588 results on '"Jonathan A. Epstein"'
Search Results
2. Landscape of Hopx expression in cells of the immune system
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Jessica Bourque, Adeleye Opejin, Alexey Surnov, Courtney A. Iberg, Cindy Gross, Rajan Jain, Jonathan A. Epstein, and Daniel Hawiger
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Hopx ,Immune cells ,scRNA-seq ,Mice ,Flow cytometry ,Expression ,Science (General) ,Q1-390 ,Social sciences (General) ,H1-99 - Abstract
Homeodomain only protein (Hopx) is a regulator of cell differentiation and function, and it has also emerged as a crucial marker of specific developmental and differentiation potentials. Hopx expression and functions have been identified in some stem cells, tumors, and in certain immune cells. However, expression of Hopx in immune cells remains insufficiently characterized. Here we report a comprehensive pattern of Hopx expression in multiple types of immune cells under steady state conditions. By utilizing single-cell RNA sequencing (scRNA-seq) and flow cytometric analysis, we characterize a constitutive expression of Hopx in specific subsets of CD4+ and CD8+ T cells and B cells, as well as natural killer (NK), NKT, and myeloid cells. In contrast, Hopx expression is not present in conventional dendritic cells and eosinophils. The utility of identifying expression of Hopx in immune cells may prove vital in delineating specific roles of Hopx under multiple immune conditions.
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- 2021
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3. An Engineered Mouse to Identify Proliferating Cells and Their Derivatives
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Jihyun Jang, Kurt A. Engleka, Feiyan Liu, Li Li, Guang Song, Jonathan A. Epstein, and Deqiang Li
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cell proliferation ,aurora kinase B ,mouse model ,lineage tracing ,regeneration ,development ,Biology (General) ,QH301-705.5 - Abstract
BackgroundCell proliferation is a fundamental event during development, disease, and regeneration. Effectively tracking and quantifying proliferating cells and their derivatives is critical for addressing many research questions. Cell cycle expression such as for Ki67, proliferating cell nuclear antigen (PCNA), or aurora kinase B (Aurkb), or measurement of 5-bromo-2′-deoxyuridine (BrdU) or 3H-thymidine incorporation have been widely used to assess and quantify cell proliferation. These are powerful tools for detecting actively proliferating cells, but they do not identify cell populations derived from proliferating progenitors over time.AimsWe developed a new mouse tool for lineage tracing of proliferating cells by targeting the Aurkb allele.ResultsIn quiescent cells or cells arrested at G1/S, little or no Aurkb mRNA is detectable. In cycling cells, Aurkb transcripts are detectable at G2 and become undetectable by telophase. These findings suggest that Aurkb transcription is restricted to proliferating cells and is tightly coupled to cell proliferation. Accordingly, we generated an AurkbER Cre/+ mouse by targeting a tamoxifen inducible Cre cassette into the start codon of Aurkb. We find that the AurkbER Cre/+ mouse faithfully labels proliferating cells in developing embryos and regenerative adult tissues such as intestine but does not label quiescent cells such as post-mitotic neurons.ConclusionThe AurkbER Cre/+ mouse faithfully labels proliferating cells and their derivatives in developing embryos and regenerative adult tissues. This new mouse tool provides a novel genetic tracing capability for studying tissue proliferation and regeneration.
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- 2020
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4. Beating the odds: programming proliferation in the mammalian heart
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Rajan Jain, Andrey Poleshko, and Jonathan A. Epstein
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Regeneration ,Cyclin ,Myocyte ,Proliferation ,Medicine ,Genetics ,QH426-470 - Abstract
Editorial summary The heart is one of the least regenerative organs in the human body; adult cardiac myocytes divide at extremely low frequency. Therefore, meaningful induction of cardiac regeneration requires in-depth understanding of myocyte cell-cycle control. Recent insights into how myocytes can be coaxed into duplicating in vivo might inform emerging therapeutics.
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- 2018
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5. Coronary vasculature patterning requires a novel endothelial ErbB2 holoreceptor
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Haig Aghajanian, Young Kuk Cho, Lauren J. Manderfield, Madison R. Herling, Mudit Gupta, Vivienne C. Ho, Li Li, Karl Degenhardt, Alla Aharonov, Eldad Tzahor, and Jonathan A. Epstein
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Science - Abstract
Semaphorin ligands and cognate receptors are important in patterning the vasculature. Here, Aghajanian et al.report an unexpected role for ErbB2 in endothelial cells where it partners with Nrp1 to form a novel semaphoring holoreceptor required for embryonic vascular patterning.
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- 2016
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6. Hippo Signaling Mediators Yap and Taz Are Required in the Epicardium for Coronary Vasculature Development
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Anamika Singh, Sindhu Ramesh, Dasan Mary Cibi, Lim Sze Yun, Jun Li, Li Li, Lauren J. Manderfield, Eric N. Olson, Jonathan A. Epstein, and Manvendra K. Singh
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Biology (General) ,QH301-705.5 - Abstract
Summary: Formation of the coronary vasculature is a complex and precisely coordinated morphogenetic process that begins with the formation of epicardium. The epicardium gives rise to many components of the coronary vasculature, including fibroblasts, smooth muscle cells, and endothelium. Hippo signaling components have been implicated in cardiac development and regeneration. However, a role of Hippo signaling in the epicardium has not been explored. Employing a combination of genetic and pharmacological approaches, we demonstrate that inhibition of Hippo signaling mediators Yap and Taz leads to impaired epicardial epithelial-to-mesenchymal transition (EMT) and a reduction in epicardial cell proliferation and differentiation into coronary endothelial cells. We provide evidence that Yap and Taz control epicardial cell behavior, in part by regulating Tbx18 and Wt1 expression. Our findings show a role for Hippo signaling in epicardial cell proliferation, EMT, and cell fate specification during cardiac organogenesis. : Singh et al. show that Hippo signaling components are expressed in proepicardial and epicardial cells and are required for coronary vasculature development. Yap and Taz regulate epicardial cell proliferation, EMT, and cell fate specification, in part by regulating Tbx18 and Wt1 expression. Keywords: epicardium, proepicardium, Hippo signaling, Yap, Taz, epithelial to mesenchymal transition (EMT)
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- 2016
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7. Hopx distinguishes hippocampal from lateral ventricle neural stem cells
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Deqiang Li, Norifumi Takeda, Rajan Jain, Lauren J. Manderfield, Feiyan Liu, Li Li, Stewart A. Anderson, and Jonathan A. Epstein
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Neural stem cell ,Neurogenesis ,Hippocampus ,Dentate gyrus ,Hopx ,Notch ,Biology (General) ,QH301-705.5 - Abstract
In the adult dentate gyrus (DG) and in the proliferative zone lining the lateral ventricle (LV-PZ), radial glia-like (RGL) cells are neural stem cells (NSCs) that generate granule neurons. A number of molecular markers including glial fibrillary acidic protein (GFAP), Sox2 and nestin, can identify quiescent NSCs in these two niches. However, to date, there is no marker that distinguishes NSC origin of DG versus LV-PZ. Hopx, an atypical homeodomain only protein, is expressed by adult stem cell populations including those in the intestine and hair follicle. Here, we show that Hopx is specifically expressed in RGL cells in the adult DG, and these cells give rise to granule neurons. Assessed by non-stereological quantitation, Hopx-null NSCs exhibit enhanced neurogenesis evident by an increased number of BrdU-positive cells and doublecortin (DCX)-positive neuroblasts. In contrast, Sox2-positive, quiescent NSCs are reduced in the DG of Hopx-null animals and Notch signaling is reduced, as evidenced by reduced expression of Notch targets Hes1 and Hey2, and a reduction of the number of cells expressing the cleaved, activated form of the Notch1 receptor, the Notch intracellular domain (NICD) in Hopx-null DG. Surprisingly, Hopx is not expressed in RGL cells of the adult LV-PZ, and Hopx-expressing cells do not give rise to interneurons of the olfactory bulb (OB). These findings establish that Hopx expression distinguishes NSCs of the DG from those of the LV-PZ, and suggest that Hopx potentially regulates hippocampal neurogenesis by modulating Notch signaling.
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- 2015
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8. The Genetic Landscape of Hematopoietic Stem Cell Frequency in Mice
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Xiaoying Zhou, Amanda L. Crow, Jaana Hartiala, Tassja J. Spindler, Anatole Ghazalpour, Lora W. Barsky, Brian J. Bennett, Brian W. Parks, Eleazar Eskin, Rajan Jain, Jonathan A. Epstein, Aldons J. Lusis, Gregor B. Adams, and Hooman Allayee
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Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Prior efforts to identify regulators of hematopoietic stem cell physiology have relied mainly on candidate gene approaches with genetically modified mice. Here we used a genome-wide association study (GWAS) strategy with the hybrid mouse diversity panel to identify the genetic determinants of hematopoietic stem/progenitor cell (HSPC) frequency. Among 108 strains, we observed ∼120- to 300-fold variation in three HSPC populations. A GWAS analysis identified several loci that were significantly associated with HSPC frequency, including a locus on chromosome 5 harboring the homeodomain-only protein gene (Hopx). Hopx previously had been implicated in cardiac development but was not known to influence HSPC biology. Analysis of the HSPC pool in Hopx−/− mice demonstrated significantly reduced cell frequencies and impaired engraftment in competitive repopulation assays, thus providing functional validation of this positional candidate gene. These results demonstrate the power of GWAS in mice to identify genetic determinants of the hematopoietic system.
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- 2015
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9. Pax3 and Hippo Signaling Coordinate Melanocyte Gene Expression in Neural Crest
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Lauren J. Manderfield, Kurt A. Engleka, Haig Aghajanian, Mudit Gupta, Steven Yang, Li Li, Julie E. Baggs, John B. Hogenesch, Eric N. Olson, and Jonathan A. Epstein
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Biology (General) ,QH301-705.5 - Abstract
Summary: Loss of Pax3, a developmentally regulated transcription factor expressed in premigratory neural crest, results in severe developmental defects and embryonic lethality. Although Pax3 mutations produce profound phenotypes, the intrinsic transcriptional activation exhibited by Pax3 is surprisingly modest. We postulated the existence of transcriptional coactivators that function with Pax3 to mediate developmental functions. A high-throughput screen identified the Hippo effector proteins Taz and Yap65 as Pax3 coactivators. Synergistic coactivation of target genes by Pax3-Taz/Yap65 requires DNA binding by Pax3, is Tead independent, and is regulated by Hippo kinases Mst1 and Lats2. In vivo, Pax3 and Yap65 colocalize in the nucleus of neural crest progenitors in the dorsal neural tube. Neural crest deletion of Taz and Yap65 results in embryo-lethal neural crest defects and decreased expression of the Pax3 target gene, Mitf. These results suggest that Pax3 activity is regulated by the Hippo pathway and that Pax factors are Hippo effectors. : Hippo signaling is a conserved kinase cascade that mediates transcription through a Yap65/Taz-Tead complex and governs organ size. Manderfield et al. have identified Yap65 and Taz as coactivators of Pax factors and established neural crest as a novel site of Hippo signaling. The Pax3-Yap65/Taz complex is regulated by upstream Hippo kinases and is Tead independent. Deletion of Yap65 and Taz in neural crest generated differentiation defects in specific neural crest derivatives.
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- 2014
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10. Single-Cell Analysis of Proxy Reporter Allele-Marked Epithelial Cells Establishes Intestinal Stem Cell Hierarchy
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Ning Li, Maryam Yousefi, Angela Nakauka-Ddamba, Rajan Jain, John Tobias, Jonathan A. Epstein, Shane T. Jensen, and Christopher J. Lengner
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Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
The recent development of targeted murine reporter alleles as proxies for intestinal stem cell activity has led to significant advances in our understanding of somatic stem cell hierarchies and dynamics. Analysis of these reporters has led to a model in which an indispensable reserve stem cell at the top of the hierarchy (marked by Bmi1 and Hopx reporters) gives rise to active intestinal stem cells (marked by an Lgr5 reporter). Despite these advances, controversy exists regarding the specificity and fidelity with which these alleles distinguish intestinal stem cell populations. Here, we undertake a comprehensive comparison of widely used proxy reporters including both CreERT2 and EGFP cassettes targeted to the Lgr5, Bmi1, and Hopx loci. Single-cell transcriptional profiling of these populations and their progeny reveals that reserve and active intestinal stem cells are molecularly and functionally distinct, supporting a two-stem-cell model for intestinal self-renewal.
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- 2014
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11. Farm biosecurity practices affecting avian influenza virus circulation in commercial chicken farms in Bangladesh.
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Ariful Islam, Mohammed Ziaur Rahman, Mohammad Mahmudul Hassan, Jonathan H. Epstein, and Marcel Klaassen
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HPAI ,H5N1 ,H9N2 ,Economic ,Zoonotic ,Spillover ,Medicine (General) ,R5-920 - Abstract
Avian influenza virus (AIV) is of major concern to livestock, wildlife, and human health. In many countries in the world, including Bangladesh, AIV is endemic in poultry, requiring improving biosecurity. In Bangladesh, we investigated how variation in biosecurity practices in commercial chicken farms affected their AIV infection status to help guide AIV mitigation strategies. We collected pooled fecal swabs from 225 farms and tested the samples for the AIV matrix gene followed by H5, H7, and H9 subtyping using rRT-PCR. We found that 39.6% of chicken farms were AIV positive, with 13% and 14% being positive for subtypes H5 and H9, respectively. Using a generalized linear mixed effects model, we identified as many as 12 significant AIV risk factors. Two major factors promoting AIV risk that cannot be easily addressed in the short term were farm size and the proximity of the farm to a live bird market. However, the other ten significant determinants of AIV risk can be more readily addressed, of which the most important ones were limiting access by visitors (reducing predicted AIV risk from 42 to 6%), isolation and treatment of sick birds (42 to 7%), prohibiting access of vehicles to poultry sheds (38 to 8%), improving hand hygiene (from 42 to 9%), not sharing farm workers across farms (37 to 8%), and limiting access by wild birds to poultry sheds (37 to 8%). Our findings can be applied to developing practical and cost-effective measures that significantly decrease the prevalence of AIV in chicken farms. Notably, in settings with limited resources, such as Bangladesh, these measures can help governments strengthen biosecurity practices in their poultry industry to limit and possibly prevent the spread of AIV.
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- 2024
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12. Pax3 and Hippo Signaling Coordinate Melanocyte Gene Expression in Neural Crest
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Lauren J. Manderfield, Kurt A. Engleka, Haig Aghajanian, Mudit Gupta, Steven Yang, Li Li, Julie E. Baggs, John B. Hogenesch, Eric N. Olson, and Jonathan A. Epstein
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Biology (General) ,QH301-705.5 - Published
- 2015
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13. NCCN Guidelines® Insights: Prostate Cancer Early Detection, Version 1.2023
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Kelvin A. Moses, Preston C. Sprenkle, Clinton Bahler, Geoffrey Box, Sigrid V. Carlsson, William J. Catalona, Douglas M. Dahl, Marc Dall’Era, John W. Davis, Bettina F. Drake, Jonathan I. Epstein, Ruth B. Etzioni, Thomas A. Farrington, Isla P. Garraway, David Jarrard, Eric Kauffman, Deborah Kaye, Adam S. Kibel, Chad A. LaGrange, Paul Maroni, Lee Ponsky, Brian Reys, Simpa S. Salami, Alejandro Sanchez, Tyler M. Seibert, Terrence M. Shaneyfelt, Marc C. Smaldone, Geoffrey Sonn, Mark D. Tyson, Neha Vapiwala, Robert Wake, Samuel Washington, Alice Yu, Bertram Yuh, Ryan A. Berardi, and Deborah A. Freedman-Cass
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Oncology - Abstract
The NCCN Guidelines for Prostate Cancer Early Detection provide recommendations for individuals with a prostate who opt to participate in an early detection program after receiving the appropriate counseling on the pros and cons. These NCCN Guidelines Insights provide a summary of recent updates to the NCCN Guidelines with regard to the testing protocol, use of multiparametric MRI, and management of negative biopsy results to optimize the detection of clinically significant prostate cancer and minimize the detection of indolent disease.
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- 2023
14. Nipah Virus Exposure in Domestic and Peridomestic Animals Living in Human Outbreak Sites, Bangladesh, 2013–2015
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Ausraful Islam, Deborah L. Cannon, Mohammed Ziaur Rahman, Salah Uddin Khan, Jonathan H. Epstein, Peter Daszak, Stephen P. Luby, Joel M. Montgomery, John D. Klena, and Emily S. Gurley
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Microbiology (medical) ,Infectious Diseases ,Epidemiology - Published
- 2023
15. Advance on curvelet application to prostate cancer tissue image classification.
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Wen-Chyi Lin, Ching-Chung Li, Jonathan I. Epstein, and Robert W. Veltri
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- 2017
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16. MED15::TFE3 Renal Cell Carcinomas: Report of Two New Cases and Review of the Literature Confirming Nearly Universal Multilocular Cystic Morphology
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Pedram Argani, Andres Matoso, Ezra G. Baraban, Jonathan I. Epstein, and Cristina R. Antonescu
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Surgery ,Anatomy ,Pathology and Forensic Medicine - Abstract
We report two novel cases of Xp11 translocation renal cell carcinomas with the MED15::TFE3 gene fusion in adult females aged 40 and 74 years. Both cases were extensively cystic and contained only minimal clear cells lining cysts and within septal walls, raising the differential diagnosis of multilocular cystic renal neoplasm of low malignant potential. By immunohistochemistry, both neoplasms labeled for PAX8, TFE3, cathepsin K and Melan A but not for HMB45. On review of the published literature and the two cases reported herein, over 90% of MED15::TFE3 renal cell carcinomas (RCCs) have been described as cystic. The correlation of the MED15::TFE3 fusion with extensively cystic morphology represents the strongest association of TFE3 fusion partner with clinicopathological features among TFE3-rearranged RCC reported to date.
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- 2023
17. Nested Subtype of Urothelial Carcinoma in the Upper Urinary Tract
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Aisha Fatima, Daniel H. Russell, and Jonathan I. Epstein
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Surgery ,Anatomy ,Pathology and Forensic Medicine - Published
- 2022
18. Clonal relationships of adjacent Gleason pattern 3 and Gleason pattern 5 lesions in Gleason Scores 3+5=8 and 5+3=8
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Hasim Bakbak, Erolcan Sayar, Harsimar B. Kaur, Daniela C. Salles, Radhika A. Patel, Jessica Hicks, Tamara L. Lotan, Angelo M. De Marzo, Roman Gulati, Jonathan I. Epstein, and Michael C. Haffner
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Male ,Prostatectomy ,Prostate ,Humans ,Prostatic Neoplasms ,Tumor Suppressor Protein p53 ,Neoplasm Grading ,Pathology and Forensic Medicine - Abstract
Genomic studies have demonstrated a high level of intra-tumoral heterogeneity in prostate cancer. There is strong evidence suggesting that individual tumor foci can arise as genetically distinct, clonally independent lesions. However, recent studies have also demonstrated that adjacent Gleason pattern (GP) 3 and GP4 lesions can originate from the same clone but follow divergent genetic and morphologic evolution. The clonal relationship of adjacent GP3 and GP5 lesions has thus far not been investigated. Here we analyzed a cohort of 14 cases-11 biopsy and 3 radical prostatectomy specimens-with a Gleason score of 3 + 5 = 8 or 5 + 3 = 8 present in the same biopsy or in a single dominant tumor nodule at radical prostatectomy. Clonal and subclonal relationships between GP3 and GP5 lesions were assessed using genetically validated immunohistochemical assays for ERG, PTEN, and P53. 9/14 (64%) cases showed ERG reactivity in both GP3 and GP5 lesions. Only 1/14 (7%) cases showed a discordant pattern with ERG staining present only in GP3. PTEN expression was lost in 2/14 (14%) cases with perfect concordance between GP5 and GP3. P53 nuclear reactivity was present in 1/14 (7%) case in both GP5 and GP3. This study provides first evidence that the majority of adjacent GP3 and GP5 lesions share driver alterations and are clonally related. In addition, we observed a lower-than-expected rate of PTEN loss in GP5 in the context of Gleason score 3 + 5 = 8 or 5 + 3 = 8 tumors.
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- 2022
19. Fibromyxoid Nephrogenic Adenoma
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Lin Li, Sean R. Williamson, Rosa P. Castillo, Katiana S. Delma, Mark L. Gonzalgo, Jonathan I. Epstein, and Oleksandr N. Kryvenko
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Surgery ,Anatomy ,Pathology and Forensic Medicine - Published
- 2022
20. Combinatorial Identification of Broad Association Regions with ChIP-seq Data.
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Jieun Jeong, Mudit Gupta, Andrey Poleshko, and Jonathan A. Epstein
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- 2016
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21. Curvelet-based texture classification of critical Gleason patterns of prostate histological images.
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Wen-Chyi Lin, Ching-Chung Li, Jonathan I. Epstein, and Robert W. Veltri
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- 2016
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22. SARS-CoV-2 disrupts host epigenetic regulation via histone mimicry
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John Kee, Samuel Thudium, David M. Renner, Karl Glastad, Katherine Palozola, Zhen Zhang, Yize Li, Yemin Lan, Joseph Cesare, Andrey Poleshko, Anna A. Kiseleva, Rachel Truitt, Fabian L. Cardenas-Diaz, Xianwen Zhang, Xuping Xie, Darrell N. Kotton, Konstantinos D. Alysandratos, Jonathan A. Epstein, Pei-Yong Shi, Wenli Yang, Edward Morrisey, Benjamin A. Garcia, Shelley L. Berger, Susan R. Weiss, and Erica Korb
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Histones ,Epigenome ,Viral Proteins ,Multidisciplinary ,Host Microbial Interactions ,SARS-CoV-2 ,Molecular Mimicry ,COVID-19 ,Humans ,Chromatin Assembly and Disassembly ,Chromatin ,Epigenesis, Genetic - Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged at the end of 2019 and caused the devastating global pandemic of coronavirus disease 2019 (COVID-19), in part because of its ability to effectively suppress host cell responses
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- 2022
23. Prostate Cancer in Male-to-Female Transgender Individuals
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Ezra, Baraban, Chien-Kuang C, Ding, Marissa, White, Poonam, Vohra, Jeffry, Simko, Karen, Boyle, Charles, Guo, Miao, Zhang, Adrian, Dobs, Suvethavarshini, Ketheeswaran, Fan, Liang, and Jonathan I, Epstein
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Male ,Prostatectomy ,Hyperplasia ,Prostatic Neoplasms ,Gender Identity ,Androgen Antagonists ,Adenocarcinoma ,Transgender Persons ,Hormones ,Pathology and Forensic Medicine ,Humans ,Surgery ,Atrophy ,Anatomy - Abstract
Male-to-female (MtF) transgender individuals are at risk for prostate cancer, although guidelines for screening and management in this population are not well established. We describe a series of 9 MtF transgender patients who underwent prostate tissue sampling and highlight histopathologic features and challenges related to pathologic interpretation of prostate tissue in this patient population. Seven of 9 total patients were diagnosed with prostate cancer and all had elevated prostate-specific antigen at the time of diagnosis. Three of the 7 patients diagnosed with prostate cancer had received different types of hormone therapy for gender affirmation before the diagnosis of prostate cancer, and in all 3 of these patients, there was histologic evidence of hormone therapy effect in both benign prostate tissue and/or the adenocarcinoma. The 2 patients with benign prostate tissue underwent transurethral resection for lower urinary tract symptoms and were previously on hormone therapy for gender affirmation. Both of these specimens showed diffuse glandular atrophy and basal cell hyperplasia, indicative of hormone therapy effect on benign prostatic tissue. In the patients diagnosed with prostate cancer, a spectrum of grades was observed, ranging from Grade Group 1 to Grade Group 5. Four patients underwent radical prostatectomy, with 2 cases showing extraprostatic extension and Grade Group 5 prostatic adenocarcinoma, and 2 showing Grade Group 2 prostatic adenocarcinoma. Three of the 4 patients who underwent radical prostatectomy had received gender-affirming hormone therapy before surgery, and all 3 of these specimens showed hormone therapy effect in non-neoplastic prostate tissue and focal hormone therapy effect in prostatic adenocarcinoma. The presence of areas of viable carcinoma without hormone therapy effect enabled the assignment of a Gleason score and Grade Group in these 3 cases. Hormone therapy administered for gender identity affirmation induces histopathologic changes to both benign prostate tissue (nonkeratinizing squamous metaplasia, diffuse atrophy, basal cell hyperplasia, and stromal dominance with decreased numbers of glands) and prostatic adenocarcinoma (nuclear pyknosis, atrophy, cytoplasmic vacuolization, and architectural patterns that would qualify for Gleason 4 and 5 in the absence of hormone therapy effect) that have been traditionally seen in cis-male prostate cancer patients receiving hormone therapy. In the absence of hormone therapy, the morphology of prostatic adenocarcinoma in transgender patients shows classic morphologic features similar to those seen in cis-male patients not on hormone therapy. Prostate cancer with hormone therapy effect may not only be histologically quite subtle and may be overlooked if not suspected, but also should not be assigned a Gleason score because the Gleason score would substantially overstate its biologic potential. Therefore, similar to cis-male patients who have received androgen deprivation therapy for prostate cancer, transgender patients on hormone therapy for gender affirmation may be at risk for both underrecognition and over-grading of prostate cancer, particularly if the pathologist is not aware of the clinical history.
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- 2022
24. Prostatic malakoplakia: clinicopathological assessment of a multi‐institutional series of 49 patients
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Andres M Acosta, Ankur R Sangoi, Fiona Maclean, Kiril Trpkov, Adeboye O Osunkoya, Katrina Collins, Hiroshi Miyamoto, Michelle S Hirsch, Emily Chan, Maria Tretiakova, Sambit K Mohanty, Seema Kaushal, Kristine M Cornejo, Manju Aron, Gabriela Quiroga‐Garza, Kanika Arora, Jane K Nguyen, Sean R Williamson, Jonathan I Epstein, and Andres Matoso
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Male ,Prostatectomy ,Histology ,Malacoplakia ,Prostate ,Humans ,Prostatic Neoplasms ,General Medicine ,Prostate-Specific Antigen ,Magnetic Resonance Imaging ,Aged ,Pathology and Forensic Medicine - Abstract
Prostatic malakoplakia (MP) is rare, with only case reports and small series ( five patients) available in the literature. In this study we analysed an international multi-institutional series of 49 patients with prostatic MP to more clearly define its clinicopathological features. The median age was 67 years and the median serum prostate-specific antigen (PSA) was 7.5 ng/ml. MP was clinically manifest in most cases (28 of 45 patients with data available, 62%). Of 43 patients with detailed clinical history available, 21 (49%) had concurrent or metachronous malignancies (including prostate cancer). Diabetes or insulin resistance was present in 11 patients (26%). Additionally, three patients had a history of solid organ transplantation and one had HIV. Of note, six of 34 patients (18%) without concurrent prostate cancer had an abnormal digital rectal examination and/or lesions on magnetic resonance imaging (MRI) with prostate imaging reporting and data system (PIRADS) scores 4-5. The initial diagnosis was made on core biopsies (25 of 49, 51%), transurethal resection specimens (12 of 49, 24%), radical prostatectomies (10 of 49, 20%), Holmium-laser enucleation (one of 49, 2%) and cystoprostatectomy (one of 49, 2%). Tissue involvement was more commonly diffuse or multifocal (40 of 49, 82%). Von Kossa and periodic acid-Schiff stains were positive in 35 of 38 (92%) and 26 of 27 lesions (96%), respectively. Of note, two cases were received in consultation by the authors with a preliminary diagnosis of mesenchymal tumour/tumour of the specialised prostatic stroma. The present study suggests that prostatic MP is often associated with clinical findings that may mimic those of prostate cancer in a subset of patients. Moreover, MP may be found incidentally in patients with concurrent prostate cancer.
- Published
- 2022
25. Pathological characterization and clinical outcome of penile intraepithelial neoplasia variants: a North American series
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Melissa M. Straub Hogan, Andrew J. Spieker, Michael Orejudos, Tarik Gheit, Michael Herfs, Massimo Tommasino, Diego F. Sanchez, Maria Jose Fernandez-Nestosa, Maria Del Carmen Rodriguez Pena, Jennifer B. Gordetsky, Jonathan I. Epstein, Sofia Canete-Portillo, Lan L. Gellert, Carlos Nicolas Prieto Granada, Cristina Magi-Galluzzi, Antonio L. Cubilla, and Giovanna A. Giannico
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Pathology and Forensic Medicine - Published
- 2022
26. Adult Wilms Tumor: Genetic Evidence of Origin of a Subset of Cases From Metanephric Adenoma
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Pedram Argani, Satish K. Tickoo, Andres Matoso, Christine A. Pratilas, Rohit Mehra, Maria Tretiakova, Mathilde Sibony, Alan K. Meeker, Ming-Tseh Lin, Victor E. Reuter, Jonathan I. Epstein, Jeffrey Gagan, and Doreen N. Palsgrove
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Adenoma ,Adult ,Male ,Proto-Oncogene Proteins B-raf ,Wilms Tumor ,Kidney Neoplasms ,Article ,Pathology and Forensic Medicine ,Mutation ,Humans ,Surgery ,Female ,Anatomy ,Child - Abstract
The genetics of nephroblastoma (Wilms tumor) occurring in adults is largely unknown, as studies have largely been limited to isolated case reports. We, therefore, studied 14 adult Wilms tumors for genetic alterations, using expanded targeted sequencing on 11 cases. The patients ranged from 17 to 46 years of age (mean and median, 31 y), and there were 8 males and 6 females. Five Wilms tumors harbored BRAF V600E mutations. All of these had better-differentiated areas identical to metanephric adenoma, as has previously been described. In 3 such cases, microdissection studies revealed that the BRAF V600E mutation was present in both the metanephric adenoma and Wilms tumor areas; however, additional genetic alterations (including TERT promoter mutations in 2 cases, ASLX1/ATR mutations in 1 other case) were limited to the Wilms tumor component. These findings suggest that the Wilms tumor developed from the metanephric adenoma. Other adult Wilms tumors harbored genetic alterations previously reported in the more common pediatric Wilms tumors, including WT1 mutations (2 cases), ASLX1 mutations (3 additional cases), NSD2 mutation (1 additional case), and 11p loss (3 cases). In summary, a significant subset of adult Wilms tumors (specifically those of epithelial type with differentiated areas) harbor targetable BRAF V600E mutations and appear to arise from metanephric adenomas as a consequence of additional acquired genetic alterations. Other adult Wilms tumors often harbor genetic alterations found in their more common pediatric counterparts, suggesting at least some similarities in their pathogenesis.
- Published
- 2023
27. Metagenomics-enabled reverse-genetics assembly and characterization of myotis bat morbillivirus
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Satoshi Ikegame, Jillian C. Carmichael, Heather Wells, Robert L. Furler O’Brien, Joshua A. Acklin, Hsin-Ping Chiu, Kasopefoluwa Y. Oguntuyo, Robert M. Cox, Aum R. Patel, Shreyas Kowdle, Christian S. Stevens, Miles Eckley, Shijun Zhan, Jean K. Lim, Ethan C. Veit, Matthew J. Evans, Takao Hashiguchi, Edison Durigon, Tony Schountz, Jonathan H. Epstein, Richard K. Plemper, Peter Daszak, Simon J. Anthony, and Benhur Lee
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Microbiology (medical) ,Immunology ,Genetics ,Cell Biology ,Applied Microbiology and Biotechnology ,Microbiology - Published
- 2023
28. Curvelet-based classification of prostate cancer histological images of critical Gleason scores.
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Wen-Chyi Lin, Ching-Chung Li, Christhunesa Christudass, Jonathan I. Epstein, and Robert W. Veltri
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- 2015
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29. Computer aided analysis of prostate histopathology images Gleason grading especially for Gleason score 7.
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Jian Ren, Evita T. Sadimin, Daihou Wang, Jonathan I. Epstein, David J. Foran, and Xin Qi 0007
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- 2015
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30. Classification of new morbillivirus and jeilongvirus sequences from bats sampled in Brazil and Malaysia
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Heather L. Wells, Elizabeth Loh, Alessandra Nava, Mónica Romero Solorio, Mei Ho Lee, Jimmy Lee, Jum R. A. Sukor, Isamara Navarrete-Macias, Eliza Liang, Cadhla Firth, Jonathan H. Epstein, Melinda K. Rostal, Carlos Zambrana-Torrelio, Kris Murray, Peter Daszak, Tracey Goldstein, Jonna A. K. Mazet, Benhur Lee, Tom Hughes, Edison Durigon, and Simon J. Anthony
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Genome ,Agricultural and Veterinary Sciences ,Malaysia ,Genome, Viral ,General Medicine ,Biological Sciences ,Medical and Health Sciences ,Infectious Diseases ,Morbillivirus ,Chiroptera ,Virology ,Paramyxoviridae ,Viruses ,Genetics ,Animals ,Humans ,SEQUENCIAMENTO GENÉTICO ,Viral ,Infection ,Brazil ,Phylogeny - Abstract
As part of a broad One Health surveillance effort to detect novel viruses in wildlife and people, we report several paramyxovirus sequences sampled primarily from bats during 2013 and 2014 in Brazil and Malaysia, including seven from which we recovered full-length genomes. Of these, six represent the first full-length paramyxovirid genomes sequenced from the Americas, including two that are the first full-length bat morbillivirus genome sequences published to date. Our findings add to the vast number of viral sequences in public repositories, which have been increasing considerably in recent years due to the rising accessibility of metagenomics. Taxonomic classification of these sequences in the absence of phenotypic data has been a significant challenge, particularly in the subfamily Orthoparamyxovirinae, where the rate of discovery of novel sequences has been substantial. Using pairwise amino acid sequence classification (PAASC), we propose that five of these sequences belong to members of the genus Jeilongvirus and two belong to members of the genus Morbillivirus. We also highlight inconsistencies in the classification of Tupaia virus and Mòjiāng virus using the same demarcation criteria and suggest reclassification of these viruses into new genera. Importantly, this study underscores the critical importance of sequence length in PAASC analysis as well as the importance of biological characteristics such as genome organization in the taxonomic classification of viral sequences.
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- 2022
31. Prevalence and risk factors for avian influenza virus (H5 and H9) contamination in peri-urban and rural live bird markets in Bangladesh
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Ariful Islam, Shariful Islam, Monjurul Islam, Mohammad Enayet Hossain, Sarah Munro, Mohammed Abdus Samad, Md. Kaisar Rahman, Tahmina Shirin, Meerjady Sabrina Flora, Mohammad Mahmudul Hassan, Mohammed Ziaur Rahman, and Jonathan H. Epstein
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Public Health, Environmental and Occupational Health - Abstract
Avian influenza viruses (AIV) have been frequently detected in live bird markets (LBMs) around the world, primarily in urban areas, and have the ability to spillover to other species, including humans. Despite frequent detection of AIV in urban LBMs, the contamination of AIV on environmental surfaces in rural and peri-urban LBMs in Bangladesh is poorly documented. Therefore, we conducted this study to determine the prevalence of AIV subtypes within a subset of peri-urban and rural LBMs in Bangladesh and to further identify associated risk factors. Between 2017 and 2018, we collected faecal and offal samples from 200 stalls in 63 LBMs across four sub-districts. We tested the samples for the AIV matrix gene (M-gene) followed by H5, H7, and H9 subtypes using real-time reverse transcriptase-polymerase chain reaction (rRT-PCR). We performed a descriptive analysis of market cleanliness and sanitation practices in order to further elucidate the relationship between LBM biosecurity and AIV subtypes by species, sample types, and landscape. Subsequently, we conducted a univariate analysis and a generalized linear mixed model (GLMM) to determine the risk factors associated with AIV contamination at individual stalls within LBMs. Our findings indicate that practices related to hygiene and the circulation of AIV significantly differed between rural and peri-urban live bird markets. 42.5% (95% CI: 35.56–49.67) of stalls were positive for AIV. A/H5, A/H9, and A HA/Untyped were detected in 10.5% (95% CI: 6.62–15.60), 9% (95% CI: 5.42–13.85), and 24.0% (95% CI: 18.26–30.53) of stalls respectively, with no detection of A/H7. Significantly higher levels of AIV were found in the Sonali chicken strain compared to the exotic broiler, and in offal samples compared to fecal samples. In the GLMM analysis, we identified several significant risk factors associated with AIV contamination in LBMs at the stall level. These include: landscape (AOR: 3.02; 95% CI: 1.18–7.72), the number of chicken breeds present (AOR: 2.4; 95% CI: 1.01–5.67), source of birds (AOR: 2.35; 95% CI: 1.0–5.53), separation of sick birds (AOR: 3.04; 95% CI: 1.34–6.92), disposal of waste/dead birds (AOR: 3.16; 95% CI: 1.41–7.05), cleaning agent (AOR: 5.99; 95% CI: 2.26–15.82), access of dogs (AOR: 2.52; 95% CI: 1.12–5.7), wild birds observed on site (AOR: 2.31; 95% CI: 1.01–5.3). The study further revealed a substantial prevalence of AIV with H5 and H9 subtypes in peri-urban and rural LBMs. The inadequate biosecurity measures at poultry stalls in Bangladesh increase the risk of AIV transmission from poultry to humans. To prevent the spread of AIV to humans and wild birds, we suggest implementing regular surveillance at live bird markets and enhancing biosecurity practices in peri-urban and rural areas in Bangladesh.
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- 2023
32. Identifying Men Who Can Remain on Active Surveillance Despite Biopsy Reclassification to Grade Group 2 Prostate Cancer
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Ezra Baraban, Eric Erak, Aisha Fatima, Amir Akbari, Jianping Zhao, Sean A. Fletcher, Yasin Bhanji, Claire M. de la Calle, Mufaddal Mamawala, Patricia Landis, Katarzyna J. Macura, Christian P. Pavlovich, and Jonathan I. Epstein
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Urology - Published
- 2023
33. Supplementary Table 1 from Rb Loss Is Characteristic of Prostatic Small Cell Neuroendocrine Carcinoma
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Tamara L. Lotan, Angelo M. De Marzo, William B. Isaacs, Wennuan Liu, George J. Netto, Jonathan I. Epstein, Christopher D. Gocke, Stacy Mosier, Jessica Hicks, Nilesh Gupta, Wenle Wang, Hameed A. Rahimi, Akshay Sood, and Hsueh-Li Tan
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PDF file - 82K, Supplementary Table 1: RB1 status (from high density SNP microarray, Reference 30) and Rb protein status across castrate resistant prostate cancer metastases. n = negative, p = positive, LOH = loss of heterozygosity.
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- 2023
34. Supp Tables from MSH2 Loss in Primary Prostate Cancer
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Tamara L. Lotan, Colin C. Pritchard, James R. Eshleman, William B. Isaacs, Jonathan I. Epstein, Angelo M. De Marzo, Mario A. Eisenberger, Jessica Hicks, Stephanie Glavaris, Jong Chul Park, Fawaz Almutairi, Nooshin Mirkheshti, Michael T. Schweizer, Emmanuel S. Antonarakis, and Liana B. Guedes
- Abstract
Supplementary Tables
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- 2023
35. Supplementary Figure S2 from Cyclin D1 Loss Distinguishes Prostatic Small-Cell Carcinoma from Most Prostatic Adenocarcinomas
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Tamara L. Lotan, Angelo M. De Marzo, Elai Davicioni, Edward M. Schaeffer, R. Jeffrey Karnes, Robert L. Vessella, Rohit Mehra, Jun Luo, William B. Isaacs, George J. Netto, Jonathan I. Epstein, Nilesh Gupta, Jessica Hicks, Zaid Haddad, Hsueh-Li Tan, Mohammed Alshalalfa, Carlos L. Morais, and Harrison Tsai
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Supplementary Figure S2: The ratio of CDKN2A/CCND1 is not as tightly correlated with Rb functional and genetic status in publicly available data from castate resistant prostate cancer (CRPC) metastases in rapid autopsy cohort.
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- 2023
36. Supp Fig S4 from MSH2 Loss in Primary Prostate Cancer
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Tamara L. Lotan, Colin C. Pritchard, James R. Eshleman, William B. Isaacs, Jonathan I. Epstein, Angelo M. De Marzo, Mario A. Eisenberger, Jessica Hicks, Stephanie Glavaris, Jong Chul Park, Fawaz Almutairi, Nooshin Mirkheshti, Michael T. Schweizer, Emmanuel S. Antonarakis, and Liana B. Guedes
- Abstract
MSH2/6 immunostains in a formalin fixed and paraffin embedded primary prostate tumor with single copy MSH2 loss by sequencing. Standard tissue section of tumor with apparent single copy somatic gene inactivation of MSH2 (MSH2 c. 1728del), showing loss of both MSH2 and MSH6 immunostaining, with intact staining in stromal cells and lymphocytes for both markers. All photomicrographs are reduced from 200x.
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- 2023
37. Data from Cyclin D1 Loss Distinguishes Prostatic Small-Cell Carcinoma from Most Prostatic Adenocarcinomas
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Tamara L. Lotan, Angelo M. De Marzo, Elai Davicioni, Edward M. Schaeffer, R. Jeffrey Karnes, Robert L. Vessella, Rohit Mehra, Jun Luo, William B. Isaacs, George J. Netto, Jonathan I. Epstein, Nilesh Gupta, Jessica Hicks, Zaid Haddad, Hsueh-Li Tan, Mohammed Alshalalfa, Carlos L. Morais, and Harrison Tsai
- Abstract
Purpose: Small-cell neuroendocrine differentiation in prostatic carcinoma is an increasingly common resistance mechanism to potent androgen deprivation therapy (ADT), but can be difficult to identify morphologically. We investigated whether cyclin D1 and p16 expression can inform on Rb functional status and distinguish small-cell carcinoma from adenocarcinoma.Experimental Design: We used gene expression data and immunohistochemistry to examine cyclin D1 and p16 levels in patient-derived xenografts (PDX), and prostatic small-cell carcinoma and adenocarcinoma specimens.Results: Using PDX, we show proof-of-concept that a high ratio of p16 to cyclin D1 gene expression reflects underlying Rb functional loss and distinguishes morphologically identified small-cell carcinoma from prostatic adenocarcinoma in patient specimens (n = 13 and 9, respectively). At the protein level, cyclin D1, but not p16, was useful to distinguish small-cell carcinoma from adenocarcinoma. Overall, 88% (36/41) of small-cell carcinomas showed cyclin D1 loss by immunostaining compared with 2% (2/94) of Gleason score 7–10 primary adenocarcinomas at radical prostatectomy, 9% (4/44) of Gleason score 9–10 primary adenocarcinomas at needle biopsy, and 7% (8/115) of individual metastases from 39 patients at autopsy. Though rare adenocarcinomas showed cyclin D1 loss, many of these were associated with clinical features of small-cell carcinoma, and in a cohort of men treated with adjuvant ADT who developed metastasis, lower cyclin D1 gene expression was associated with more rapid onset of metastasis and death.Conclusions: Cyclin D1 loss identifies prostate tumors with small-cell differentiation and may identify a small subset of adenocarcinomas with poor prognosis. Clin Cancer Res; 21(24); 5619–29. ©2015 AACR.
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- 2023
38. Data from MSH2 Loss in Primary Prostate Cancer
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Tamara L. Lotan, Colin C. Pritchard, James R. Eshleman, William B. Isaacs, Jonathan I. Epstein, Angelo M. De Marzo, Mario A. Eisenberger, Jessica Hicks, Stephanie Glavaris, Jong Chul Park, Fawaz Almutairi, Nooshin Mirkheshti, Michael T. Schweizer, Emmanuel S. Antonarakis, and Liana B. Guedes
- Abstract
Purpose: Inactivation of mismatch repair (MMR) genes may predict sensitivity to immunotherapy in metastatic prostate cancers. We studied primary prostate tumors with MMR defects.Experimental Design: A total of 1,133 primary prostatic adenocarcinomas and 43 prostatic small cell carcinomas (NEPC) were screened by MSH2 immunohistochemistry with confirmation by next-generation sequencing (NGS). Microsatellite instability (MSI) was assessed by PCR and NGS (mSINGS).Results: Of primary adenocarcinomas and NEPC, 1.2% (14/1,176) had MSH2 loss. Overall, 8% (7/91) of adenocarcinomas with primary Gleason pattern 5 (Gleason score 9–10) had MSH2 loss compared with 0.4% (5/1,042) of tumors with any other scores (P < 0.05). Five percent (2/43) of NEPC had MSH2 loss. MSH2 was generally homogenously lost, suggesting it was an early/clonal event. NGS confirmed MSH2 loss-of-function alterations in all (12/12) samples, with biallelic inactivation in 83% (10/12) and hypermutation in 83% (10/12). Overall, 61% (8/13) and 58% (7/12) of patients had definite MSI by PCR and mSINGS, respectively. Three patients (25%) had germline mutations in MSH2. Tumors with MSH2 loss had a higher density of infiltrating CD8+ lymphocytes compared with grade-matched controls without MSH2 loss (390 vs. 76 cells/mm2; P = 0.008), and CD8+ density was correlated with mutation burden among cases with MSH2 loss (r = 0.72, P = 0.005). T-cell receptor sequencing on a subset revealed a trend toward higher clonality in cases versus controls.Conclusions: Loss of MSH2 protein is correlated with MSH2 inactivation, hypermutation, and higher tumor-infiltrating lymphocyte density, and appears most common among very high-grade primary tumors, for which routine screening may be warranted if validated in additional cohorts. Clin Cancer Res; 23(22); 6863–74. ©2017 AACR.
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- 2023
39. Data from A Novel Quantitative Multiplex Tissue Immunoblotting for Biomarkers Predicts a Prostate Cancer Aggressive Phenotype
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Robert W. Veltri, M. Craig Miller, Stephen M. Hewitt, Joon-Yong Chung, Hui Zhang, Patricia Landis, H. Ballentine Carter, Christhunesa S. Christudass, Christine Davis, Jonathan I. Epstein, Zhi Liu, and Guangjing Zhu
- Abstract
Background: Early prediction of disease progression in men with very low-risk (VLR) prostate cancer who selected active surveillance (AS) rather than immediate treatment could reduce morbidity associated with overtreatment.Methods: We evaluated the association of six biomarkers [Periostin, (−5, −7) proPSA, CACNA1D, HER2/neu, EZH2, and Ki-67] with different Gleason scores and biochemical recurrence (BCR) on prostate cancer TMAs of 80 radical prostatectomy (RP) cases. Multiplex tissue immunoblotting (MTI) was used to assess these biomarkers in cancer and adjacent benign areas of 5 μm sections. Multivariate logistic regression (MLR) was applied to model our results.Results: In the RP cases, CACNA1D, HER2/neu, and Periostin expression were significantly correlated with aggressive phenotype in cancer areas. An MLR model in the cancer area yielded a ROC-AUC = 0.98, whereas in cancer-adjacent benign areas, yielded a ROC-AUC = 0.94. CACNA1D and HER2/neu expression combined with Gleason score in a MLR model yielded a ROC-AUC = 0.79 for BCR prediction. In the small biopsies from an AS cohort of 61 VLR cases, an MLR model for prediction of progressors at diagnosis retained (−5, −7) proPSA and CACNA1D, yielding a ROC-AUC of 0.78, which was improved to 0.82 after adding tPSA into the model.Conclusions: The molecular profile of biomarkers is capable of accurately predicting aggressive prostate cancer on retrospective RP cases and identifying potential aggressive prostate cancer requiring immediate treatment on the AS diagnostic biopsy but limited in BCR prediction.Impact: Comprehensive profiling of biomarkers using MTI predicts prostate cancer aggressive phenotype in RP and AS biopsies. Cancer Epidemiol Biomarkers Prev; 24(12); 1864–72. ©2015 AACR.
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- 2023
40. supplemental figure legend and Materials and Methods from Cyclin D1 Loss Distinguishes Prostatic Small-Cell Carcinoma from Most Prostatic Adenocarcinomas
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Tamara L. Lotan, Angelo M. De Marzo, Elai Davicioni, Edward M. Schaeffer, R. Jeffrey Karnes, Robert L. Vessella, Rohit Mehra, Jun Luo, William B. Isaacs, George J. Netto, Jonathan I. Epstein, Nilesh Gupta, Jessica Hicks, Zaid Haddad, Hsueh-Li Tan, Mohammed Alshalalfa, Carlos L. Morais, and Harrison Tsai
- Abstract
supplemental figure legend and Materials and Methods
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- 2023
41. Supplementary Tables S1-S5 from A Novel Quantitative Multiplex Tissue Immunoblotting for Biomarkers Predicts a Prostate Cancer Aggressive Phenotype
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Robert W. Veltri, M. Craig Miller, Stephen M. Hewitt, Joon-Yong Chung, Hui Zhang, Patricia Landis, H. Ballentine Carter, Christhunesa S. Christudass, Christine Davis, Jonathan I. Epstein, Zhi Liu, and Guangjing Zhu
- Abstract
Table S1. Information of antibodies used in MTI Table S2. Multiple logistic regression models for the prediction of aggressiveness and BCR in prostatectomy TMAs: parameters included. Table S3. Multiple logistic regression models for the prediction of aggressiveness and BCR in prostatectomy TMAs: Model accuracy Table S4. Standard/Multiple logistic regression models for the prediction of progressors in AS biopsies: parameters included Table S5. Standard/Multiple logistic regression models for the prediction of progressors in AS biopsies: Model accuracy
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- 2023
42. Data from Rb Loss Is Characteristic of Prostatic Small Cell Neuroendocrine Carcinoma
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Tamara L. Lotan, Angelo M. De Marzo, William B. Isaacs, Wennuan Liu, George J. Netto, Jonathan I. Epstein, Christopher D. Gocke, Stacy Mosier, Jessica Hicks, Nilesh Gupta, Wenle Wang, Hameed A. Rahimi, Akshay Sood, and Hsueh-Li Tan
- Abstract
Purpose: Small cell neuroendocrine carcinoma of the prostate is likely to become increasingly common with recent advances in pharmacologic androgen suppression. Thus, developing molecular markers of small cell differentiation in prostate cancer will be important to guide the diagnosis and therapy of this aggressive tumor.Experimental Design: We examined the status of RB1, TP53, and PTEN in prostatic small cell and acinar carcinomas via immunohistochemistry (IHC), copy-number alteration analysis, and sequencing of formalin-fixed paraffin-embedded specimens.Results: We found retinoblastoma (Rb) protein loss in 90% of small cell carcinoma cases (26 of 29) with RB1 allelic loss in 85% of cases (11 of 13). Of acinar tumors occurring concurrently with prostatic small cell carcinoma, 43% (3 of 7) showed Rb protein loss. In contrast, only 7% of primary high-grade acinar carcinomas (10 of 150), 11% of primary acinar carcinomas with neuroendocrine differentiation (4 of 35), and 15% of metastatic castrate-resistant acinar carcinomas (2 of 13) showed Rb protein loss. Loss of PTEN protein was seen in 63% of small cell carcinomas (17 of 27), with 38% (5 of 13) showing allelic loss. By IHC, accumulation of p53 was observed in 56% of small cell carcinomas (14 of 25), with 60% of cases (6 of 10) showing TP53 mutation.Conclusions: Loss of RB1 by deletion is a common event in prostatic small cell carcinoma and can be detected by a validated IHC assay. As Rb protein loss rarely occurs in high-grade acinar tumors, these data suggest that Rb loss is a critical event in the development of small cell carcinomas and may be a useful diagnostic and potential therapeutic target. Clin Cancer Res; 20(4); 890–903. ©2013 AACR.
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- 2023
43. Supplementary Figure 1 from Rb Loss Is Characteristic of Prostatic Small Cell Neuroendocrine Carcinoma
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Tamara L. Lotan, Angelo M. De Marzo, William B. Isaacs, Wennuan Liu, George J. Netto, Jonathan I. Epstein, Christopher D. Gocke, Stacy Mosier, Jessica Hicks, Nilesh Gupta, Wenle Wang, Hameed A. Rahimi, Akshay Sood, and Hsueh-Li Tan
- Abstract
PDF file - 284K, Supplementary Figure S1: (A) High grade prostatic adenocarcinoma with neuroendocrine differentiation by diffuse expression of immunohistochemical markers. This case shows lack of small cell differentiation by hematoxylin and eosin staining (left panel, 200x and inset) based on presence of prominent nucleoli and abundant cytoplasms, without nuclear molding. However, neuroendocrine immunohistochemical markers are diffusely positive (middle panel). Rb protein is present in this case (right panel). (B) Large cell neuroendocrine prostate carcinoma (LCNEC) shows cords and trabeculae of cells, but with abundant pink cytoplasm, which is inconsistent with a diagnosis of small cell carcinoma (left panel and inset). Neuroendocrine markers are diffusely positive (middle panel), however Rb protein is preserved (right panel). (C) Castrate resistant prostate cancer metastasis from autopsy study that has been previously reported (reference 30). This liver metastasis from case 30 (Supplementary Table 1) is heterogeneously positive for Rb protein, with one nodule staining positive (lower left) and nearby nodules staining negative, despite Rb protein in endothelial cells (arrowhead) as an internal positive control. Additional liver and bone tumors from this patient were found to have homozygous deletion of RB1, suggesting inter-metastatic heterogeneity in RB1 status.
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- 2023
44. Data from Development and Clinical Validation of an In Situ Biopsy-Based Multimarker Assay for Risk Stratification in Prostate Cancer
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Fred Saad, Philip Kantoff, Jonathan I. Epstein, Mathieu Latour, Cristina Magi-Galluzzi, Eric A. Klein, Massimo Loda, James Dunyak, Julie Nardone, Eldar Giladi, Hua Chang, Alex Kaprelyants, Aeron Hurley, Christina Ernst, Louis Coupal, Teresa Capela, Sibgat Choudhury, Clayton Small, Thomas P. Nifong, Mathew Putzi, Michail Shipitsin, David L. Rimm, David M. Berman, and Peter Blume-Jensen
- Abstract
Purpose: Prostate cancer aggressiveness and appropriate therapy are routinely determined following biopsy sampling. Current clinical and pathologic parameters are insufficient for accurate risk prediction leading primarily to overtreatment and also missed opportunities for curative therapy.Experimental Design: An 8-biomarker proteomic assay for intact tissue biopsies predictive of prostate pathology was defined in a study of 381 patient biopsies with matched prostatectomy specimens. A second blinded study of 276 cases validated this assay's ability to distinguish “favorable” versus “nonfavorable” pathology independently and relative to current risk classification systems National Comprehensive Cancer Network (NCCN and D'Amico).Results: A favorable biomarker risk score of ≤0.33, and a nonfavorable risk score of >0.80 (possible range between 0 and 1) were defined on “false-negative” and “false-positive” rates of 10% and 5%, respectively. At a risk score ≤0.33, predictive values for favorable pathology in very low-risk and low-risk NCCN and low-risk D'Amico groups were 95%, 81.5%, and 87.2%, respectively, higher than for these current risk classification groups themselves (80.3%, 63.8%, and 70.6%, respectively). The predictive value for nonfavorable pathology was 76.9% at biomarker risk scores >0.8 across all risk groups. Increased biomarker risk scores correlated with decreased frequency of favorable cases across all risk groups. The validation study met its two coprimary endpoints, separating favorable from nonfavorable pathology (AUC, 0.68; P < 0.0001; OR, 20.9) and GS-6 versus non–GS-6 pathology (AUC, 0.65; P < 0.0001; OR, 12.95).Conclusions: The 8-biomarker assay provided individualized, independent prognostic information relative to current risk stratification systems, and may improve the precision of clinical decision making following prostate biopsy. Clin Cancer Res; 21(11); 2591–600. ©2015 AACR.
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- 2023
45. Data from Pro–Prostate-Specific Antigen Measurements in Serum and Tissue Are Associated with Treatment Necessity among Men Enrolled in Expectant Management for Prostate Cancer
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Robert W. Veltri, H. Ballentine Carter, Alan W. Partin, Jonathan I. Epstein, Cameron Marlow, Patricia Landis, Lori J. Sokoll, Sumit Isharwal, and Danil V. Makarov
- Abstract
Purpose: We assessed the association of quantitative clinical and pathologic information, including serum and tissue pro–prostate-specific antigen (proPSA) measurements, with outcomes among men with prostate cancer in an expectant management (active surveillance) program.Experimental Design: We identified 71 men enrolled in expectant management with frozen serum and tissue available from diagnosis: 39 subsequently developed unfavorable biopsies (Gleason score ≥7, ≥3 cores positive for cancer, >50% of any core involved with cancer), whereas 32 maintained favorable biopsies (median follow-up, 3.93 years). Serum total PSA, free PSA (fPSA), and [−2]proPSA were measured by the Beckman Coulter immunoassay. [−5/−7]proPSA was evaluated in cancer and benign-adjacent areas (BAA) by quantitative immunohistochemistry. Cox proportional hazards and Kaplan-Meier analyses were used to identify significant associations with unfavorable biopsy conversion.Results: The ratio [−2]proPSA/% fPSA in serum was significantly higher at diagnosis (0.87 ± 0.44 versus 0.65 ± 0.36 pg/mL; P = 0.02) in men developing unfavorable biopsies. [−5/−7]proPSA tissue staining was more intense (4104.09 ± 3033.50 versus 2418.06 ± 1606.04; P = 0.03) and comprised a greater fractional area (11.58 ± 7.08% versus 6.88 ± 5.20%; P = 0.01) in BAA of these men. Serum [−2]proPSA/% fPSA [hazard ratio, 2.53 (1.18-5.41); P = 0.02], BAA [−5/−7]proPSA % area [hazard ratio, 1.06 (1.01-1.12); P = 0.02] and BAA [−5/−7]proPSA stain intensity [hazard ratio, 1.000213 (1.000071-1.000354); P = 0.003] were significantly associated with unfavorable biopsy in Kaplan-Meier and Cox analyses. Serum [−2]proPSA/% fPSA significantly correlated with BAA [−5/−7]proPSA % area (ρ = 0.40; P = 0.002) and BAA [−5/−7]proPSA stain intensity (ρ = 0.33; P = 0.016).Conclusions: In a prospective cohort of men enrolled into expectant management for prostate cancer, serum and tissue levels of proPSA at diagnosis are associated with need for subsequent treatment. The increase in serum proPSA/% fPSA might be driven by increased proPSA production from “premalignant” cells in the prostate BAA. (Clin Cancer Res 2009;15(23):7316–21)
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- 2023
46. Supplementary Methods, Table S1, Figures S1-7 from Development and Clinical Validation of an In Situ Biopsy-Based Multimarker Assay for Risk Stratification in Prostate Cancer
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Fred Saad, Philip Kantoff, Jonathan I. Epstein, Mathieu Latour, Cristina Magi-Galluzzi, Eric A. Klein, Massimo Loda, James Dunyak, Julie Nardone, Eldar Giladi, Hua Chang, Alex Kaprelyants, Aeron Hurley, Christina Ernst, Louis Coupal, Teresa Capela, Sibgat Choudhury, Clayton Small, Thomas P. Nifong, Mathew Putzi, Michail Shipitsin, David L. Rimm, David M. Berman, and Peter Blume-Jensen
- Abstract
Supplementary Methods, Table S1, Figures S1-7. Methods for quantitative multiplex proteomics imaging (QMPI) Clinical studies: Statistical plan Table S1. Clinical Validation Study. Comparison of Predictive Value of the 8-Biomarker Assay for Favorable Pathology with D'Amico Risk Categories. Figure S1. Outline of all four quantitative multiplex immunofluorescence triplex assay formats Figure S2. Clinical validation study, full cohort (N=276): performance for "GS 6" pathology (surgical Gleason =3+3 and localized {less than or equal to}T3a). A) Sensitivity (P[risk score> threshold| "non-GS 6" pathology]) of the assay, as a function of medical decision level. Figure S3. Clinical validation study, full cohort (N=274): performance for prediction of favorable pathology (surgical Gleason {less than or equal to}3+4 and organ-confined {less than or equal to}T2). Figure S4. Clinical validation study, Subset of validation cohort that contained sufficient annotation for National Comprehensive Cancer Network (NCCN) and D'Amico categorization (N=256) Figure S5. Clinical validation study: performance for prediction of favorable pathology. Figure S6. Net Reclassification Index analysis illustrates how biomarker assay categories of favorable (risk score {less than or equal to}0·33) and non-favorable (risk score >0·8) may supplement NCCN Figure S7. Decision Curve Analysis provides another method for characterizing performance of different risk systems and at different cut points.
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- 2023
47. Data from Roles for the Stem Cell–Associated Intermediate Filament Nestin in Prostate Cancer Migration and Metastasis
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David M. Berman, Jonathan I. Epstein, Ai-Ying Chuang, Mehsati Herawi, Matthew E. Nielsen, G. Steven Bova, and Wolfram Kleeberger
- Abstract
The intermediate filament protein Nestin identifies stem/progenitor cells in adult tissues, but the function of Nestin is poorly understood. We investigated Nestin expression and function in common lethal cancers. Nestin mRNA was detected in cell lines from small cell lung, and breast cancers, and particularly elevated in cell lines derived from prostate cancer metastases. Whereas the androgen-independent lines PC3, 22RV1, and DU145 all expressed Nestin transcripts under standard culture conditions, the androgen-dependent line LnCaP expressed Nestin only on androgen withdrawal. We confirmed associations of Nestin expression, androgen withdrawal, and metastatic potential by immunohistochemical analysis of samples from 254 prostate cancer patients. Cytoplasmic Nestin protein was readily identifiable in prostate cancer cells from 75% of patients with lethal androgen-independent disease, even in cancer sampled from the prostate itself. However, Nestin expression was undetectable in localized androgen-deprived tumors and in metastases without prior androgen deprivation. To address its function, we reduced Nestin levels with short hairpin RNAs, markedly inhibiting in vitro migration and invasion in prostate cancer cells but leaving cell growth intact. Nestin knockdown also diminished metastases 5-fold compared with controls despite uncompromised tumorigenicity at the site of inoculation. These results specify a function for Nestin in cell motility and identify a novel pathway for prostate cancer metastasis. Activity of this pathway may be selected by the extraprostatic environment or, as supported by our data, may originate within the prostate after androgen deprivation. Further dissection of this novel Nestin migration pathway may lead to strategies to prevent and neutralize metastatic spread. [Cancer Res 2007;67(19):9199–206]
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- 2023
48. Supplementary Figure 1 Legend from Roles for the Stem Cell–Associated Intermediate Filament Nestin in Prostate Cancer Migration and Metastasis
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David M. Berman, Jonathan I. Epstein, Ai-Ying Chuang, Mehsati Herawi, Matthew E. Nielsen, G. Steven Bova, and Wolfram Kleeberger
- Abstract
Supplementary Figure 1 Legend from Roles for the Stem Cell–Associated Intermediate Filament Nestin in Prostate Cancer Migration and Metastasis
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- 2023
49. Supplementary Tables 1-2 from Roles for the Stem Cell–Associated Intermediate Filament Nestin in Prostate Cancer Migration and Metastasis
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David M. Berman, Jonathan I. Epstein, Ai-Ying Chuang, Mehsati Herawi, Matthew E. Nielsen, G. Steven Bova, and Wolfram Kleeberger
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Supplementary Tables 1-2 from Roles for the Stem Cell–Associated Intermediate Filament Nestin in Prostate Cancer Migration and Metastasis
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- 2023
50. Supplementary Figure 1 from Roles for the Stem Cell–Associated Intermediate Filament Nestin in Prostate Cancer Migration and Metastasis
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David M. Berman, Jonathan I. Epstein, Ai-Ying Chuang, Mehsati Herawi, Matthew E. Nielsen, G. Steven Bova, and Wolfram Kleeberger
- Abstract
Supplementary Figure 1 from Roles for the Stem Cell–Associated Intermediate Filament Nestin in Prostate Cancer Migration and Metastasis
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- 2023
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