrial carcinogenesis." Gynecologic Oncology 110.2 (2008): 206-215.
PMID
18499237
Source
scival
Published In
Gynecologic Oncology
Volume
110
Issue
2
Publish Date
2008
Start Page
206
End Page
215
DOI
10.1016/j.ygyno.2008.03.023

Pharmacogenomic strategies provide a rational approach to the treatment of cisplatin-resistant patients with advanced cancer.

PURPOSE: Standard treatment for advanced non-small-cell lung cancer (NSCLC) includes the use of a platinum-based chemotherapy regimen. However, response rates are highly variable. Newer agents, such as pemetrexed, have shown significant activity as second-line therapy and are currently being evaluated in the front-line setting. We utilized a genomic strategy to develop signatures predictive of chemotherapeutic response to both cisplatin and pemetrexed to provide a rational approach to effective individualized medicine. METHODS: Using in vitro drug sensitivity data, coupled with microarray data, we developed gene expression signatures predicting sensitivity to cisplatin and pemetrexed. Signatures were validated with response data from 32 independent ovarian and lung cancer cell lines as well as 59 samples from patients previously treated with cisplatin. RESULTS: Genomic-derived signatures of cisplatin and pemetrexed sensitivity were shown to accurately predict sensitivity in vitro and, in the case of cisplatin, to predict treatment response in patients treated with cisplatin. The accuracy of the cisplatin predictor, based on available clinical data, was 83.1% (sensitivity, 100%; specificity 57%; positive predictive value, 78%; negative predictive value, 100%). Interestingly, an inverse correlation was seen between in vitro cisplatin and pemetrexed sensitivity, and importantly, between the likelihood of cisplatin and pemetrexed response in patients. CONCLUSION: The use of genomic predictors of response to cisplatin and pemetrexed can be incorporated into strategies to optimize therapy for advanced solid tumors.

Authors
Hsu, DS; Balakumaran, BS; Acharya, CR; Vlahovic, V; Walters, KS; Garman, K; Anders, C; Riedel, RF; Lancaster, J; Harpole, D; Dressman, HK; Nevins, JR; Febbo, PG; Potti, A
MLA Citation
Hsu, DS, Balakumaran, BS, Acharya, CR, Vlahovic, V, Walters, KS, Garman, K, Anders, C, Riedel, RF, Lancaster, J, Harpole, D, Dressman, HK, Nevins, JR, Febbo, PG, and Potti, A. "Pharmacogenomic strategies provide a rational approach to the treatment of cisplatin-resistant patients with advanced cancer." J Clin Oncol 25.28 (October 1, 2007): 4350-4357.
PMID
17906199
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
25
Issue
28
Publish Date
2007
Start Page
4350
End Page
4357
DOI
10.1200/JCO.2007.11.0593

Gene expression signatures that predict radiation exposure in mice and humans.

BACKGROUND: The capacity to assess environmental inputs to biological phenotypes is limited by methods that can accurately and quantitatively measure these contributions. One such example can be seen in the context of exposure to ionizing radiation. METHODS AND FINDINGS: We have made use of gene expression analysis of peripheral blood (PB) mononuclear cells to develop expression profiles that accurately reflect prior radiation exposure. We demonstrate that expression profiles can be developed that not only predict radiation exposure in mice but also distinguish the level of radiation exposure, ranging from 50 cGy to 1,000 cGy. Likewise, a molecular signature of radiation response developed solely from irradiated human patient samples can predict and distinguish irradiated human PB samples from nonirradiated samples with an accuracy of 90%, sensitivity of 85%, and specificity of 94%. We further demonstrate that a radiation profile developed in the mouse can correctly distinguish PB samples from irradiated and nonirradiated human patients with an accuracy of 77%, sensitivity of 82%, and specificity of 75%. Taken together, these data demonstrate that molecular profiles can be generated that are highly predictive of different levels of radiation exposure in mice and humans. CONCLUSIONS: We suggest that this approach, with additional refinement, could provide a method to assess the effects of various environmental inputs into biological phenotypes as well as providing a more practical application of a rapid molecular screening test for the diagnosis of radiation exposure.

Authors
Dressman, HK; Muramoto, GG; Chao, NJ; Meadows, S; Marshall, D; Ginsburg, GS; Nevins, JR; Chute, JP
MLA Citation
Dressman, HK, Muramoto, GG, Chao, NJ, Meadows, S, Marshall, D, Ginsburg, GS, Nevins, JR, and Chute, JP. "Gene expression signatures that predict radiation exposure in mice and humans." PLoS Med 4.4 (April 2007): e106-.
Website
http://hdl.handle.net/10161/11574
PMID
17407386
Source
pubmed
Published In
PLoS medicine
Volume
4
Issue
4
Publish Date
2007
Start Page
e106
DOI
10.1371/journal.pmed.0040106

Genetic analysis of intracranial tumors in a murine model of glioma demonstrate a shift in gene expression in response to host immunity.

For the study of malignant glioma, we have previously characterized a highly tumorigenic murine astrocytoma, SMA-560, which arose spontaneously in an inbred, immunocompetent VM/Dk mouse. Using this cell line as a model of murine glioma, we performed DNA microarray analysis of autologous normal murine astroctyes (NMA) and SMA-560 tumor cells grown in monolayer culture or intracranially in syngeneic immunocompetent or immunocompromised hosts in order to determine whether tumors grown in vitro recreate the complex genetic regulation that occurs in vivo. Our findings support our hypothesis that glioma phenotype in vitro may be quite different in vivo and significantly altered by in situ growth factors and other invading cell populations.

Authors
Learn, CA; Grossi, PM; Schmittling, RJ; Xie, W; Mitchell, DA; Karikari, I; Wei, Z; Dressman, H; Sampson, JH
MLA Citation
Learn, CA, Grossi, PM, Schmittling, RJ, Xie, W, Mitchell, DA, Karikari, I, Wei, Z, Dressman, H, and Sampson, JH. "Genetic analysis of intracranial tumors in a murine model of glioma demonstrate a shift in gene expression in response to host immunity." Journal of neuroimmunology 182.1-2 (January 2007): 63-72.
PMID
17137636
Source
epmc
Published In
Journal of Neuroimmunology
Volume
182
Issue
1-2
Publish Date
2007
Start Page
63
End Page
72
DOI
10.1016/j.jneuroim.2006.09.016

Failure of definitive erythropoiesis in EKLF-deficient mice

Authors
Gallagher, PG; Pilon, AM; Arcasoy, MO; Vayda, SE; Dressman, HK; Bieker, JJ; Bodine, DM
MLA Citation
Gallagher, PG, Pilon, AM, Arcasoy, MO, Vayda, SE, Dressman, HK, Bieker, JJ, and Bodine, DM. "Failure of definitive erythropoiesis in EKLF-deficient mice." 2007.
Source
wos-lite
Published In
Blood Cells, Molecules and Diseases
Volume
38
Issue
2
Publish Date
2007
Start Page
140
End Page
141
DOI
10.1016/j.bcmd.2006.10.050

EKLF-deficiency leads to multiple defects in erythropoiesis: Dysregulation of AHSP and E2F

Authors
Pilon, AM; Arcasoy, MO; Vayda, SE; Dressman, HK; Bieker, JJ; Bodine, DM; Gallagher, PG
MLA Citation
Pilon, AM, Arcasoy, MO, Vayda, SE, Dressman, HK, Bieker, JJ, Bodine, DM, and Gallagher, PG. "EKLF-deficiency leads to multiple defects in erythropoiesis: Dysregulation of AHSP and E2F." 2007.
Source
wos-lite
Published In
Blood Cells, Molecules and Diseases
Volume
38
Issue
2
Publish Date
2007
Start Page
172
End Page
172
DOI
10.1016/j.bcmd.2006.10.118

Profiling of CD4+, CD8+, and CD4+CD25+CD45RO+FoxP3+ T cells in patients with malignant glioma reveals differential expression of the immunologic transcriptome compared with T cells from healthy volunteers.

PURPOSE: Analyses of T-cell mRNA expression profiles in glioblastoma multiforme has not been previously reported but may help to define and characterize the immunosuppressed phenotype in patients with this type of cancer. EXPERIMENTAL DESIGN: We did microarray studies that have shown significant and fundamental differences in the expression profiles of CD4(+) and CD8(+) T cells and immunosuppressive CD4(+)CD25(+)CD45RO(+)FoxP3(+) regulatory T cells (T(reg)) from normal healthy volunteers compared with patients with newly diagnosed glioblastoma multiforme. For these investigations, we isolated total RNA from enriched CD4(+) and CD8(+) T cell or T(reg) cell populations from age-matched individuals and did microarray analyses. RESULTS: ANOVA and principal components analysis show that the various T cell compartments exhibit consistently similar mRNA expression profiles among individuals within either healthy or brain tumor groups but reflect significant differences between these groups. Compared with healthy volunteers, CD4(+) and CD8(+) T cells from patients with glioblastoma multiforme display coordinate down-regulation of genes involved in T cell receptor ligation, activation, and intracellular signaling. In contrast, T(regs) from patients with glioblastoma multiforme exhibit increased levels of transcripts involved in inhibiting host immunity. CONCLUSION: Our findings support the notion that key differences between expression profiles in T-cell populations from patients with glioblastoma multiforme results from differential expression of the immunologic transcriptome, such that a limited number of genes are principally important in producing the dysregulated T-cell phenotype.

Authors
Learn, CA; Fecci, PE; Schmittling, RJ; Xie, W; Karikari, I; Mitchell, DA; Archer, GE; Wei, Z; Dressman, H; Sampson, JH
MLA Citation
Learn, CA, Fecci, PE, Schmittling, RJ, Xie, W, Karikari, I, Mitchell, DA, Archer, GE, Wei, Z, Dressman, H, and Sampson, JH. "Profiling of CD4+, CD8+, and CD4+CD25+CD45RO+FoxP3+ T cells in patients with malignant glioma reveals differential expression of the immunologic transcriptome compared with T cells from healthy volunteers." Clinical cancer research : an official journal of the American Association for Cancer Research 12.24 (December 2006): 7306-7315.
PMID
17189402
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
12
Issue
24
Publish Date
2006
Start Page
7306
End Page
7315
DOI
10.1158/1078-0432.ccr-06-1727

Defects in E2F1/2 expression are associated with abnormalities in cell cycle and differentiation in EKLF-deficient erythroid cells.

Authors
Pilon, AM; Arcasoy, MO; Vayda, SE; Dressman, HK; Bieker, JJ; Bodine, DM; Gallagher, PG
MLA Citation
Pilon, AM, Arcasoy, MO, Vayda, SE, Dressman, HK, Bieker, JJ, Bodine, DM, and Gallagher, PG. "Defects in E2F1/2 expression are associated with abnormalities in cell cycle and differentiation in EKLF-deficient erythroid cells." November 16, 2006.
Source
wos-lite
Published In
Blood
Volume
108
Issue
11
Publish Date
2006
Start Page
29A
End Page
29A

Genomic prediction of locoregional recurrence after mastectomy in breast cancer.

PURPOSE: This study aims to explore gene expression profiles that are associated with locoregional (LR) recurrence in breast cancer after mastectomy. PATIENTS AND METHODS: A total of 94 breast cancer patients who underwent mastectomy between 1990 and 2001 and had DNA microarray study on the primary tumor tissues were chosen for this study. Eligible patient should have no evidence of LR recurrence without postmastectomy radiotherapy (PMRT) after a minimum of 3-year follow-up (n = 67) and any LR recurrence (n = 27). They were randomly split into training and validation sets. Statistical classification tree analysis and proportional hazards models were developed to identify and validate gene expression profiles that relate to LR recurrence. RESULTS: Our study demonstrates two sets of gene expression profiles (one with 258 genes and the other 34 genes) to be of predictive value with respect to LR recurrence. The overall accuracy of the prediction tree model in validation sets is estimated 75% to 78%. Of patients in validation data set, the 3-year LR control rate with predictive index more than 0.8 derived from 34-gene prediction models is 91%, and predictive index 0.8 or less is 40% (P = .008). Multivariate analysis of all patients reveals that estrogen receptor and genomic predictive index are independent prognostic factors that affect LR control. CONCLUSION: Using gene expression profiles to develop prediction tree models effectively identifies breast cancer patients who are at higher risk for LR recurrence. This gene expression-based predictive index can be used to select patients for PMRT.

Authors
Cheng, SH; Horng, C-F; West, M; Huang, E; Pittman, J; Tsou, M-H; Dressman, H; Chen, C-M; Tsai, SY; Jian, JJ; Liu, M-C; Nevins, JR; Huang, AT
MLA Citation
Cheng, SH, Horng, C-F, West, M, Huang, E, Pittman, J, Tsou, M-H, Dressman, H, Chen, C-M, Tsai, SY, Jian, JJ, Liu, M-C, Nevins, JR, and Huang, AT. "Genomic prediction of locoregional recurrence after mastectomy in breast cancer." J Clin Oncol 24.28 (October 1, 2006): 4594-4602.
PMID
17008701
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
28
Publish Date
2006
Start Page
4594
End Page
4602
DOI
10.1200/JCO.2005.02.5676

Identification of genes associated with ovarian cancer metastasis using microarray expression analysis.

Although the transition from early- to advanced-stage ovarian cancer is a critical determinant of survival, little is known about the molecular underpinnings of ovarian metastasis. We hypothesize that microarray analysis of global gene expression patterns in primary ovarian cancer and metastatic omental implants can identify genes that underlie the metastatic process in epithelial ovarian cancer. We utilized Affymetrix U95Av2 microarrays to characterize the molecular alterations that underlie omental metastasis from 47 epithelial ovarian cancer samples collected from multiple sites in 20 patients undergoing primary surgical cytoreduction for advanced-stage (IIIC/IV) serous ovarian cancer. Fifty-six genes demonstrated differential expression between ovarian and omental samples (P < 0.01), and twenty of these 56 differentially expressed genes have previously been implicated in metastasis, cell motility, or cytoskeletal function. Ten of the 56 genes are involved in p53 gene pathways. A Bayesian statistical tree analysis was used to identify a 27-gene expression pattern that could accurately predict the site of tumor (ovary versus omentum). This predictive model was evaluated using an external data set. Nine of the 27 predictive genes have previously been shown to be involved in oncogenesis and/or metastasis, and 10/27 genes have been implicated in p53 pathways. Microarray findings were validated by real-time quantitative PCR. We conclude that gene expression patterns that distinguish omental metastasis from primary epithelial ovarian cancer can be identified and that many of the genes have functions that are biologically consistent with a role in oncogenesis, metastasis, and p53 gene networks.

Authors
Lancaster, JM; Dressman, HK; Clarke, JP; Sayer, RA; Martino, MA; Cragun, JM; Henriott, AH; Gray, J; Sutphen, R; Elahi, A; Whitaker, RS; West, M; Marks, JR; Nevins, JR; Berchuck, A
MLA Citation
Lancaster, JM, Dressman, HK, Clarke, JP, Sayer, RA, Martino, MA, Cragun, JM, Henriott, AH, Gray, J, Sutphen, R, Elahi, A, Whitaker, RS, West, M, Marks, JR, Nevins, JR, and Berchuck, A. "Identification of genes associated with ovarian cancer metastasis using microarray expression analysis." Int J Gynecol Cancer 16.5 (September 2006): 1733-1745.
PMID
17009964
Source
pubmed
Published In
International Journal of Gynecological Cancer
Volume
16
Issue
5
Publish Date
2006
Start Page
1733
End Page
1745
DOI
10.1111/j.1525-1438.2006.00660.x

Phase I trial of sequential low-dose 5-aza-2'-deoxycytidine plus high-dose intravenous bolus interleukin-2 in patients with melanoma or renal cell carcinoma.

PURPOSE: The silencing of gene expression through DNA methylation contributes to defects in antigen presentation and apoptosis in melanoma and renal cell cancer. To determine how a hypomethylating agent would modulate the toxicity and antitumor activity of immunotherapy, we initiated a phase I trial of 5-aza-2'-deoxycytidine (decitabine) plus high-dose interleukin 2 (IL-2). EXPERIMENTAL DESIGN: Patients received s.c. decitabine daily x 5 days on weeks 1 and 2 of a 12-week cycle. High-dose IL-2, consisting of two cycles of IL-2 600,000 IU/kg i.v. q8 hours x 14 doses separated by a 2-week break, was administered starting on week 3. Decitabine was escalated from 0.1 to 0.25 mg/kg. The hypomethylating activity of decitabine was assessed during cycle 1 by measuring hemoglobin F levels and changes in DNA methylation in peripheral blood mononuclear cells. RESULTS: Twenty-one patients with melanoma or renal cell cancer were enrolled. Decitabine did not alter the tolerability of IL-2 but caused grade 4 neutropenia in most patients. Grade 4 neutropenia lasting more than 7 days was the only dose-limiting toxicity, with a trend toward a higher incidence with increasing decitabine doses. Infection occurred in only one patient despite the high incidence of neutropenia, and granulocyte colony-stimulating factor use in several patients expedited neutrophil recovery. Decitabine augmented hemoglobin F levels and altered DNA methylation and gene expression in peripheral blood mononuclear cells in a dose-independent manner that overlapped with the administration of IL-2. Objective responses occurred in 31% of melanoma patients. CONCLUSIONS: Decitabine can be safely administered with high-dose IL-2 and may enhance the activity of IL-2 in melanoma.

Authors
Gollob, JA; Sciambi, CJ; Peterson, BL; Richmond, T; Thoreson, M; Moran, K; Dressman, HK; Jelinek, J; Issa, J-PJ
MLA Citation
Gollob, JA, Sciambi, CJ, Peterson, BL, Richmond, T, Thoreson, M, Moran, K, Dressman, HK, Jelinek, J, and Issa, J-PJ. "Phase I trial of sequential low-dose 5-aza-2'-deoxycytidine plus high-dose intravenous bolus interleukin-2 in patients with melanoma or renal cell carcinoma." Clin Cancer Res 12.15 (August 1, 2006): 4619-4627.
PMID
16899610
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
12
Issue
15
Publish Date
2006
Start Page
4619
End Page
4627
DOI
10.1158/1078-0432.CCR-06-0883

Genomic signatures in non-small-cell lung cancer: targeting the targeted therapies.

Despite major developments in targeted biologic agents, patients with advanced non-small-cell lung cancer have a poor prognosis. Recent development of targeted biologic agents have given us insight into possibilities of matching therapy with disease; however, the success of these agents has been marginal. In this article, we discuss the use of genomic signatures that have been developed to identify unique aspects of individual lung tumors and provide insight on how novel strategies can be used to identify populations susceptible to specific targeted agents.

Authors
Dressman, HK; Bild, A; Garst, J; Harpole, D; Potti, A
MLA Citation
Dressman, HK, Bild, A, Garst, J, Harpole, D, and Potti, A. "Genomic signatures in non-small-cell lung cancer: targeting the targeted therapies." Curr Oncol Rep 8.4 (July 2006): 252-257. (Review)
PMID
17254524
Source
pubmed
Published In
Current Oncology Reports
Volume
8
Issue
4
Publish Date
2006
Start Page
252
End Page
257

Molecular profile and partial functional analysis of novel endothelial cell-derived growth factors that regulate hematopoiesis.

Recent progress has been made in the identification of the osteoblastic cellular niche for hematopoietic stem cells (HSCs) within the bone marrow (BM). Attempts to identify the soluble factors that regulate HSC self-renewal have been less successful. We have demonstrated that primary human brain endothelial cells (HUBECs) support the ex vivo amplification of primitive human BM and cord blood cells capable of repopulating non-obese diabetic/severe combined immunodeficient repopulating (SCID) mice (SCID repopulating cells [SRCs]). In this study, we sought to characterize the soluble hematopoietic activity produced by HUBECs and to identify the growth factors secreted by HUBECs that contribute to this HSC-supportive effect. Extended noncontact HUBEC cultures supported an eight-fold increase in SRCs when combined with thrombopoietin, stem cell factor, and Flt-3 ligand compared with input CD34(+) cells or cytokines alone. Gene expression analysis of HUBEC biological replicates identified 65 differentially expressed, nonredundant transcripts without annotated hematopoietic activity. Gene ontology studies of the HUBEC transcriptome revealed a high concentration of genes encoding extracellular proteins with cell-cell signaling function. Functional analyses demonstrated that adrenomedullin, a vasodilatory hormone, synergized with stem cell factor and Flt-3 ligand to induce the proliferation of primitive human CD34(+)CD38(-)lin(-) cells and promoted the expansion of CD34(+) progenitors in culture. These data demonstrate the potential of primary HUBECs as a reservoir for the discovery of novel secreted proteins that regulate human hematopoiesis.

Authors
Chute, JP; Muramoto, GG; Dressman, HK; Wolfe, G; Chao, NJ; Lin, S
MLA Citation
Chute, JP, Muramoto, GG, Dressman, HK, Wolfe, G, Chao, NJ, and Lin, S. "Molecular profile and partial functional analysis of novel endothelial cell-derived growth factors that regulate hematopoiesis." Stem Cells 24.5 (May 2006): 1315-1327.
PMID
16373696
Source
pubmed
Published In
Stem Cells
Volume
24
Issue
5
Publish Date
2006
Start Page
1315
End Page
1327
DOI
10.1634/stemcells.2005-0029

ALK1 signalling analysis identifies angiogenesis related genes and reveals disparity between TGF-beta and constitutively active receptor induced gene expression.

BACKGROUND: TGF-beta1 is an important angiogenic factor involved in the different aspects of angiogenesis and vessel maintenance. TGF-beta signalling is mediated by the TbetaRII/ALK5 receptor complex activating the Smad2/Smad3 pathway. In endothelial cells TGF-beta utilizes a second type I receptor, ALK1, activating the Smad1/Smad5 pathway. Consequently, a perturbance of ALK1, ALK5 or TbetaRII activity leads to vascular defects. Mutations in ALK1 cause the vascular disorder hereditary hemorrhagic telangiectasia (HHT). METHODS: The identification of ALK1 and not ALK5 regulated genes in endothelial cells, might help to better understand the development of HHT. Therefore, the human microvascular endothelial cell line HMEC-1 was infected with a recombinant constitutively active ALK1 adenovirus, and gene expression was studied by using gene arrays and quantitative real-time PCR analysis. RESULTS: After 24 hours, 34 genes were identified to be up-regulated by ALK1 signalling. Analysing ALK1 regulated gene expression after 4 hours revealed 13 genes to be up- and 2 to be down-regulated. Several of these genes, including IL-8, ET-1, ID1, HPTPeta and TEAD4 are reported to be involved in angiogenesis. Evaluation of ALK1 regulated gene expression in different human endothelial cell types was not in complete agreement. Further on, disparity between constitutively active ALK1 and TGF-beta1 induced gene expression in HMEC-1 cells and primary HUVECs was observed. CONCLUSION: Gene array analysis identified 49 genes to be regulated by ALK1 signalling and at least 14 genes are reported to be involved in angiogenesis. There was substantial agreement between the gene array and quantitative real-time PCR data. The angiogenesis related genes might be potential HHT modifier genes. In addition, the results suggest endothelial cell type specific ALK1 and TGF-beta signalling.

Authors
Lux, A; Salway, F; Dressman, HK; Kröner-Lux, G; Hafner, M; Day, PJR; Marchuk, DA; Garland, J
MLA Citation
Lux, A, Salway, F, Dressman, HK, Kröner-Lux, G, Hafner, M, Day, PJR, Marchuk, DA, and Garland, J. "ALK1 signalling analysis identifies angiogenesis related genes and reveals disparity between TGF-beta and constitutively active receptor induced gene expression. (Published online)" BMC Cardiovasc Disord 6 (April 4, 2006): 13-.
PMID
16594992
Source
pubmed
Published In
BMC Cardiovascular Disorders
Volume
6
Publish Date
2006
Start Page
13
DOI
10.1186/1471-2261-6-13

Toxicogenomic studies of the rat brain at an early time point following acute sarin exposure.

We have studied sarin-induced global gene expression patterns at an early time point (2 h: 0.5 x LD50) using Affymetrix Rat Neurobiology U34 chips and male Sprague-Dawley rats. A total of 46 genes showed statistically significant alterations from control levels. Three gene categories contained more of the altered genes than any other groups: ion channel (8 genes) and calcium channel and binding proteins (6 genes). Alterations were also found in the following gene groups: ATPases and ATP-based transporters (4), growth factors (4), G-protein-coupled receptor pathway-related molecules (3), neurotransmission and neurotransmitter transporters (3), cytoskeletal and cell adhesion molecules (2), hormones (2), mitochondria-associated proteins (2), myelin proteins (2), stress-activated molecules (2), cytokine (1), caspase (1), GABAnergic (1), glutamergic (1), immediate early gene (1), prostaglandin (1), transcription factor (1), and tyrosine phosphorylation molecule (1). Persistent alteration of the following genes also were noted: Arrb1, CaMKIIa, CaMKIId, Clcn5, IL-10, c-Kit, and Plp1, suggesting altered GPCR, kinase, channel, and cytokine pathways. Selected genes from the microarray data were further validated using relative RT-PCR. Some of those genes (GFAP, NF-H, CaMKIIa, Calm, and MBP) have been shown by other laboratories and ours, to be involved in the pathogenesis of sarin-induced pathology and organophosphate-induced delayed neurotoxicity (OPIDN). Induction of both proapoptotic (Bcl2l11, Casp6) and antiapoptotic (Bcl-X) genes, besides suppression of p21, suggest complex cell death/protection-related mechanisms operating early on. Principal component analysis (PCA) of the expression data confirmed that the changes in gene expression are a function of sarin exposure, since the control and treatment groups separated clearly. Our model (based on current and previous studies) indicates that both degenerative and regenerative pathways are activated early and contribute to the level of neurodegeneration at a later time, leading to neuro-pathological alterations.

Authors
Damodaran, TV; Greenfield, ST; Patel, AG; Dressman, HK; Lin, SK; Abou-Donia, MB
MLA Citation
Damodaran, TV, Greenfield, ST, Patel, AG, Dressman, HK, Lin, SK, and Abou-Donia, MB. "Toxicogenomic studies of the rat brain at an early time point following acute sarin exposure." Neurochem Res 31.3 (March 2006): 367-381.
PMID
16733813
Source
pubmed
Published In
Neurochemical Research
Volume
31
Issue
3
Publish Date
2006
Start Page
367
End Page
381
DOI
10.1007/s11064-005-9023-5

Gene-expression patterns predict phenotypes of immune-mediated thrombosis.

Antiphospholipid antibody syndrome (APS) is a complex autoimmune thrombotic disorder with defined clinical phenotypes. Although not all patients with elevated antiphospholipid antibody (aPLA) levels develop complications, the severity of these potential events mandates aggressive and extended lifelong anti-thrombotic therapy. One hundred twenty-nine patients (57 patients with APS and venous thromboembolism [VTE], 32 patients with VTE without aPLA, 32 patients with aPLA only, and 8 healthy patients) were enrolled. RNA from peripheral-blood collection was used for DNA microarray analysis. Patterns of gene expression that characterize APS as well as thrombosis in the presence of aPLA were identified by hierarchical clustering and binary regression methods. Gene-expression profiles identify and predict individuals with APS from patients with VTE without aPLA. Importantly, similar methods identified expression profiles that accurately predicted those patients with aPLA at high risk for thrombotic events. All profiles were validated in independent cohorts of patients. The ability to predict APS, but more importantly, those patients at risk for venous thrombosis, represents a paradigm for a genomic approach that can be applied to other populations of patients with venous thrombosis, providing for more effective clinical management of disease, while also reflecting the possible underlying biologic processes.

Authors
Potti, A; Bild, A; Dressman, HK; Lewis, DA; Nevins, JR; Ortel, TL
MLA Citation
Potti, A, Bild, A, Dressman, HK, Lewis, DA, Nevins, JR, and Ortel, TL. "Gene-expression patterns predict phenotypes of immune-mediated thrombosis." Blood 107.4 (February 15, 2006): 1391-1396.
PMID
16263789
Source
pubmed
Published In
Blood
Volume
107
Issue
4
Publish Date
2006
Start Page
1391
End Page
1396
DOI
10.1182/blood-2005-07-2669

Gene expression profiles of the rat brain both immediately and 3 months following acute sarin exposure.

We have studied sarin-induced global gene expression patterns at an early time point (15 min; 0.5xLD50) and a later time point (3 months; 1xLD50) using Affymetrix: Rat Neurobiology U34 chips in male, Sprague-Dawley rats and have identified a total of 65 (early) and 38 (late) genes showing statistically significant alterations from control levels at 15 min and 3 months, respectively. At the early time point, those that are classified as ion channel, cytoskeletal and cell adhesion molecules, in addition to neuropeptides and their receptors predominated over all other groups. The other groups included: cholinergic signaling, calcium channel and binding proteins, transporters, chemokines, GABAnergic, glutamatergic, aspartate, catecholaminergic, nitric oxide synthase, purinergic, and serotonergic signaling molecules. At the late time point, genes that are classified as calcium channel and binding proteins, cytoskeletal and cell adhesion molecules and GABAnergic signaling molecules were most prominent. Seven molecules (Ania-9, Arrb-1, CX-3C, Gabab-1d, Nos-2a, Nrxn-1b, PDE2) were identified that showed altered persistent expression in both time points. Selected genes from each of these time points were further validated using semi quantitative RT-PCR approaches. Some of the genes that were identified in the present study have been shown to be involved in organophosphate-induced neurotoxicity by both other groups as well as ours. Principal component analysis (PCA) of the expression data from both time points was used for comparative analysis of the gene expression, which indicated that the changes in gene expression were a function of dose and time of euthanasia after the treatment. Our model also predicts that besides dose and duration of post-treatment period, age and possibly other factors may be playing important roles in the regulation of pathways, leading to the neurotoxicity.

Authors
Damodaran, TV; Patel, AG; Greenfield, ST; Dressman, HK; Lin, SM; Abou-Donia, MB
MLA Citation
Damodaran, TV, Patel, AG, Greenfield, ST, Dressman, HK, Lin, SM, and Abou-Donia, MB. "Gene expression profiles of the rat brain both immediately and 3 months following acute sarin exposure." Biochem Pharmacol 71.4 (February 14, 2006): 497-520.
PMID
16376859
Source
pubmed
Published In
Biochemical Pharmacology
Volume
71
Issue
4
Publish Date
2006
Start Page
497
End Page
520
DOI
10.1016/j.bcp.2005.10.051

Gene expression profiles of multiple breast cancer phenotypes and response to neoadjuvant chemotherapy.

PURPOSE: Breast cancer is a heterogeneous disease, and markers for disease subtypes and therapy response remain poorly defined. For that reason, we employed a prospective neoadjuvant study in locally advanced breast cancer to identify molecular signatures of gene expression correlating with known prognostic clinical phenotypes, such as inflammatory breast cancer or the presence of hypoxia. In addition, we defined molecular signatures that correlate with response to neoadjuvant chemotherapy. EXPERIMENTAL DESIGN: Tissue was collected under ultrasound guidance from patients with stage IIB/III breast cancer before four cycles of neoadjuvant liposomal doxorubicin paclitaxel chemotherapy combined with local whole breast hyperthermia. Gene expression analysis was done using Affymetrix U133 Plus 2.0 GeneChip arrays. RESULTS: Gene expression patterns were identified that defined the phenotypes of inflammatory breast cancer as well as tumor hypoxia. In addition, molecular signatures were identified that predicted the persistence of malignancy in the axillary lymph nodes after neoadjuvant chemotherapy. This persistent lymph node signature significantly correlated with disease-free survival in two separate large populations of breast cancer patients. CONCLUSIONS: Gene expression signatures have the capacity to identify clinically significant features of breast cancer and can predict which individual patients are likely to be resistant to neoadjuvant therapy, thus providing the opportunity to guide treatment decisions.

Authors
Dressman, HK; Hans, C; Bild, A; Olson, JA; Rosen, E; Marcom, PK; Liotcheva, VB; Jones, EL; Vujaskovic, Z; Marks, J; Dewhirst, MW; West, M; Nevins, JR; Blackwell, K
MLA Citation
Dressman, HK, Hans, C, Bild, A, Olson, JA, Rosen, E, Marcom, PK, Liotcheva, VB, Jones, EL, Vujaskovic, Z, Marks, J, Dewhirst, MW, West, M, Nevins, JR, and Blackwell, K. "Gene expression profiles of multiple breast cancer phenotypes and response to neoadjuvant chemotherapy." Clin Cancer Res 12.3 Pt 1 (February 1, 2006): 819-826.
PMID
16467094
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
12
Issue
3 Pt 1
Publish Date
2006
Start Page
819
End Page
826
DOI
10.1158/1078-0432.CCR-05-1447

Oncogenic pathway signatures in human cancers as a guide to targeted therapies.

The development of an oncogenic state is a complex process involving the accumulation of multiple independent mutations that lead to deregulation of cell signalling pathways central to the control of cell growth and cell fate. The ability to define cancer subtypes, recurrence of disease and response to specific therapies using DNA microarray-based gene expression signatures has been demonstrated in multiple studies. Various studies have also demonstrated the potential for using gene expression profiles for the analysis of oncogenic pathways. Here we show that gene expression signatures can be identified that reflect the activation status of several oncogenic pathways. When evaluated in several large collections of human cancers, these gene expression signatures identify patterns of pathway deregulation in tumours and clinically relevant associations with disease outcomes. Combining signature-based predictions across several pathways identifies coordinated patterns of pathway deregulation that distinguish between specific cancers and tumour subtypes. Clustering tumours based on pathway signatures further defines prognosis in respective patient subsets, demonstrating that patterns of oncogenic pathway deregulation underlie the development of the oncogenic phenotype and reflect the biology and outcome of specific cancers. Predictions of pathway deregulation in cancer cell lines are also shown to predict the sensitivity to therapeutic agents that target components of the pathway. Linking pathway deregulation with sensitivity to therapeutics that target components of the pathway provides an opportunity to make use of these oncogenic pathway signatures to guide the use of targeted therapeutics.

Authors
Bild, AH; Yao, G; Chang, JT; Wang, Q; Potti, A; Chasse, D; Joshi, M-B; Harpole, D; Lancaster, JM; Berchuck, A; Olson, JA; Marks, JR; Dressman, HK; West, M; Nevins, JR
MLA Citation
Bild, AH, Yao, G, Chang, JT, Wang, Q, Potti, A, Chasse, D, Joshi, M-B, Harpole, D, Lancaster, JM, Berchuck, A, Olson, JA, Marks, JR, Dressman, HK, West, M, and Nevins, JR. "Oncogenic pathway signatures in human cancers as a guide to targeted therapies." Nature 439.7074 (January 19, 2006): 353-357.
PMID
16273092
Source
pubmed
Published In
Nature
Volume
439
Issue
7074
Publish Date
2006
Start Page
353
End Page
357
DOI
10.1038/nature04296

Assessing incomplete deprotection of microarray oligonucleotides in situ.

En masse analysis of gene structure and function by array technologies will have a lasting and profound effect on biology and medicine. This impact can be compromised by low quality of probes within arrays, which we show can be caused by incomplete removal of chemical protecting groups. To solve this quality control problem, we present a sensitive, specific and facile method to detect these groups in situ on arrays using monoclonal antibodies and existing instrumentation. Screening of microarrays with these monoclonal antibodies should guide the consideration given to data derived from these and should enhance the accuracy of the results obtained.

Authors
Dressman, HK; Barley-Maloney, L; Rowlette, L-L; Agris, PF; Garcia-Blanco, MA
MLA Citation
Dressman, HK, Barley-Maloney, L, Rowlette, L-L, Agris, PF, and Garcia-Blanco, MA. "Assessing incomplete deprotection of microarray oligonucleotides in situ." Nucleic Acids Res 34.19 (2006): e131-.
PMID
17020916
Source
pubmed
Published In
Nucleic Acids Research
Volume
34
Issue
19
Publish Date
2006
Start Page
e131
DOI
10.1093/nar/gkl713

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

A differentiation block in erythroid cells lacking erythroid krupple-like factor (EKLF).

Authors
Gallagher, PG; Arcasoy, MO; Vayda, SE; Dressman, HK; Bieker, JJ; Bodine, DM
MLA Citation
Gallagher, PG, Arcasoy, MO, Vayda, SE, Dressman, HK, Bieker, JJ, and Bodine, DM. "A differentiation block in erythroid cells lacking erythroid krupple-like factor (EKLF)." November 16, 2005.
Source
wos-lite
Published In
Blood
Volume
106
Issue
11
Publish Date
2005
Start Page
157A
End Page
157A

Distinctions in the specificity of E2F function revealed by gene expression signatures.

The E2F family of transcription factors provides essential activities for coordinating the control of cellular proliferation and cell fate. Both E2F1 and E2F3 proteins have been shown to be particularly important for cell proliferation, whereas the E2F1 protein has the capacity to promote apoptosis. To explore the basis for this specificity of function, we used DNA microarray analysis to probe for the distinctions in the two E2F activities. Gene expression profiles that distinguish either E2F1- or E2F3-expressing cells from quiescent cells are enriched in genes encoding cell cycle and DNA replication activities, consistent with many past studies. E2F1 profile is also enriched in genes known to function in apoptosis. We also identified patterns of gene expression that specifically differentiate the activity of E2F1 and E2F3; this profile is enriched in genes known to function in mitosis. The specificity of E2F function has been attributed to protein interactions mediated by the marked box domain, and we now show that chimeric E2F proteins generate expression signatures that reflect the origin of the marked box, thus linking the biochemical mechanism for specificity of function with specificity of gene activation.

Authors
Black, EP; Hallstrom, T; Dressman, HK; West, M; Nevins, JR
MLA Citation
Black, EP, Hallstrom, T, Dressman, HK, West, M, and Nevins, JR. "Distinctions in the specificity of E2F function revealed by gene expression signatures." Proc Natl Acad Sci U S A 102.44 (November 1, 2005): 15948-15953.
PMID
16249342
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
102
Issue
44
Publish Date
2005
Start Page
15948
End Page
15953
DOI
10.1073/pnas.0504300102

Oncogenic pathway signatures in human cancers as a guide to targeted therapies.

Authors
Bild, AH; Yao, G; Chang, JT; Wang, QL; Potti, A; Harpole, D; Lancaster, J; Berchuck, A; Olson, JA; Marks, J; Dressman, HK; West, M; Nevins, JR
MLA Citation
Bild, AH, Yao, G, Chang, JT, Wang, QL, Potti, A, Harpole, D, Lancaster, J, Berchuck, A, Olson, JA, Marks, J, Dressman, HK, West, M, and Nevins, JR. "Oncogenic pathway signatures in human cancers as a guide to targeted therapies." November 2005.
Source
wos-lite
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
14
Issue
11
Publish Date
2005
Start Page
2743S
End Page
2743S

Gene expression changes and signaling events associated with the direct antimelanoma effect of IFN-gamma.

IFN-gamma plays a role in the response to melanoma indirectly through its effect on the immune system and directly through its antiproliferative and proapoptotic effects on melanoma cells. To understand the molecular basis for the direct antimelanoma effect of IFN-gamma, we studied IFN-induced changes in gene expression and signaling among three human melanoma cell lines (DM6, DM93, and 501mel). These were resistant to the antimelanoma effect of IFN-alpha, and only DM6 cells exhibited growth inhibition and apoptosis with IFN-gamma. Through DNA microarray analysis, we found that the antimelanoma effect of IFN-gamma in DM6 was associated with the down-regulation of multiple genes involved in G-protein signaling and phospholipase C activation (including Rap2B and calpain 3) as well as the down-regulation of genes involved in melanocyte/melanoma survival (MITF and SLUG), apoptosis inhibition (Bcl2A1 and galectin-3), and cell cycling (CDK2). The antimelanoma effect of IFN-gamma was also associated with the up-regulation of the proapoptotic dependence receptor UNC5H2 and the Wnt inhibitor Dkk-1. Whereas both IFNs were able to activate Stat1 in all cell lines, the delayed activation of the extracellular signal-regulated kinase, p38, and c-Jun NH2-terminal kinase mitogen-activated protein kinases occurred only in DM6 with IFN-gamma, and the effect of IFN-gamma on cell growth and survival as well as gene expression in DM6 was dependent on the coordinate activation of MEK1 and p38. These findings provide new insights into the signaling events and gene expression changes associated with growth inhibition and apoptosis in melanoma and may thereby assist in identifying new targets for the treatment of melanoma.

Authors
Gollob, JA; Sciambi, CJ; Huang, Z; Dressman, HK
MLA Citation
Gollob, JA, Sciambi, CJ, Huang, Z, and Dressman, HK. "Gene expression changes and signaling events associated with the direct antimelanoma effect of IFN-gamma." Cancer Res 65.19 (October 1, 2005): 8869-8877.
PMID
16204058
Source
pubmed
Published In
Cancer Research
Volume
65
Issue
19
Publish Date
2005
Start Page
8869
End Page
8877
DOI
10.1158/0008-5472.CAN-05-1387

Gene expression changes and signaling events associated with the direct antimelanoma effect of IFN-gamma

Authors
Gollob, JA; Sciambi, CJ; Huang, ZQ; Dressman, HK
MLA Citation
Gollob, JA, Sciambi, CJ, Huang, ZQ, and Dressman, HK. "Gene expression changes and signaling events associated with the direct antimelanoma effect of IFN-gamma." CANCER RESEARCH 65.19 (October 1, 2005): 8869-8877.
Source
wos-lite
Published In
Cancer Research
Volume
65
Issue
19
Publish Date
2005
Start Page
8869
End Page
8877
DOI
10.1158/008-5472.can-05-1387

DIG--a system for gene annotation and functional discovery.

SUMMARY: We describe a database and information discovery system named DIG (Duke Integrated Genomics) designed to facilitate the process of gene annotation and the discovery of functional context. The DIG system collects and organizes gene annotation and functional information, and includes tools that support an understanding of genes in a functional context by providing a framework for integrating and visualizing gene expression, protein interaction and literature-based interaction networks.

Authors
Delong, M; Yao, G; Wang, Q; Dobra, A; Black, EP; Chang, JT; Bild, A; West, M; Nevins, JR; Dressman, H
MLA Citation
Delong, M, Yao, G, Wang, Q, Dobra, A, Black, EP, Chang, JT, Bild, A, West, M, Nevins, JR, and Dressman, H. "DIG--a system for gene annotation and functional discovery." Bioinformatics (Oxford, England) 21.13 (July 2005): 2957-2959.
PMID
15870167
Source
epmc
Published In
Bioinformatics
Volume
21
Issue
13
Publish Date
2005
Start Page
2957
End Page
2959
DOI
10.1093/bioinformatics/bti467

Expression analysis of genes involved in ovarian cancer metastasis.

Authors
Martino, MA; Elahi, A; Sutphen, R; Klippel, C; Boren, T; Dressman, HK; Berchuck, A; Lancaster, JM
MLA Citation
Martino, MA, Elahi, A, Sutphen, R, Klippel, C, Boren, T, Dressman, HK, Berchuck, A, and Lancaster, JM. "Expression analysis of genes involved in ovarian cancer metastasis." June 1, 2005.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
23
Issue
16
Publish Date
2005
Start Page
464S
End Page
464S

Gene expression profiling and genetic markers in glioblastoma survival.

Despite the strikingly grave prognosis for older patients with glioblastomas, significant variability in patient outcome is experienced. To explore the potential for developing improved prognostic capabilities based on the elucidation of potential biological relationships, we did analyses of genes commonly mutated, amplified, or deleted in glioblastomas and DNA microarray gene expression data from tumors of glioblastoma patients of age >50 for whom survival is known. No prognostic significance was associated with genetic changes in epidermal growth factor receptor (amplified in 17 of 41 patients), TP53 (mutated in 11 of 41 patients), p16INK4A (deleted in 15 of 33 patients), or phosphatase and tensin homologue (mutated in 15 of 41 patients). Statistical analysis of the gene expression data in connection with survival involved exploration of regression models on small subsets of genes, based on computational search over multiple regression models with cross-validation to assess predictive validity. The analysis generated a set of regression models that, when weighted and combined according to posterior probabilities implied by the statistical analysis, identify patterns in expression of a small subset of genes that are associated with survival and have value in assessing survival risks. The dominant genes across such multiple regression models involve three key genes-SPARC (Osteonectin), Doublecortex, and Semaphorin3B-which play key roles in cellular migration processes. Additional analysis, based on statistical graphical association models constructed using similar computational analysis methods, reveals other genes which support the view that multiple mediators of tumor invasion may be important prognostic factor in glioblastomas in older patients.

Authors
Rich, JN; Hans, C; Jones, B; Iversen, ES; McLendon, RE; Rasheed, BKA; Dobra, A; Dressman, HK; Bigner, DD; Nevins, JR; West, M
MLA Citation
Rich, JN, Hans, C, Jones, B, Iversen, ES, McLendon, RE, Rasheed, BKA, Dobra, A, Dressman, HK, Bigner, DD, Nevins, JR, and West, M. "Gene expression profiling and genetic markers in glioblastoma survival." Cancer Res 65.10 (May 15, 2005): 4051-4058.
PMID
15899794
Source
pubmed
Published In
Cancer Research
Volume
65
Issue
10
Publish Date
2005
Start Page
4051
End Page
4058
DOI
10.1158/0008-5472.CAN-04-3936

Patterns of gene expression that characterize long-term survival in advanced stage serous ovarian cancers.

PURPOSE: A better understanding of the underlying biology of invasive serous ovarian cancer is critical for the development of early detection strategies and new therapeutics. The objective of this study was to define gene expression patterns associated with favorable survival. EXPERIMENTAL DESIGN: RNA from 65 serous ovarian cancers was analyzed using Affymetrix U133A microarrays. This included 54 stage III/IV cases (30 short-term survivors who lived <3 years and 24 long-term survivors who lived >7 years) and 11 stage I/II cases. Genes were screened on the basis of their level of and variability in expression, leaving 7,821 for use in developing a predictive model for survival. A composite predictive model was developed that combines Bayesian classification tree and multivariate discriminant models. Leave-one-out cross-validation was used to select and evaluate models. RESULTS: Patterns of genes were identified that distinguish short-term and long-term ovarian cancer survivors. The expression model developed for advanced stage disease classified all 11 early-stage ovarian cancers as long-term survivors. The MAL gene, which has been shown to confer resistance to cancer therapy, was most highly overexpressed in short-term survivors (3-fold compared with long-term survivors, and 29-fold compared with early-stage cases). These results suggest that gene expression patterns underlie differences in outcome, and an examination of the genes that provide this discrimination reveals that many are implicated in processes that define the malignant phenotype. CONCLUSIONS: Differences in survival of advanced ovarian cancers are reflected by distinct patterns of gene expression. This biological distinction is further emphasized by the finding that early-stage cancers share expression patterns with the advanced stage long-term survivors, suggesting a shared favorable biology.

Authors
Berchuck, A; Iversen, ES; Lancaster, JM; Pittman, J; Luo, J; Lee, P; Murphy, S; Dressman, HK; Febbo, PG; West, M; Nevins, JR; Marks, JR
MLA Citation
Berchuck, A, Iversen, ES, Lancaster, JM, Pittman, J, Luo, J, Lee, P, Murphy, S, Dressman, HK, Febbo, PG, West, M, Nevins, JR, and Marks, JR. "Patterns of gene expression that characterize long-term survival in advanced stage serous ovarian cancers." Clin Cancer Res 11.10 (May 15, 2005): 3686-3696.
PMID
15897565
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
11
Issue
10
Publish Date
2005
Start Page
3686
End Page
3696
DOI
10.1158/1078-0432.CCR-04-2398

Standardizing global gene expression analysis between laboratories and across platforms.

To facilitate collaborative research efforts between multi-investigator teams using DNA microarrays, we identified sources of error and data variability between laboratories and across microarray platforms, and methods to accommodate this variability. RNA expression data were generated in seven laboratories, which compared two standard RNA samples using 12 microarray platforms. At least two standard microarray types (one spotted, one commercial) were used by all laboratories. Reproducibility for most platforms within any laboratory was typically good, but reproducibility between platforms and across laboratories was generally poor. Reproducibility between laboratories increased markedly when standardized protocols were implemented for RNA labeling, hybridization, microarray processing, data acquisition and data normalization. Reproducibility was highest when analysis was based on biological themes defined by enriched Gene Ontology (GO) categories. These findings indicate that microarray results can be comparable across multiple laboratories, especially when a common platform and set of procedures are used.

Authors
Bammler, T; Beyer, RP; Bhattacharya, S; Boorman, GA; Boyles, A; Bradford, BU; Bumgarner, RE; Bushel, PR; Chaturvedi, K; Choi, D; Cunningham, ML; Deng, S; Dressman, HK; Fannin, RD; Farin, FM; Freedman, JH; Fry, RC; Harper, A; Humble, MC; Hurban, P; Kavanagh, TJ; Kaufmann, WK; Kerr, KF; Jing, L; Lapidus, JA; Lasarev, MR; Li, J; Li, Y-J; Lobenhofer, EK; Lu, X; Malek, RL; Milton, S; Nagalla, SR; O'malley, JP; Palmer, VS; Pattee, P; Paules, RS; Perou, CM; Phillips, K; Qin, L-X; Qiu, Y; Quigley, SD et al.
MLA Citation
Bammler, T, Beyer, RP, Bhattacharya, S, Boorman, GA, Boyles, A, Bradford, BU, Bumgarner, RE, Bushel, PR, Chaturvedi, K, Choi, D, Cunningham, ML, Deng, S, Dressman, HK, Fannin, RD, Farin, FM, Freedman, JH, Fry, RC, Harper, A, Humble, MC, Hurban, P, Kavanagh, TJ, Kaufmann, WK, Kerr, KF, Jing, L, Lapidus, JA, Lasarev, MR, Li, J, Li, Y-J, Lobenhofer, EK, Lu, X, Malek, RL, Milton, S, Nagalla, SR, O'malley, JP, Palmer, VS, Pattee, P, Paules, RS, Perou, CM, Phillips, K, Qin, L-X, Qiu, Y, and Quigley, SD et al. "Standardizing global gene expression analysis between laboratories and across platforms." Nat Methods 2.5 (May 2005): 351-356.
PMID
15846362
Source
pubmed
Published In
Nature Methods
Volume
2
Issue
5
Publish Date
2005
Start Page
351
End Page
356
DOI
10.1038/nmeth754

Transcriptional response to endotoxin in young adult and aged rats.

Authors
Burch, LH; Yang, IV; Dressman, HK; Schwartz, DA; Guo, H; Kuo, PC; Cohen, HJ; Lagoo-Deenadayalan, SA
MLA Citation
Burch, LH, Yang, IV, Dressman, HK, Schwartz, DA, Guo, H, Kuo, PC, Cohen, HJ, and Lagoo-Deenadayalan, SA. "Transcriptional response to endotoxin in young adult and aged rats." April 2005.
Source
wos-lite
Published In
Journal of American Geriatrics Society
Volume
53
Issue
4
Publish Date
2005
Start Page
S70
End Page
S70

Standardizing global gene expression analysis between laboratories and across platforms

To facilitate collaborative research efforts between multi-investigator teams using DNA microarrays, we identified sources of error and data variability between laboratories and across microarray platforms, and methods to accommodate this variability. RNA expression data were generated in seven laboratories, which compared two standard RNA samples using 12 microarray platforms. At least two standard microarray types (one spotted, one commercial) were used by all laboratories. Reproducibility for most platforms within any laboratory was typically good, but reproducibility between platforms and across laboratories was generally poor. Reproducibility between laboratories increased markedly when standardized protocols were implemented for RNA labeling, hybridization, microarray processing, data acquisition and data normalization. Reproducibility was highest when analysis was based on biological themes defined by enriched Gene Ontology (GO) categories. These findings indicate that microarray results can be comparable across multiple laboratories, especially when a common platform and set of procedures are used. © 2005 Nature Publishing Group.

Authors
Bammler, T; Beyer, RP; Bhattacharya, S; Boorman, GA; Boyles, A; Bradford, BU; Bumgarner, RE; Bushel, PR; Chaturvedi, K; Choi, D; al, E
MLA Citation
Bammler, T, Beyer, RP, Bhattacharya, S, Boorman, GA, Boyles, A, Bradford, BU, Bumgarner, RE, Bushel, PR, Chaturvedi, K, Choi, D, and al, E. "Standardizing global gene expression analysis between laboratories and across platforms." Nature Methods 2.5 (2005): 1-6.
Source
scival
Published In
Nature Methods
Volume
2
Issue
5
Publish Date
2005
Start Page
1
End Page
6
DOI
10.1038/NMETH754

Gene expression phenotypes of atherosclerosis.

OBJECTIVE: Fulfilling the promise of personalized medicine by developing individualized diagnostic and therapeutic strategies for atherosclerosis will depend on a detailed understanding of the genes and gene variants that contribute to disease susceptibility and progression. To that end, our group has developed a nonbiased approach congruent with the multigenic concept of complex diseases by identifying gene expression patterns highly associated with disease states in human target tissues. METHODS AND RESULTS: We have analyzed a collection of human aorta samples with varying degrees of atherosclerosis to identify gene expression patterns that predict a disease state or potential susceptibility. We find gene expression signatures that relate to each of these disease measures and are reliable and robust in predicting the classification for new samples with >93% in each analysis. The genes that provide the predictive power include many previously suspected to play a role in atherosclerosis and additional genes without prior association with atherosclerosis. CONCLUSIONS: Hence, we are reporting a novel method for generating a molecular phenotype of disease and then identifying genes whose discriminatory capability strongly implicates their potential roles in human atherosclerosis.

Authors
Seo, D; Wang, T; Dressman, H; Herderick, EE; Iversen, ES; Dong, C; Vata, K; Milano, CA; Rigat, F; Pittman, J; Nevins, JR; West, M; Goldschmidt-Clermont, PJ
MLA Citation
Seo, D, Wang, T, Dressman, H, Herderick, EE, Iversen, ES, Dong, C, Vata, K, Milano, CA, Rigat, F, Pittman, J, Nevins, JR, West, M, and Goldschmidt-Clermont, PJ. "Gene expression phenotypes of atherosclerosis." Arterioscler Thromb Vasc Biol 24.10 (October 2004): 1922-1927.
PMID
15297278
Source
pubmed
Published In
Arteriosclerosis, Thrombosis, and Vascular Biology
Volume
24
Issue
10
Publish Date
2004
Start Page
1922
End Page
1927
DOI
10.1161/01.ATV.0000141358.65242.1f

Integrated modeling of clinical and gene expression information for personalized prediction of disease outcomes.

We describe a comprehensive modeling approach to combining genomic and clinical data for personalized prediction in disease outcome studies. This integrated clinicogenomic modeling framework is based on statistical classification tree models that evaluate the contributions of multiple forms of data, both clinical and genomic, to define interactions of multiple risk factors that associate with the clinical outcome and derive predictions customized to the individual patient level. Gene expression data from DNA microarrays is represented by multiple, summary measures that we term metagenes; each metagene characterizes the dominant common expression pattern within a cluster of genes. A case study of primary breast cancer recurrence demonstrates that models using multiple metagenes combined with traditional clinical risk factors improve prediction accuracy at the individual patient level, delivering predictions more accurate than those made by using a single genomic predictor or clinical data alone. The analysis also highlights issues of communicating uncertainty in prediction and identifies combinations of clinical and genomic risk factors playing predictive roles. Implicated metagenes identify gene subsets with the potential to aid biological interpretation. This framework will extend to incorporate any form of data, including emerging forms of genomic data, and provides a platform for development of models for personalized prognosis.

Authors
Pittman, J; Huang, E; Dressman, H; Horng, C-F; Cheng, SH; Tsou, M-H; Chen, C-M; Bild, A; Iversen, ES; Huang, AT; Nevins, JR; West, M
MLA Citation
Pittman, J, Huang, E, Dressman, H, Horng, C-F, Cheng, SH, Tsou, M-H, Chen, C-M, Bild, A, Iversen, ES, Huang, AT, Nevins, JR, and West, M. "Integrated modeling of clinical and gene expression information for personalized prediction of disease outcomes." Proc Natl Acad Sci U S A 101.22 (June 1, 2004): 8431-8436.
PMID
15152076
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
101
Issue
22
Publish Date
2004
Start Page
8431
End Page
8436
DOI
10.1073/pnas.0401736101

Prediction of optimal versus suboptimal cytoreduction of advanced-stage serous ovarian cancer with the use of microarrays.

OBJECTIVE: The purpose of this study was to define gene expression patterns that are associated with the optimal versus suboptimal debulking of advanced-stage serous ovarian cancers. STUDY DESIGN: RNA from 44 advanced serous ovarian cancers (19 optimal, 25 suboptimal) was evaluated with microarrays that contain >22,000 genes. Genes were screened on the basis of their association with debulking status to obtain the top 120 differentially expressed genes. These genes were then used to develop a predictive model for debulking status, which was subjected to out-of-sample cross validation. RESULTS: We found that patterns of expression of 32 genes can distinguish between optimal and suboptimal debulking with 72.7% predictive accuracy. An analysis of the data that were based on clusters of co-ordinately expressed genes resulted in only a marginal improvement in predictive accuracy (75%). CONCLUSION: These data support the hypothesis that favorable survival that is associated with optimal debulking of advanced ovarian cancers is due to, at least in part, the underlying biologic characteristics of these cancers.

Authors
Berchuck, A; Iversen, ES; Lancaster, JM; Dressman, HK; West, M; Nevins, JR; Marks, JR
MLA Citation
Berchuck, A, Iversen, ES, Lancaster, JM, Dressman, HK, West, M, Nevins, JR, and Marks, JR. "Prediction of optimal versus suboptimal cytoreduction of advanced-stage serous ovarian cancer with the use of microarrays." Am J Obstet Gynecol 190.4 (April 2004): 910-925.
PMID
15118612
Source
pubmed
Published In
American Journal of Obstetrics & Gynecology
Volume
190
Issue
4
Publish Date
2004
Start Page
910
End Page
925
DOI
10.1016/j.ajog.2004.02.005

Elevated expression of a subset of interferon inducible genes in primary bone marrow cells expressing p185 Bcr-Abl versus p210 Bcr-Abl by DNA microarray analysis.

p185 Bcr-Abl has a more aggressive biological/clinical leukemia phenotype than p210 Bcr-Abl. In this study, we examined differential gene expression using microarrays to determine if upregulation or downregulation of specific genes may explain the distinct phenotypes produced by the two Bcr-Abl forms. RNA was collected from mouse bone marrow mononuclear cells expressing equivalent levels of p185 or p210, and the RNAs were subjected to microarray analysis. Significant differences in gene expression were observed on hierarchical clustering. A group of interferon-gamma-inducible genes, including those encoding a family of 47 kDa GTPases, were significantly increased in p185 versus p210. This family of GTPases has previously been implicated in interferon-gamma-induced resistance against intracellular pathogens, however their exact cellular functions are unknown. Our data suggest that their increased expression may contribute to the biological/clinical phenotype associated with p185.

Authors
Advani, AS; Dressman, HK; Quiroz, M; Taylor, GA; Pendergast, AM
MLA Citation
Advani, AS, Dressman, HK, Quiroz, M, Taylor, GA, and Pendergast, AM. "Elevated expression of a subset of interferon inducible genes in primary bone marrow cells expressing p185 Bcr-Abl versus p210 Bcr-Abl by DNA microarray analysis." Leuk Res 28.3 (March 2004): 285-294.
PMID
14687624
Source
pubmed
Published In
Leukemia Research
Volume
28
Issue
3
Publish Date
2004
Start Page
285
End Page
294

Gene microarray analysis of human brain arteriovenous malformations.

OBJECTIVE: Human brain arteriovenous malformations (BAVMs) display abnormal expression of various angiogenesis-related genes and their products. We examined gene expression patterns in BAVMs by the gene microarray technique. METHODS: We analyzed BAVM and control brain samples obtained by temporal lobectomy for medically intractable seizure by Affymetrix Human Gene Set U95Av2 (Affymetrix, Inc., Santa Clara, CA). The gene microarray data were compared with new and previously published data that used conventional molecular biology techniques. RESULTS: We analyzed six BAVM and five control brain samples. From 12,625 gene probes assayed, 1781 gene probes showed differential expression between BAVMs and controls. BAVM samples had a gene expression pattern that was distinct from those of control brain samples. Increased messenger ribonucleic acid expression of vascular endothelial growth factor A was accompanied by increased expression of its protein product. A majority of the gene data was in agreement with previously published data. The gene microarray data generated a new testable hypothesis regarding integrin, and we found increased expression of integrin alphavbeta3 protein in BAVMs. CONCLUSION: The gene expression pattern of BAVMs was distinct from those of control brain samples. We verified the gene microarray data by demonstrating that increased gene expression levels for angiogenesis-related molecules were accompanied by increased levels of their protein product expression. The gene microarray technique may be a useful tool to study multiple pathways simultaneously in BAVM specimens.

Authors
Hashimoto, T; Lawton, MT; Wen, G; Yang, G-Y; Chaly, T; Stewart, CL; Dressman, HK; Barbaro, NM; Marchuk, DA; Young, WL
MLA Citation
Hashimoto, T, Lawton, MT, Wen, G, Yang, G-Y, Chaly, T, Stewart, CL, Dressman, HK, Barbaro, NM, Marchuk, DA, and Young, WL. "Gene microarray analysis of human brain arteriovenous malformations." Neurosurgery 54.2 (February 2004): 410-423.
PMID
14744289
Source
pubmed
Published In
Neurosurgery
Volume
54
Issue
2
Publish Date
2004
Start Page
410
End Page
423

Gene expression patterns that characterize advanced stage serous ovarian cancers.

OBJECTIVE: To identify gene expression patterns that characterize advanced stage serous ovarian cancers by using microarray expression analysis. METHODS: Using genome-wide expression analysis, we compared a series of 31 advanced stage (III or IV) serous ovarian cancers from patients who survived either less than 2 years or more than 7 years with three normal ovarian epithelial samples. Array findings were validated by analysis of expression of the insulin-like growth factor binding protein 2 (IGFBP2) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) genes using quantitative real-time polymerase chain reaction (QRT-PCR). RESULTS: Hierarchical clustering identified patterns of gene expression that distinguished cancer from normal ovarian epithelium. We also identified gene expression patterns that distinguish cancers on the basis of patient survival. These genes include many that are associated with immune function. Expression of IGFBP2 and TRAIL genes measured by array and QRT-PCR analysis demonstrated correlation coefficients of 0.63 and 0.78, respectively. CONCLUSION: Global expression analysis can identify expression patterns and individual genes that contribute to ovarian cancer development and outcome. Many of the genes that determine ovarian cancer survival are associated with the immune response, suggesting that immune function influences ovarian cancer virulence. With the generation of newer arrays with more transcripts, larger studies are possible to fully characterize genetic signatures that predict survival that may ultimately be used to guide therapeutic decision-making.

Authors
Lancaster, JM; Dressman, HK; Whitaker, RS; Havrilesky, L; Gray, J; Marks, JR; Nevins, JR; Berchuck, A
MLA Citation
Lancaster, JM, Dressman, HK, Whitaker, RS, Havrilesky, L, Gray, J, Marks, JR, Nevins, JR, and Berchuck, A. "Gene expression patterns that characterize advanced stage serous ovarian cancers." J Soc Gynecol Investig 11.1 (January 2004): 51-59.
PMID
14706684
Source
pubmed
Published In
Journal of the Society for Gynecologic Investigation (Elsevier)
Volume
11
Issue
1
Publish Date
2004
Start Page
51
End Page
59

Prediction of optimal versus suboptimal cytoreduction of advanced-stage serious ovarian cancer with the use of microarrays

Authors
Andrew, B; Iversen, ES; Lancaster, JM; Dressman, HK; West, M; Nevins, JR; Marks, JR; Miller, BE
MLA Citation
Andrew, B, Iversen, ES, Lancaster, JM, Dressman, HK, West, M, Nevins, JR, Marks, JR, and Miller, BE. "Prediction of optimal versus suboptimal cytoreduction of advanced-stage serious ovarian cancer with the use of microarrays." Women's Oncology Review 4.3 (2004): 203-204.
Source
scival
Published In
Women's Oncology Review
Volume
4
Issue
3
Publish Date
2004
Start Page
203
End Page
204
DOI
10.1080/14733400412331312585

Empirical evaluation of data transformations and ranking statistics for microarray analysis

There are many options in handling microarray data that can affect study conclusions, sometimes drastically. Working with a two-color platform, this study uses ten spike-in microarray experiments to evaluate the relative effectiveness of some of these options for the experimental goal of detecting differential expression. We consider two data transformations, background subtraction and intensity normalization, as well as six different statistics for detecting differentially expressed genes. Findings support the use of an intensity-based normalization procedure and also indicate that local background subtraction can be detrimental for effectively detecting differential expression. We also verify that robust statistics out-perform t-statistics in identifying differentially expressed genes when there are few replicates. Finally, we find that choice of image analysis software can also substantially influence experimental conclusions. © Oxford University Press 2004; all rights reserved.

Authors
Qin, L-X; Kerr, KF; Boyles, A; Dressman, HK; Freedman, JH; Li, Y-J; Malek, RL; Schwartz, DA; Slifer, S; Speer, MC; al, E
MLA Citation
Qin, L-X, Kerr, KF, Boyles, A, Dressman, HK, Freedman, JH, Li, Y-J, Malek, RL, Schwartz, DA, Slifer, S, Speer, MC, and al, E. "Empirical evaluation of data transformations and ranking statistics for microarray analysis." Nucleic Acids Research 32.18 (2004): 5471-5479.
PMID
15479783
Source
scival
Published In
Nucleic Acids Research
Volume
32
Issue
18
Publish Date
2004
Start Page
5471
End Page
5479
DOI
10.1093/nar/gkh866

Predictive models that combine multiple forms of genomic and clinical data to achieve personalized prediction of outcomes in breast cancer

Authors
Pittman, JL; Tebbit, CL; Black, EP; Dressman, HK; Huang, ES; Olson, JA; Marks, JR; Marcom, PK; Huang, AT; West, M; Nevins, JR
MLA Citation
Pittman, JL, Tebbit, CL, Black, EP, Dressman, HK, Huang, ES, Olson, JA, Marks, JR, Marcom, PK, Huang, AT, West, M, and Nevins, JR. "Predictive models that combine multiple forms of genomic and clinical data to achieve personalized prediction of outcomes in breast cancer." 2004.
Source
wos-lite
Published In
Breast Cancer Research and Treatment
Volume
88
Publish Date
2004
Start Page
S21
End Page
S22

Towards integrated clinico-genomic models for personalized medicine: combining gene expression signatures and clinical factors in breast cancer outcomes prediction.

Genomic data, particularly genome-scale measures of gene expression derived from DNA microarray studies, has the potential for adding enormous information to the analysis of biological phenotypes. Perhaps the most successful application of this data has been in the characterization of human cancers, including the ability to predict clinical outcomes. Nevertheless, most analyses have used gene expression profiles to define broad group distinctions, similar to the use of traditional clinical risk factors. As a result, there remains considerable heterogeneity within the broadly defined groups and thus predictions fall short of providing accurate predictions for individual patients. One strategy to resolve this heterogeneity is to make use of multiple gene expression patterns that are more powerful in defining individual characteristics and predicting outcomes than any single gene expression pattern. Statistical tree-based classification systems provide a framework for assessing multiple patterns, that we term metagenes, selecting those that are most capable of resolving the biological heterogeneity. Moreover, this framework provides a mechanism to combine multiple forms of data, both genomic and clinical, to most effectively characterize individual patients and achieve the goal of personalized predictions of clinical outcomes.

Authors
Nevins, JR; Huang, ES; Dressman, H; Pittman, J; Huang, AT; West, M
MLA Citation
Nevins, JR, Huang, ES, Dressman, H, Pittman, J, Huang, AT, and West, M. "Towards integrated clinico-genomic models for personalized medicine: combining gene expression signatures and clinical factors in breast cancer outcomes prediction." Hum Mol Genet 12 Spec No 2 (October 15, 2003): R153-R157. (Review)
PMID
12928487
Source
pubmed
Published In
Human Molecular Genetics
Volume
12 Spec No 2
Publish Date
2003
Start Page
R153
End Page
R157
DOI
10.1093/hmg/ddg287

Gene expression phenotypes of oncogenic signaling pathways.

Authors
Huang, ES; Black, EP; Dressman, H; West, M; Nevins, JR
MLA Citation
Huang, ES, Black, EP, Dressman, H, West, M, and Nevins, JR. "Gene expression phenotypes of oncogenic signaling pathways." Cell Cycle 2.5 (September 2003): 415-417. (Review)
PMID
12963829
Source
pubmed
Published In
Cell Cycle
Volume
2
Issue
5
Publish Date
2003
Start Page
415
End Page
417

Neoadjuvant comparisons of aromatase inhibitors and tamoxifen: pretreatment determinants of response and on-treatment effect.

Adjuvant endocrine therapy reduces the risk of relapse and death from early stage hormone receptor positive breast cancer. However, tamoxifen is only partially effective because of the development of tumor resistance. Aromatase inhibitors (letrozole, anastrozole and exemestane) are also prone to the development of resistance but the pharmacologic action (estrogen deprivation) is distinct and so different mechanisms may be responsible. The problem of endocrine resistance can be directly studied in patients by examining the relationship between predictive tumor biomarkers and clinical outcome. In an example of a prospectively planned biomarker study, tumor samples were examined from a randomized trial of neoadjuvant endocrine treatment in which letrozole proved more effective than tamoxifen in terms of the rate of breast conservation and tumor regression. Interestingly letrozole was more effective at all levels of ER expression and was particularly more efficacious than tamoxifen for tumors that expressed HER1 and/or HER2 (with ER). This suggests that HER1/2 predicts primary tamoxifen resistance and relative sensitivity to potent estrogen deprivation, perhaps because HER1/2 signaling promotes the partial agonist effects of tamoxifen. A Phase 2 study of neoadjuvant letrozole is now underway to focus on gene expression profiling as a mechanism to further investigate the transcriptional programs that underlie resistance and sensitivity to estrogen deprivation. Expression profiles taken at baseline and after 1 month of therapy reveal dramatic reductions in the expression from genes responsible for DNA replication and synthesis, cell cycle progression, suppression of apoptosis and tissue invasion. When enough profiles have been generated it should be possible to detect complex interaction patterns that correctly reclassify ER+ disease into treatment responsive and resistant categories with high probability.

Authors
Ellis, MJ; Rosen, E; Dressman, H; Marks, J
MLA Citation
Ellis, MJ, Rosen, E, Dressman, H, and Marks, J. "Neoadjuvant comparisons of aromatase inhibitors and tamoxifen: pretreatment determinants of response and on-treatment effect." J Steroid Biochem Mol Biol 86.3-5 (September 2003): 301-307. (Review)
PMID
14623525
Source
pubmed
Published In
The Journal of Steroid Biochemistry and Molecular Biology
Volume
86
Issue
3-5
Publish Date
2003
Start Page
301
End Page
307

Distinct gene expression phenotypes of cells lacking Rb and Rb family members.

The study of tumor suppressor gene function has been aided by the creation of discrete gene alterations in the mouse. One such example can be seen in the study of tumor suppressor gene function in general and the retinoblastoma (Rb) tumor suppressor in particular. Because the phenotype of a cell is a direct reflection of the gene activity within that cell, a comprehensive analysis of changes in gene activity resulting from the loss of Rb function has the potential to greatly enhance our understanding of Rb biology. We have used DNA microarray analysis to identify gene expression profiles in wild-type and Rb-null mouse embryo fibroblasts, as well as cells lacking other Rb family members, as an approach to developing a more complete understanding of Rb function. In so doing, we have identified gene expression phenotypes that characterize the loss of Rb function, that distinguish a Rb-null cell from a wild-type cell as well as a p107/p130-null cell, and that identify gene regulatory pathways unique to these events. Importantly, the Rb gene expression patterns can identify murine tumors that result from Rb loss of function. We suggest that this is an approach to the eventual understanding of gene regulatory pathways that define a phenotypic state, including those events that lead to tumor development.

Authors
Black, EP; Huang, E; Dressman, H; Rempel, R; Laakso, N; Asa, SL; Ishida, S; West, M; Nevins, JR
MLA Citation
Black, EP, Huang, E, Dressman, H, Rempel, R, Laakso, N, Asa, SL, Ishida, S, West, M, and Nevins, JR. "Distinct gene expression phenotypes of cells lacking Rb and Rb family members." Cancer Res 63.13 (July 1, 2003): 3716-3723.
PMID
12839964
Source
pubmed
Published In
Cancer Research
Volume
63
Issue
13
Publish Date
2003
Start Page
3716
End Page
3723

Gene expression phenotypic models that predict the activity of oncogenic pathways.

High-density DNA microarrays measure expression of large numbers of genes in one assay. The ability to find underlying structure in complex gene expression data sets and rigorously test association of that structure with biological conditions is essential to developing multi-faceted views of the gene activity that defines cellular phenotype. We sought to connect features of gene expression data with biological hypotheses by integrating 'metagene' patterns from DNA microarray experiments in the characterization and prediction of oncogenic phenotypes. We applied these techniques to the analysis of regulatory pathways controlled by the genes HRAS (Harvey rat sarcoma viral oncogene homolog), MYC (myelocytomatosis viral oncogene homolog) and E2F1, E2F2 and E2F3 (encoding E2F transcription factors 1, 2 and 3, respectively). The phenotypic models accurately predict the activity of these pathways in the context of normal cell proliferation. Moreover, the metagene models trained with gene expression patterns evoked by ectopic production of Myc or Ras proteins in primary tissue culture cells properly predict the activity of in vivo tumor models that result from deregulation of the MYC or HRAS pathways. We conclude that these gene expression phenotypes have the potential to characterize the complex genetic alterations that typify the neoplastic state, whether in vitro or in vivo, in a way that truly reflects the complexity of the regulatory pathways that are affected.

Authors
Huang, E; Ishida, S; Pittman, J; Dressman, H; Bild, A; Kloos, M; D'Amico, M; Pestell, RG; West, M; Nevins, JR
MLA Citation
Huang, E, Ishida, S, Pittman, J, Dressman, H, Bild, A, Kloos, M, D'Amico, M, Pestell, RG, West, M, and Nevins, JR. "Gene expression phenotypic models that predict the activity of oncogenic pathways." Nat Genet 34.2 (June 2003): 226-230.
PMID
12754511
Source
pubmed
Published In
Nature Genetics
Volume
34
Issue
2
Publish Date
2003
Start Page
226
End Page
230
DOI
10.1038/ng1167

Gene expression predictors of breast cancer outcomes.

BACKGROUND: Correlation of risk factors with genomic data promises to provide specific treatment for individual patients, and needs interpretation of complex, multivariate patterns in gene expression data, as well as assessment of their ability to improve clinical predictions. We aimed to predict nodal metastatic states and relapse for breast cancer patients. METHODS: We analysed DNA microarray data from samples of primary breast tumours, using non-linear statistical analyses to assess multiple patterns of interactions of groups of genes that have predictive value for the individual patient, with respect to lymph node metastasis and cancer recurrence. FINDINGS: We identified aggregate patterns of gene expression (metagenes) that associate with lymph node status and recurrence, and that are capable of predicting outcomes in individual patients with about 90% accuracy. The metagenes defined distinct groups of genes, suggesting different biological processes underlying these two characteristics of breast cancer. Initial external validation came from similarly accurate predictions of nodal status of a small sample in a distinct population. INTERPRETATION: Multiple aggregate measures of profiles of gene expression define valuable predictive associations with lymph node metastasis and disease recurrence for individual patients. Gene expression data have the potential to aid accurate, individualised, prognosis. Importantly, these data are assessed in terms of precise numerical predictions, with ranges of probabilities of outcome. Precise and statistically valid assessments of risks specific for patients, will ultimately be of most value to clinicians faced with treatment decisions.

Authors
Huang, E; Cheng, SH; Dressman, H; Pittman, J; Tsou, MH; Horng, CF; Bild, A; Iversen, ES; Liao, M; Chen, CM; West, M; Nevins, JR; Huang, AT
MLA Citation
Huang, E, Cheng, SH, Dressman, H, Pittman, J, Tsou, MH, Horng, CF, Bild, A, Iversen, ES, Liao, M, Chen, CM, West, M, Nevins, JR, and Huang, AT. "Gene expression predictors of breast cancer outcomes." Lancet 361.9369 (May 10, 2003): 1590-1596.
PMID
12747878
Source
pubmed
Published In
The Lancet
Volume
361
Issue
9369
Publish Date
2003
Start Page
1590
End Page
1596
DOI
10.1016/S0140-6736(03)13308-9

Erratum: Gene expression phenotypic models that predict the activity of oncogenic pathways (Nature Genetics (2003) 34 (226-230))

Authors
Huang, E; Ishida, S; Pittmann, J; Dressman, H; Bild, A; Kloos, M; D'Amico, M; Pestell, RG; West, M; Nevins, JR
MLA Citation
Huang, E, Ishida, S, Pittmann, J, Dressman, H, Bild, A, Kloos, M, D'Amico, M, Pestell, RG, West, M, and Nevins, JR. "Erratum: Gene expression phenotypic models that predict the activity of oncogenic pathways (Nature Genetics (2003) 34 (226-230))." Nature Genetics 34.4 (2003): 465--.
Source
scival
Published In
Nature Genetics
Volume
34
Issue
4
Publish Date
2003
Start Page
465-
DOI
10.1038/ng0803-465

Elevated expression of numerous interferon inducible genes in primary bone marrow cells expressing p185 Bcr-Abl versus p210 Bcr-Abl by DNA microarray analysis.

Authors
Advani, AS; Dressman, HK; Quiroz, M; Taylor, GA; Pendergast, AM
MLA Citation
Advani, AS, Dressman, HK, Quiroz, M, Taylor, GA, and Pendergast, AM. "Elevated expression of numerous interferon inducible genes in primary bone marrow cells expressing p185 Bcr-Abl versus p210 Bcr-Abl by DNA microarray analysis." November 16, 2002.
Source
wos-lite
Published In
Blood
Volume
100
Issue
11
Publish Date
2002
Start Page
584A
End Page
584A

Dissecting the fidelity of bacteriophage RB69 DNA polymerase: site-specific modulation of fidelity by polymerase accessory proteins.

Bacteriophage RB69 encodes a replicative B-family DNA polymerase (RB69 gp43) with an associated proofreading 3' exonuclease. Crystal structures have been determined for this enzyme with and without DNA substrates. We previously described the mutation rates and kinds of mutations produced in vivo by the wild-type (Pol(+) Exo(+)) enzyme, an exonuclease-deficient mutator variant (Pol(+) Exo(-)), mutator variants with substitutions at Tyr(567) in the polymerase active site (Pol(M) Exo(+)), and the double mutator Pol(M) Exo(-). Comparing the mutational spectra of the Pol(+) Exo(-) and Pol(+) Exo(+) enzymes revealed the patterns and efficiencies of proofreading, while Tyr(567) was identified as an important determinant of base-selection fidelity. Here, we sought to determine how well the fidelities of the same enzymes are reflected in vitro. Compared to their behavior in vivo, the three mutator polymerases exhibited modestly higher mutation rates in vitro and their mutational predilections were also somewhat different. Although the RB69 gp43 accessory proteins exerted little or no effect on total mutation rates in vitro, they strongly affected mutation rates at many specific sites, increasing some rates and decreasing others.

Authors
Bebenek, A; Carver, GT; Dressman, HK; Kadyrov, FA; Haseman, JK; Petrov, V; Konigsberg, WH; Karam, JD; Drake, JW
MLA Citation
Bebenek, A, Carver, GT, Dressman, HK, Kadyrov, FA, Haseman, JK, Petrov, V, Konigsberg, WH, Karam, JD, and Drake, JW. "Dissecting the fidelity of bacteriophage RB69 DNA polymerase: site-specific modulation of fidelity by polymerase accessory proteins." Genetics 162.3 (November 2002): 1003-1018.
PMID
12454051
Source
pubmed
Published In
Genetics
Volume
162
Issue
3
Publish Date
2002
Start Page
1003
End Page
1018

Predicting the clinical status of human breast cancer by using gene expression profiles.

Prognostic and predictive factors are indispensable tools in the treatment of patients with neoplastic disease. For the most part, such factors rely on a few specific cell surface, histological, or gross pathologic features. Gene expression assays have the potential to supplement what were previously a few distinct features with many thousands of features. We have developed Bayesian regression models that provide predictive capability based on gene expression data derived from DNA microarray analysis of a series of primary breast cancer samples. These patterns have the capacity to discriminate breast tumors on the basis of estrogen receptor status and also on the categorized lymph node status. Importantly, we assess the utility and validity of such models in predicting the status of tumors in crossvalidation determinations. The practical value of such approaches relies on the ability not only to assess relative probabilities of clinical outcomes for future samples but also to provide an honest assessment of the uncertainties associated with such predictive classifications on the basis of the selection of gene subsets for each validation analysis. This latter point is of critical importance in the ability to apply these methodologies to clinical assessment of tumor phenotype.

Authors
West, M; Blanchette, C; Dressman, H; Huang, E; Ishida, S; Spang, R; Zuzan, H; Olson, JA; Marks, JR; Nevins, JR
MLA Citation
West, M, Blanchette, C, Dressman, H, Huang, E, Ishida, S, Spang, R, Zuzan, H, Olson, JA, Marks, JR, and Nevins, JR. "Predicting the clinical status of human breast cancer by using gene expression profiles." Proc Natl Acad Sci U S A 98.20 (September 25, 2001): 11462-11467.
PMID
11562467
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
98
Issue
20
Publish Date
2001
Start Page
11462
End Page
11467
DOI
10.1073/pnas.201162998

Interacting fidelity defects in the replicative DNA polymerase of bacteriophage RB69.

The DNA polymerases (gp43s) of the related bacteriophages T4 and RB69 are B family (polymerase alpha class) enzymes that determine the fidelity of phage DNA replication. A T4 whose gene 43 has been mutationally inactivated can be replicated by a cognate RB69 gp43 encoded by a recombinant plasmid in T4-infected Escherichia coli. We used this phage-plasmid complementation assay to obtain rapid and sensitive measurements of the mutational specificities of mutator derivatives of the RB69 enzyme. RB69 gp43s lacking proofreading function (Exo(-) enzymes) and/or substituted with alanine, serine, or threonine at the conserved polymerase function residue Tyr(567) (Pol(Y567(A/S/T)) enzymes) were examined for their effects on the reversion of specific mutations in the T4 rII gene and on forward mutation in the T4 rI gene. The results reveal that Tyr(567) is a key determinant of the fidelity of base selection and that the Pol and Exo functions are strongly coupled in this B family enzyme. In vitro assays show that the Pol(Y567A) Exo(-) enzyme generates mispairs more frequently but extends them less efficiently than does a Pol(+) Exo(-) enzyme. Other replicative DNA polymerases may control fidelity by strategies similar to those used by RB69 gp43.

Authors
Bebenek, A; Dressman, HK; Carver, GT; Ng, S; Petrov, V; Yang, G; Konigsberg, WH; Karam, JD; Drake, JW
MLA Citation
Bebenek, A, Dressman, HK, Carver, GT, Ng, S, Petrov, V, Yang, G, Konigsberg, WH, Karam, JD, and Drake, JW. "Interacting fidelity defects in the replicative DNA polymerase of bacteriophage RB69." J Biol Chem 276.13 (March 30, 2001): 10387-10397.
PMID
11133987
Source
pubmed
Published In
The Journal of biological chemistry
Volume
276
Issue
13
Publish Date
2001
Start Page
10387
End Page
10397
DOI
10.1074/jbc.M007707200

Lysis and lysis inhibition in bacteriophage T4: rV mutations reside in the holin t gene.

Upon infecting populations of susceptible host cells, T-even bacteriophages maximize their yield by switching from lysis at about 25 to 35 min at 37 degrees C after infection by a single phage particle to long-delayed lysis (lysis inhibition) under conditions of sequential infection occurring when free phages outnumber host cells. The timing of lysis depends upon gene t and upon one or more rapid-lysis (r) genes whose inactivation prevents lysis inhibition. t encodes a holin that mediates the movement of the T4 endolysin though the inner cell membrane to its target, the cell wall. The rI protein has been proposed to sense superinfection. Of the five reasonably well characterized r genes, only two, rI and rV, are clearly obligatory for lysis inhibition. We show here that rV mutations are alleles of t that probably render the t protein unable to respond to the lysis inhibition signal. The tr alleles cluster in the 5' third of t and produce a strong r phenotype, whereas conditional-lethal t alleles produce the classical t phenotype (inability to lyse) and other t alleles produce additional, still poorly understood phenotypes. tr mutations are dominant to t+, a result that suggests specific ways to probe T4 holin function.

Authors
Dressman, HK; Drake, JW
MLA Citation
Dressman, HK, and Drake, JW. "Lysis and lysis inhibition in bacteriophage T4: rV mutations reside in the holin t gene." J Bacteriol 181.14 (July 1999): 4391-4396.
PMID
10400598
Source
pubmed
Published In
Journal of bacteriology
Volume
181
Issue
14
Publish Date
1999
Start Page
4391
End Page
4396

The roles of the bacteriophage T4 r genes in lysis inhibition and fine-structure genetics: a new perspective.

Seldom has the study of a set of genes contributed more to our understanding of molecular genetics than has the characterization of the rapid-lysis genes of bacteriophage T4. For example, T4 rII mutants were used to define gene structure and mutagen effects at the molecular level and to help unravel the genetic code. The large-plaque morphology of these mutants reflects a block in expressing lysis inhibition (LIN), the ability to delay lysis for several hours in response to sensing external related phages attacking the cell, which is a unique and highly adaptive attribute of the T4 family of phages. However, surprisingly little is known about the mechanism of LIN, or how the various r genes affect its expression. Here, we review the extensive old literature about the r genes and the lysis process and try to sort out the major players affecting lysis inhibition. We confirm that superinfection can induce lysis inhibition even while infected cells are lysing, suggesting that the signal response is virtually instantaneous and thus probably the result of post-translational regulation. We identify the rI gene as ORF tk.-2, based on sequence analysis of canonical rI mutants. The rI gene encodes a peptide of 97 amino acids (Mr = 11.1 kD; pI = 4.8) that probably is secreted into the periplasmic space. This gene is widely conserved among T-even phage. We then present a model for LIN, postulating that rI is largely responsible for regulating the gpt holin protein in response to superinfection. The evidence suggests that the rIIA and B genes are not directly involved in lysis inhibition; rather, when they are absent, an alternate pathway for lysis develops which depends on the presence of genes from any of several possible prophages and is not sensitive to lysis inhibition.

Authors
Paddison, P; Abedon, ST; Dressman, HK; Gailbreath, K; Tracy, J; Mosser, E; Neitzel, J; Guttman, B; Kutter, E
MLA Citation
Paddison, P, Abedon, ST, Dressman, HK, Gailbreath, K, Tracy, J, Mosser, E, Neitzel, J, Guttman, B, and Kutter, E. "The roles of the bacteriophage T4 r genes in lysis inhibition and fine-structure genetics: a new perspective." Genetics 148.4 (April 1998): 1539-1550.
PMID
9560373
Source
pubmed
Published In
Genetics
Volume
148
Issue
4
Publish Date
1998
Start Page
1539
End Page
1550

Retention of replication fidelity by a DNA polymerase functioning in a distantly related environment.

The primary structures of the replicative DNA polymerases (gp43s) of bacteriophage T4 and its distant phylogenetic relative RB69 are diverged, retaining only 61% identity and 74% similarity. Nevertheless, RB69 gp43 substitutes effectively for T4 gp43 in T4 DNA replication in vivo. We show here that RB69 gp43 replicates T4 genomes in vivo with a fidelity similar to that achieved by T4 gp43. Furthermore, replication by RB69 gp43 in the distantly related environment does not enhance the mutator activities of mutations in T4 genes that encode other components of the multienzyme DNA replicase. We also show that the fidelities of RB69 gp43 and T4 gp43 are both high in vitro and that they are similarly and sharply reduced in vivo by mutations that eliminate the 3'-exonucleolytic proofreading function. We conclude that gp43 interactions with the other replication proteins are probably nonessential for polymerase fidelity.

Authors
Dressman, HK; Wang, CC; Karam, JD; Drake, JW
MLA Citation
Dressman, HK, Wang, CC, Karam, JD, and Drake, JW. "Retention of replication fidelity by a DNA polymerase functioning in a distantly related environment." Proc Natl Acad Sci U S A 94.15 (July 22, 1997): 8042-8046.
PMID
9223311
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
94
Issue
15
Publish Date
1997
Start Page
8042
End Page
8046

Immunoglobulin gene rearrangement in multiple myeloma: limitations of Southern blot analysis.

Thirty-six patients with early and advanced multiple myeloma were investigated with Southern blot analysis to determine the presence of immunoglobulin gene rearrangement as evidence of clonality. Rearrangements were not uniformly found, being detected in only 14 of 19 patients with newly diagnosed myeloma and in 15 of 17 cases of clinically advanced myeloma. A correlation between percentage of bone marrow plasma cells and detection of immunoglobulin gene rearrangement was noted; however, in four cases of early myeloma with > 10% marrow plasma cells, no rearrangement was found. These results suggest that Southern blot analysis may not be an optimal method for the determination of clonality in plasma cell dyscrasias or, alternatively, that a proportion of the plasma cells found on bone marrow examination in some patients with early myeloma may not be monoclonal.

Authors
Humphries, JE; Dressman, HK; Williams, ME
MLA Citation
Humphries, JE, Dressman, HK, and Williams, ME. "Immunoglobulin gene rearrangement in multiple myeloma: limitations of Southern blot analysis." Hum Pathol 22.10 (October 1991): 966-971.
PMID
1842385
Source
pubmed
Published In
Human Pathology
Volume
22
Issue
10
Publish Date
1991
Start Page
966
End Page
971
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