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Dive into the research topics where Paul H. Duray is active.

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Featured researches published by Paul H. Duray.


Nature Genetics | 2003

High frequency of BRAF mutations in nevi.

Pamela M. Pollock; Ursula Harper; Katherine S. Hansen; Laura M. Yudt; Mitchell S. Stark; Christiane M. Robbins; Tracy Moses; Galen Hostetter; Urs Wagner; John W. Kakareka; Ghadi Salem; Tom Pohida; Peter J. Heenan; Paul H. Duray; Olli Kallioniemi; Nicholas K. Hayward; Jeffrey M. Trent; Paul S. Meltzer

To evaluate the timing of mutations in BRAF (v-raf murine sarcoma viral oncogene homolog B1) during melanocytic neoplasia, we carried out mutation analysis on microdissected melanoma and nevi samples. We observed mutations resulting in the V599E amino-acid substitution in 41 of 60 (68%) melanoma metastases, 4 of 5 (80%) primary melanomas and, unexpectedly, in 63 of 77 (82%) nevi. These data suggest that mutational activation of the RAS/RAF/MAPK pathway in nevi is a critical step in the initiation of melanocytic neoplasia but alone is insufficient for melanoma tumorigenesis.


Proceedings of the National Academy of Sciences of the United States of America | 2003

Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma

Giao Q. Phan; James Chih-Hsin Yang; Richard M. Sherry; Patrick Hwu; Suzanne L. Topalian; Douglas J. Schwartzentruber; Nicholas P. Restifo; Leah R. Haworth; Claudia A. Seipp; Linda J. Freezer; Kathleen E. Morton; Sharon A. Mavroukakis; Paul H. Duray; Seth M. Steinberg; James P. Allison; Thomas A. Davis; Steven A. Rosenberg

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a critical immunoregulatory molecule (expressed on activated T cells and a subset of regulatory T cells) capable of down-regulating T cell activation. Blockade of CTLA-4 has been shown in animal models to improve the effectiveness of cancer immunotherapy. We thus treated 14 patients with metastatic melanoma by using serial i.v. administration of a fully human anti-CTLA-4 antibody (MDX-010) in conjunction with s.c. vaccination with two modified HLA-A*0201-restricted peptides from the gp100 melanoma-associated antigen, gp100:209–217(210M) and gp100:280–288(288V). This blockade of CTLA-4 induced grade III/IV autoimmune manifestations in six patients (43%), including dermatitis, enterocolitis, hepatitis, and hypophysitis, and mediated objective cancer regression in three patients (21%; two complete and one partial responses). This study establishes CTLA-4 as an important molecule regulating tolerance to “self” antigens in humans and suggests a role for CTLA-4 blockade in breaking tolerance to human cancer antigens for cancer immunotherapy.


Cancer Cell | 2002

Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma.

Ashani T. Weeraratna; Yuan Jiang; Galen Hostetter; Kevin Rosenblatt; Paul H. Duray; Michael L. Bittner; Jeffrey M. Trent

Gene expression profiling identified human melanoma cells demonstrating increased cell motility and invasiveness. The gene WNT5A best determined in vitro invasive behavior. Melanoma cells were transfected with vectors constitutively overexpressing Wnt5a. Consistent changes included actin reorganization and increased cell adhesion. No increase in beta-catenin expression or nuclear translocation was observed. There was, however, a dramatic increase in activated PKC. In direct correlation with Wnt5a expression and PKC activation, there was an increase in melanoma cell invasion. Blocking this pathway using antibodies to Frizzled-5, the receptor for Wnt5a, inhibited PKC activity and cellular invasion. Furthermore, Wnt5a expression in human melanoma biopsies directly correlated to increasing tumor grade. These observations support a role for Wnt5a in human melanoma progression.


Cancer Cell | 2002

Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome

Michael L. Nickerson; Michelle B. Warren; Jorge R. Toro; Vera Matrosova; Gladys M. Glenn; Maria L. Turner; Paul H. Duray; Maria J. Merino; Peter L. Choyke; Christian P. Pavlovich; Nirmala Sharma; McClellan M. Walther; David J. Munroe; Robert Hill; Eamonn R. Maher; Cheryl R. Greenberg; Michael I. Lerman; W. Marston Linehan; Berton Zbar; Laura S. Schmidt

Birt-Hogg-Dubé (BHD) syndrome is a rare inherited genodermatosis characterized by hair follicle hamartomas, kidney tumors, and spontaneous pneumothorax. Recombination mapping in BHD families delineated the susceptibility locus to 700 kb on chromosome 17p11.2. Protein-truncating mutations were identified in a novel candidate gene in a panel of BHD families, with a 44% frequency of insertion/deletion mutations within a hypermutable C(8) tract. Tissue expression of the 3.8 kb transcript was widespread, including kidney, lung, and skin. The full-length BHD sequence predicted a novel protein, folliculin, that was highly conserved across species. Discovery of disease-causing mutations in BHD, a novel kidney cancer gene associated with renal oncocytoma or chromophobe renal cancer, will contribute to understanding the role of folliculin in pathways common to skin, lung, and kidney development.


American Journal of Human Genetics | 2003

Mutations in the Fumarate Hydratase Gene Cause Hereditary Leiomyomatosis and Renal Cell Cancer in Families in North America

Jorge R. Toro; Michael L. Nickerson; Ming-Hui Wei; Michelle B. Warren; Gladys M. Glenn; Maria L. Turner; Laveta Stewart; Paul H. Duray; Ousman Tourre; Nirmala Sharma; Peter L. Choyke; Pamela Stratton; Maria J. Merino; McClellan M. Walther; W. Marston Linehan; Laura S. Schmidt; Berton Zbar

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder characterized by smooth-muscle tumors of the skin and uterus and/or renal cancer. Although the identification of germline mutations in the fumarate hydratase (FH) gene in European families supports it as the susceptibility gene for HLRCC, its role in families in North America has not been studied. We screened for germline mutations in FH in 35 families with cutaneous leiomyomas. Sequence analysis revealed mutations in FH in 31 families (89%). Twenty different mutations in FH were identified, of which 18 were novel. Of these 20 mutations, 2 were insertions, 5 were small deletions that caused frameshifts leading to premature truncation of the protein, and 13 were missense mutations. Eleven unrelated families shared a common mutation: R190H. Eighty-one individuals (47 women and 34 men) had cutaneous leiomyomas. Ninety-eight percent (46/47) of women with cutaneous leiomyomas also had uterine leiomyomas. Eighty-nine percent (41/46) of women with cutaneous and uterine leiomyomas had a total hysterectomy, 44% at age < or =30 years. We identified 13 individuals in 5 families with unilateral and solitary renal tumors. Seven individuals from four families had papillary type II renal cell carcinoma, and another individual from one of these families had collecting duct carcinoma of the kidney. The present study shows that mutations in FH are associated with HLRCC in North America. HLRCC is associated with clinically significant uterine fibroids and aggressive renal tumors. The present study also expands the histologic spectrum of renal tumors and FH mutations associated with HLRCC.


Nature | 2001

Neonatal sunburn and melanoma in mice.

Frances P. Noonan; Juan A. Recio; Hisashi Takayama; Paul H. Duray; Miriam R. Anver; Walter L. Rush; Edward C. De Fabo; Glenn Merlino

Retrospective epidemiological data have indicated that cutaneous malignant melanoma may arise as a consequence of intense, intermittent exposure of the skin to ultraviolet radiation, particularly in children, rather than from the cumulative lifetime exposure that is associated with other forms of skin cancer. Here we use a genetically engineered mouse model to show that a single dose of burning ultraviolet radiation to neonates, but not adults, is necessary and sufficient to induce tumours with high penetrance which are reminiscent of human melanoma. Our results provide experimental support for epidemiological evidence that childhood sunburn poses a significant risk of developing this potentially fatal disease.


American Journal of Human Genetics | 2001

Birt-Hogg-Dubé syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2.

Laura S. Schmidt; Michelle B. Warren; Michael L. Nickerson; Gregor Weirich; Vera Matrosova; Jorge R. Toro; Maria L. Turner; Paul H. Duray; Maria J. Merino; Stephen M. Hewitt; Christian P. Pavlovich; Gladys M. Glenn; Cheryl R. Greenberg; W. Marston Linehan; Berton Zbar

Birt-Hogg-Dubé syndrome (BHD), an inherited autosomal genodermatosis characterized by benign tumors of the hair follicle, has been associated with renal neoplasia, lung cysts, and spontaneous pneumothorax. To identify the BHD locus, we recruited families with cutaneous lesions and associated phenotypic features of the BHD syndrome. We performed a genomewide scan in one large kindred with BHD and, by linkage analysis, localized the gene locus to the pericentromeric region of chromosome 17p, with a LOD score of 4.98 at D17S740 (recombination fraction 0). Two-point linkage analysis of eight additional families with BHD produced a maximum LOD score of 16.06 at D17S2196. Haplotype analysis identified critical recombinants and defined the minimal region of nonrecombination as being within a <4-cM distance between D17S1857 and D17S805. One additional family, which had histologically proved fibrofolliculomas, did not show evidence of linkage to chromosome 17p, suggesting genetic heterogeneity for BHD. The BHD locus lies within chromosomal band 17p11.2, a genomic region that, because of the presence of low-copy-number repeat elements, is unstable and that is associated with a number of diseases. Identification of the gene for BHD may reveal a new genetic locus responsible for renal neoplasia and for lung and hair-follicle developmental defects.


Cancer Research | 2005

Gene Expression Profiling of Human Sarcomas: Insights into Sarcoma Biology

Kristin Baird; Sean Davis; Cristina R. Antonescu; Ursula Harper; Robert L. Walker; Yidong Chen; Arthur A. Glatfelter; Paul H. Duray; Paul S. Meltzer

Sarcomas are a biologically complex group of tumors of mesenchymal origin. By using gene expression microarray analysis, we aimed to find clues into the cellular differentiation and oncogenic pathways active in these tumors as well as potential biomarkers and therapeutic targets. We examined 181 tumors representing 16 classes of human bone and soft tissue sarcomas on a 12,601-feature cDNA microarray. Remarkably, 2,766 probes differentially expressed across this sample set clearly delineated the various tumor classes. Several genes of potential biological and therapeutic interest were associated with each sarcoma type, including specific tyrosine kinases, transcription factors, and homeobox genes. We also identified subgroups of tumors within the liposarcomas, leiomyosarcomas, and malignant fibrous histiocytomas. We found significant gene ontology correlates for each tumor group and identified similarity to normal tissues by Gene Set Enrichment Analysis. Mutation analysis done on 275 tumor samples revealed that the high expression of epidermal growth factor receptor (EGFR) in certain tumors was not associated with gene mutations. Finally, to further the investigation of human sarcoma biology, we have created an online, publicly available, searchable database housing the data from the gene expression profiles of these tumors (http://watson.nhgri.nih.gov/sarcoma), allowing the user to interactively explore this data set in depth.


American Journal of Pathology | 2002

Evaluation of Non-Formalin Tissue Fixation for Molecular Profiling Studies

John W. Gillespie; Carolyn J.M. Best; Verena E. Bichsel; Kristina A. Cole; Susan F. Greenhut; Stephen M. Hewitt; Mamoun Ahram; Yvonne Gathright; Maria J. Merino; Robert L. Strausberg; Jonathan I. Epstein; Stanley R. Hamilton; Gallya Gannot; Galina V. Baibakova; Valerie S. Calvert; Michael J. Flaig; Rodrigo F. Chuaqui; Judi Herring; John Pfeifer; Emmanuel F. Petricoin; W. Marston Linehan; Paul H. Duray; G. Steven Bova; Michael R. Emmert-Buck

Using a general strategy for evaluating clinical tissue specimens, we found that 70% ethanol fixation and paraffin embedding is a useful method for molecular profiling studies. Human prostate and kidney were used as test tissues. The protein content of the samples was analyzed by one-dimensional gel electrophoresis, immunoblot, two-dimensional gel electrophoresis, and layered expression scanning. In each case, the fixed and embedded tissues produced results similar to that obtained from snap-frozen specimens, although the protein quantity was somewhat decreased. Recovery of mRNA was reduced in both quantity and quality in the ethanol-fixed samples, but was superior to that obtained from formalin-fixed samples and sufficient to perform reverse transcription polymerase chain reactions. Recovery of DNA from ethanol-fixed specimens was superior to formalin-fixed samples as determined by one-dimensional gel electrophoresis and polymerase chain reaction. In conclusion, specimens fixed in 70% ethanol and embedded in paraffin produce good histology and permit recovery of DNA, mRNA, and proteins sufficient for several downstream molecular analyses. Complete protocols and additional discussion of relevant issues are available on an accompanying website (http://cgap-mf.nih.gov/).


Electrophoresis | 2000

Proteomic analysis of laser capture microdissected human prostate cancer and in vitro prostate cell lines

David K. Ornstein; John W. Gillespie; Cloud P. Paweletz; Paul H. Duray; Judi Herring; Cathy D. Vocke; Suzanne L. Topalian; David G. Bostwick; W. Marston Linehan; Emanuel F. Petricoin; Michael R. Emmert-Buck

Specific populations of normal and malignant epithelium from three radical prostatectomy tissue specimes were procured by laser capture microdissection (LCM) and analyzed by two‐dimensional polyacrylamide gel electrophoresis (2‐D PAGE). Six proteins that were only seen in malignant cells and two proteins that were only seen in benign epithelium were reproducibly observed in two of two cases examined. Furthermore, these proteins were not observed in the 2‐D PAGE profiles from the patient‐matched microdissected stromal cell populations, but were seen in the protein profiles from the undissected whole cryostat sections. One of these proteins was determined to be prostate‐specific antigen (PSA) by Western blot analysis, and intriguingly the remaining protein candidates were found to be at least as abundant as the PSA protein. Comparison of 2‐D PAGE profiles of microdissected cell with matched in vitro cell lines from the same patient, and metastatic prostate cancer cell lines (LnCaP and PC3) showed striking differences between prostate cells in vivo and in vitro with less than 20% shared proteins. The data demonstrate that 2‐D PAGE analysis of LCM‐derived cells can reliably detect alterations in protein expression associated with prostate cancer, and that these differentially expressed proteins are produced in high enough levels which could allow for their clinical utility as new targets for therapeutic intervention, serum markers, and/or imaging markers.

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W. Marston Linehan

Science Applications International Corporation

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Maria J. Merino

National Institutes of Health

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John W. Gillespie

Science Applications International Corporation

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Lance A. Liotta

Food and Drug Administration

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Rodrigo F. Chuaqui

National Institutes of Health

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Cathy D. Vocke

National Institutes of Health

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