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Division of Genitourinary Pathology


Email jepstein@jhmi.edu
Phone (410) 955-5043

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Division of Surgical Pathology

New Contemporary Prostate Cancer Grading System


Jonathan I. Epstein, M.D.

Director, Division of Genitourinary Pathology
Director, Division of Surgical Pathology
Primary Appointment in Pathology
Secondary Appointments in Oncology and Urology


Carcinoma of the prostate can vary from extremely indolent lesions such as those found incidentally at autopsy to aggressive tumors responsible for the second leading cause of cancer death in men. We have the largest number of completely studied radical prostatectomy specimens in the world and the largest anatomic pathology consult service of genitourinary specimens (>60/day). We are involved in multiple clinico-pathologic studies using a wide range of techniques on both biopsy and prostatectomy specimens to enhance our prognostic capabilities. Tissue microarrays are available for bladder and prostate cancer projects. The consult material also provides the unique opportunity to identify and describe new entities in genitourinary pathology.

Publications
Epstein JI, Walsh PC, CarMichael M, Brendler CB. Pathological and clinical findings to predict tumor extent of non-palpable (stage T1c) prostate cancer JAMA 271:368-374, 1994. Epstein JI, Allsbrook Jr. WC, Amin MB, Egevad LL & The ISUP grading committee. The 2005 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma. Am J Surg Pathol 29: 1228-42, 2005.

Epstein JI, Amin MB, Reuter VR, Mostofi FK, and the Bladder Consensus Conference Committee. The World Health Organization/International Society of Urological Pathology Consensus Classification of Urothelial (Transitional Cell) Neoplasms of the Urinary Bladder. Am J Surg Pathol 22:1435-1448, 1998.

Pan C-C, Potter SR, Partin AW, Epstein, JI. The prognostic significance of tertiary Gleason patterns of higher grade in radical prostatectomy specimens: a proposal to modify the Gleason grading system Am J Surg Pathol 24:563-569, 2000.

Duffield A, Epstein JI. Detection of cancer in radical prostatectomy specimens with no residual carcinoma in the initial specimen. Am J Surg Pathol (January) 33:120-125,2009.




Email ljarend@jhu.edu
Phone (443) 287-0166
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Lois J. Arend, M.D., Ph.D.

Primary Appointment in Pathology


My laboratory studies the mechanisms of mammalian kidney development. Specifically, our studies involve various cell and molecular biology techniques to determine the role of the bioactive sphingolipid, sphingosine-1-phosphate (S1P), in organogenesis of the kidney. Our research indicates that S1P may be involved in development of conditions such as cystic kidney disease and Meckel syndrome. We also study the pathologic aspects of other kidney disease by various morphologic techniques, including light, immunofluorescence, and electron microscopy.

Publications
Arend LJ, Smart AM, and JP Briggs. Metanephric rat-mouse chimeras to study cell lineage of the nephron. Developmental Genetics 24(3/4):230-240, 1999

Arend LJ, Smart A, and JP Briggs. Mouse beta 6 integrin sequence, pattern of expression, and role in kidney development. J Am Soc Nephrol 11:2297-2305, 2000

Phillips CL, Arend LJ, Filson A, Kojetin D, Clendenon J, Fang S, and KW Dunn. Three dimensional imaging of embryonic mouse kidney by two-photon microscopy. Am J Pathol 158(1):49-55, 2001

Fu J, Jin Y, and LJ Arend. Smac3, a novel Smac/DIABLO splicing variant, attenuates the stability and apoptosis-inhibiting activity of XIAP. J Biol Chem Dec 26;278(52):52660-72, 2003

Lorenz, JN, L.J. Arend, R Robitz, RJ Paul, AJ MacLennan. Vascular dysfunction in S1P2 sphingosine-1-phosphate receptor knockout mice. American Journal of Physiology- Regulatory, Integrative and Comparative Physiol 292(1):R440-6, 2007

Kirby RJ, Jin Y, Fu J, Cubillos J, Swertfeger, D, Arend LJ. Dynamic regulation of sphingosine-1-phosphate homeostasis is critical for branching morphogenesis of the mouse metanephric kidney. Am J Physiol Renal Physiol 296:F634-F641, 2009

Kirby RJ, Swertfeger, D, Arend LJ. Crosstalk between GDNF/RET and S1P/S1PR signaling pathways regulates kidney epithelial cell migration. In Preparation.




Email sbagnas1@jhmi.edu
Phone (410) 502-0812
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Serena M. Bagnasco, M.D.

Primary Appointment in Pathology


Research interests currently include pathologic aspects and molecular markers of renal allograft dysfunction, and of native kidney disease. Studies are ongoing exploring new sources of potential biomarkers that can improve distinguishing among different types of injury in the transplanted kidney. Digital pathology of morphologic features of native kidney biopsies is being applied in correlation with clinical and molecular parameters for the analysis of proteinuric glomerular diseases in large multicenter, prospective, observational studies.

Publications
Pisitkun T, Gandolfo MT, Knepper M, Bagnasco SM. Application of system biology principles to protein biomarker discovery: urinary exosomal proteome in renal transplantation. Proteomics Clin. Appl. 2012;6(5-6):268-78.

Barisoni L, Nast CC, Jennette JC, Hodgin JB, Herzenberg AM, Lemley KV, Conway CM, Kopp JB, Kretzler M, Lienczewski C, Avila-Casado C, Bagnasco SM, Sethi S, Tomazewski J, Gasim AH, Hewitt SM. Digital pathology evaluation in the multicenter nephritic syndrome study network (NEPTUNE). Clin J Am Soc Nephrol. 2013;8:1449-59.

Bagnasco SM, Zachary AA, Racusen LC, Arend LJ, Carter-Monroe N, Alachkar N, Nazarian SM, Lonze BE, Montgomery RA, Kraus ES. Time Course of Pathologic Changes in Kidney Allografts of Positive Crossmatch HLA-Incompatible Transplant Recipients. Transplantation. 2014; 97:440-445.

Jackson AM, Sigdel TK, Delville M, Hsieh SC, Dai H, Bagnasco SM, Montgomery RA, Sarwal MM. Endothelial cell antibodies associated with novel targets and increased rejection. J Am Soc Nephrol. 2015; 26:1161-71.

Sampson MG, Robertson CC, Martini S, Mariani L, Lemley K, Gillies CE, Otto EA, Kopp JB, Randolph A, Vega-Warner V, Eichinger F, Nair V, Gipson DS, Cattran D, Johnstone D, O’Toole J, Bagnasco S, Song P, Barisoni L, Troost J, Kretzler M, Sedor J, and the Nephrotic Syndrome Study Network: Integrative genomics identifies novel associations with APOL1 risk genotype in African American NEPTUNE subjects. J Am Soc Nephrol 2015 (in press)

Bagnasco SM. Intimal arteritis in renal allografts: new takes on an old lesion. -Current Opinion in Transplantation, 2015 (in press).




Email ademarz@jhmi.edu
Phone (410) 614-5686

Related Websites
DeMarzo Laboratory

Tissue Microarray Core

Brady Urological Institute

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Angelo M. DeMarzo, M.D., Ph.D.

Primary Appointment in Pathology
Secondary Appointments in Oncology and Urology
Member; Graduate Program in Pathobiology


We study the molecular pathogenesis of prostate cancer development and progression including:

i) studies of etiological factors including the role of inflammation; and
ii) the molecular alterations responsible for driving the development of neoplastic precursors (prostatic intraepithelial neoplasia – PIN) as well as disease progression.

We study how MYC oncogene overexpression leads to PIN and prostate cancer and how MYC cooperates with PTEN loss in disease progression. We employ a number of molecular pathology techniques to human tissues as well mouse models, and, molecular techniques to cell culture systems.

We collaborate extensively with a number of other investigators as well as research team consisting of basic scientists/molecular biologists, epidemiologists, bioinformaticists, medical oncologists and urologists.

Publications

Nelson, W.G., De Marzo, A.M., and Isaacs, W.B. Mechanisms of disease. The molecular pathogenesis of prostate cancer: a new role for inflammation? New Eng. J. Med., 349:366-81, 2003.

De Marzo AM, Platz EA, Sutcliffe S, Xu J, Grönberg H, Drake CG, Nakai Y, Isaacs WB, Nelson WG. Inflammation in prostate carcinogenesis. Nat Rev Cancer. 2007;7:256-69.

Koh CM, Gurel B, Sutcliffe S, Aryee MJ, Schultz D, Iwata T, Uemura M, Zeller KI, Anele U, Zheng Q, Hicks JL, Nelson WG, Dang CV, Yegnasubramanian S, De Marzo AM. Alterations in nucleolar structure and gene expression programs in prostatic neoplasia are driven by the MYC oncogene. Am J Pathol. 2011 Apr;178(4):1824-34.

Xu J, Hicks JL, Park BH, Humphreys E, Partin AW, Han M, Netto GJ, Isaacs WB, De Marzo AM. PTEN protein loss by immunostaining: analytic validation and prognostic indicator for a high risk surgical cohort of prostate cancer patients. Clin Cancer Res. 2011; 17:6563-73.

Sfanos KS, Canene-Adams K, Hempel H, Yu SH, Simons BW, Schaeffer AJ, Schaeffer EM, Nelson WG, De Marzo AM. Bacterial Prostatitis Enhances 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]Pyridine (PhIP)-Induced Cancer at Multiple Sites. Cancer Prev Res. 2015; 8:683-92.

Haffner MC, Weier C, Xu M, Vaghasia A, Gürel B, Gümüşkaya B, Esopi DM, Fedor H, Tan HL, Kulac I, Hicks J, Isaacs WB, Lotan TL, Nelson WG, Yegnasubramanian S, De Marzo AM. Molecular evidence that invasive adenocarcinoma can mimic prostatic intraepithelial neoplasia (PIN) and intraductal carcinoma through retrograde glandular colonization. J Pathol. 2015 Aug 31. doi: 10.1002/path.4628.

Hubbard GK, Mutton LN, Khalilia M, McMullin RP, Hicks JL, Bianchi-Frias D, Horn LA, Kulac I, Moubarek MS, Nelson PS, Yegnasubramanian S, De Marzo AM, and Bieberich CJ. Combined MYC activation and Pten loss are sufficient to create genomic instability and lethal metastatic prostate cancer. Can Res, 2015, In Press




Email cheaphy@jhmi.edu
Phone (443) 287-4730
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Christopher M. Heaphy, Ph.D.

Primary Appointment in Pathology


The overall research goal of my laboratory is to further understand the contribution of telomere biology in cancer development and progression. For a variety of human cancers (eg. prostate, breast, ovarian, brain, pancreas), new molecular biomarkers are urgently needed for improving risk assessment and for accurate prognostication of the disease to improve upon current prevention and treatment strategies. One molecular marker that may address these clinical problems is tissue-based telomere length measurements. Telomeres are nucleoprotein complexes that function to protect and stabilize the chromosomal ends by preventing chromosome fusions, masking inappropriate double strand DNA break damage signals, and inhibiting exonucleolytic degradation. In addition to assessing the translational potential of telomere length measurements, my laboratory also is working to elucidate the underlying mechanisms of tumor initiation and progression (e.g through telomere length alterations), as well as understanding how the interactions between the tumor and its' tissue microenvironment may facilitate this process.

Publications
Heaphy CM, de Wilde RF, Jiao Y, Klein AP, Edil BH, Shi C, Bettegowda C, Rodriguez FJ, Eberhart CG, Hebbar S, Offerhaus GJ, McLendon R, Rasheed BA, He Y, Yan H, Bigner DD, Oba-Shinjo SM, Nagahashi Marie SK, Riggins GJ, Kinzler KW, Vogelstein B, Hruban RH, Maitra A, Papadopoulos N, Meeker AK. Altered telomeres in tumors with ATRX and DAXX mutations. Science, 333:425, 2011.

Heaphy CM, Subhawong AP, Hong SM, Goggins MG, Montgomery EA, Gabrielson E, Netto GJ, Epstein JI, Lotan TL, Westra WH, Shih IM, Iacobuzio-Donahue CA, Maitra A, Li QK, Eberhart CG, Taube JM, Rakheja D, Kurman RJ, Wu T, Roden RB, Argani P, De Marzo AM, Terracciano L, Torbenson M, Meeker AK. Prevalence of the Alternative Lengthening of Telomeres (ALT) telomere maintenance mechanism in human cancer subtypes. The American Journal of Pathology, 179:1608-1615, 2011.

Heaphy CM, Schreck KC, Raabe E, Mao X, Chu Q, An P, Poh W, Jiao Y, Rodriguez FJ, Odia Y, Meeker AK, Eberhart CG. A glioblastoma neurosphere line with alternative lengthening of telomeres. Acta Neuropathologica, 126:607-8, 2013.

Heaphy CM, Yoon GS, Peskoe SB, Joshu CE, Lee TK, Giovannucci E, Mucci LA, Kenfield SA, Stampfer MJ, Hicks JL, De Marzo AM, Platz EA, Meeker AK. Prostate cancer cell telomere length variability and stromal cell telomere length as prognostic markers for metastasis and death. Cancer Discovery, 3:1130-41, 2013.

Heaphy CM, Gaonkar G, Peskoe SB, Joshu CE, De Marzo AM, Lucia MS, Goodman PJ, Lippman SM, Thompson IM, Platz EA, Meeker AK. Prostate stromal cell telomere shortening is associated with risk of prostate cancer in the placebo arm of the Prostate Cancer Prevention Trial. The Prostate, 2015. doi: 10.1002/pros.22997.




Email tlotan1@jhmi.edu
Phone (410) 434-1003

Related Websites
Institute for Basic Biomedical Sciences

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Tamara Lotan, M.D.

Primary Appointment in Pathology; Secondary Appointment in Oncology


I am a urologic pathologist with a research laboratory focused on the role of PTEN/PI3K/mTOR signaling in epithelial development and tumorigenesis. My basic science lab works with a number of epithelial systems (prostate, breast, skin) and we are principally interested in understanding how these oncogenic signaling pathways regulate epithelial differentiation, apico-basal polarity and cell migration. Using transgenic mouse models combined with 3D culture and state-of-the-art live cell imaging techniques, our hope is that by understanding the role of this signal transduction network in epithelial embryonic development, we can help to elucidate the significance of these oncogenic signals during tumorigenesis and tumor progression.

The more translational arm of my laboratory effort is focused on validating PTEN as a potential predictive and prognostic biomarker in prostate cancer, and on defining alternative mechanisms of PTEN inactivation in prostate cancer. We also have an ongoing interest in the molecular phenotype of rare subtypes of prostate cancer, including small cell carcinoma, p63-positive prostatic carcinoma and intraductal prostatic carcinoma.

Publications

Lotan TL, Wang W,Gupta NS, Toubaji A, Haffner MC, Meeker AK, De Marzo AM, Epstein JI, and Netto GJ. ERG Gene Rearrangements are Common in Prostatic Small Cell Carcinoma. Modern Pathology. 2011; 24(6):820-8.

Lotan TL, Gurel B, Sutcliffe S, Esopi D, Liu W, Xu J, Hicks JL, Park BH, Humphreys E, Partin AW, Han M, Netto GJ, Isaacs WB, De Marzo AM. PTEN Protein Loss by Immunostaining: Analytic Validation and Prognostic Indicator for a High Risk Surgical Cohort of Prostate Cancer Patients. Clinical Cancer Research. 2011; 17(20):6563-73.

Ghosh S, Lau H, Simons BW, Powell JD, Meyers DJ, De Marzo AM, Berman DM, Lotan TL. PI3K/mTOR Signaling Regulates Prostatic Branching Morphogenesis. Developmental Biology. 2011; 360(2):329-42.




Email ameeker@mail.jhmi.edu
Phone (410) 502-3398
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Alan K. Meeker, Ph.D.

Primary Appointment in Pathology; Secondary Appointment in Urology


Telomere Shortening in Cancer

The genesis and progression of cancer is thought to depend upon genetic instability. This is clearly seen at the chromosomal level in epithelial cancers, such as prostate and breast cancers, which show chromosomal instability as reflected by aberrations in both chromosomal number and structure, yet the molecular mechanisms responsible for chromosome destabilization during carcinogenesis and progression are largely unknown. Our lab is examining defective telomeres which appear to be an important route to chromosomal instability. Telomeres are specialized chromosomal structures consisting of terminal DNA tracts and associated binding proteins. Telomeres protect chromosome ends from fusing with other chromosome ends or other chromosomes containing DNA double strand breaks. In the absence of the telomere synthetic enzyme telomerase, telomeric DNA is subject to loss during cell division. Results from telomerase knockout mouse models indicate that telomere shortening can lead to an increased incidence of cancer in these animals, thus apparently playing a role in cancer initiation.

In close collaboration with Angelo De Marzo’s lab in the John Hopkins Pathology Department, we developed a novel quantitative fluorescence microscopy technique to measure telomere lengths directly in archival tissues, in order to find out if telomere shortening is playing a role in the initiation of human cancers. Making use of this technique in collaborative efforts with other faculty members in the Johns Hopkins Department of Pathology (Drs. Pedram Argani, Theresa Chan, Christine Iacobuzio-Donahue, Elizabeth Montgomery, Bridgette Ronnett and William Westra) we found that, indeed, telomeres are abnormally short in the vast majority of microscopic cancer precursor lesions in common epithelial cancers, including those of the bladder, breast, cervix, colon, esophagus, gall bladder, oral cavity and prostate.

Telomere length abnormalities appear to be one of the earliest and most prevalent molecular genetic alterations acquired in the multi-step process of tumorigenesis. These findings support a model whereby telomere dysfunction induces a mutator phenotype that acts at the chromosomal and sub-chromosomal levels to accelerate tumor development. We hypothesize that pre-malignant lesions displaying short telomeres are poised on the edge of genetic instability, and are therefore at risk of progressing on to fully invasive carcinomas.

Practically speaking, telomere shortening may have utility in cancer diagnosis, as well as an intermediate endpoint marker in chemoprevention studies. In addition, if telomere shortening is indeed playing a causal role in cancer initiation, then it represents a valid prevention target in its own right.

Telomere Shortening in Aging

Cells normally respond to short telomeres by halting their cell division activities or by committing cellular suicide (apoptosis). It is thought that these responses evolved in long-lived multicellular organisms to prevent the outgrowth of potentially cancerous cell populations. It has been postulated that a loss of division potential due to telomere shortening in proliferating tissues might contribute to certain age-related pathologies, such as the decreased wound healing seen in the elderly. This theory has been difficult to evaluate, as previous methods of telomere length measurement only gave information on the average telomere length of a large number of cells combined.

We believe that our telomere length assay, which features single cell resolution, can be used to test the hypothesized link between telomere shortening and human aging.

Publications

Meeker, A.K., Gage, W.R., Simon, I., Coffman, J.R., Platz, E.A., March, G., and DeMarzo, A.M. Telomere Length Assessment in Human Archival Tissues: Combined Telomere Fluorescent in Situ Hybridization and Immunostaining. American Journal of Pathology. 160:1259-1268, 2002.

Meeker, A.K., Hicks, J.L., Platz, E.A., March, G.E., Bennett, C.J., and De Marzo, A.M. Telomere Shortening is an Early Somatic DNA Alteration in Human Prostate Tumorigenesis. Cancer Research. 62:6405-6409, 2002.

Montgomery, E.A., Argani, P., Hicks, J.L., DeMarzo, A.M., and Meeker, A.K. Telomere Lengths of Translocation Associated and Non-Translocation Associated Sarcomas Differ Dramatically. American Journal of Pathology. 164:1523-1529, 2004.

Meeker, A.K., Hicks, J.L., Iacobuzio-Donahue, C.A., Montgomery, E.A., Westra, W.H., Chan, T.Y., Ronnett, B.M., and DeMarzo, A.M. Telomere Length Abnormalities Occur Early in the Initiation of Epithelial Carcinogenesis. Clinical Cancer Research. 10:3317-3326, 2004.

Meeker, A.K., Hicks, J.L., Gabrielson, E., Strauss, W.M., De Marzo, A.M., and Argani, P. Telomere Shortening Occurs in Subsets of Normal Breast Epithelium as well as In Situ and Invasive Carcinoma. American Journal of Pathology. 164:925-935, 2004.




Email lracusen@jhmi.edu
Phone (410) 955-2386
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Lorraine C. Racusen, M.D.

Primary Appointment in Pathology


The focus of our research is on injury to the kidney. We are also studying morphologic aspects of native kidney and renal allograft injury and rejection, utilizing in-house biopsies and consultant cases, and computerized morphometric techniques. Current projects include pathologic correlates of antibody mediated rejection, assessment of chronic changes in renal allografts, and urinary molecule markers of renal allograft rejection. We are also collaborating with colleagues in nephrology to characterize animal models of acute and chronic renal injury.

Publications
Messias NC, Eustace J, Zachary AA, Tucker PC, Charney D, Racusen LC. Cohost study of the prognostic significance of acute transplant glomerulitisin acutely rejecting renal allografts. Transplantation 74: 655-60, 2001.

Solez K, Racusen LC. Role of renal biopsy in acute renal failure. Contrib. Nephrol. 132: 68-75, 2001.

Racusen LC, Solez K, Colvin R. Fibrosis and atrophy in the renal allograft - Interim report and new directions. Am J Transplan 2:203-6, 2002

Racusen LD, Colvin RB, Solez K, et al. Antibody-mediated rejection criteria - An addition to the Banff 97 classification of renal allograft rejection. Am J Transplant 3:708-14, 2003




Email ksfanos@jhmi.edu
Phone (443) 287-4592

Related Websites
DeMarzo Laboratory

The Sfanos Lab

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Karen S. Sfanos, Ph.D.

Primary Appointment in Pathology


The Sfanos lab focuses on the study of human prostate cancer, with a particular emphasis on cancer prevention strategies as well as the etiological factors which may contribute to prostate cancer initiation and/or progression. We are specifically interested in agents that may lead to chronic prostatic inflammation, such as bacterial infections and prostatic concretions called corpora amylacea. Our work is based on the hypothesis that inflammation plays a key role in the development of the proposed “risk factor lesions” to human prostate cancer, i.e., proliferative inflammatory atrophy (PIA) and high grade prostatic intraepithelial neoplasia (PIN). Our previous studies have demonstrated the presence of multiple microbial species in the prostate of cancer patients and, importantly, many of the organisms identified are consistent with genera associated with inflammation-associated conditions including bacterial prostatitis and/or urinary tract infections. Dr. Sfanos works very closely with both genitourinary pathologists as well as epidemiologists in an effort to correlate discoveries in the laboratory with prostate cancer risk as well as disease pathology.

Publications

Sfanos K.S., Bruno T.C., Maris C.H., Xu L., Thoburn C.J., De Marzo A.M., Meeker A.K., Isaacs W.B., Drake C.G. Phenotypic analysis of prostate-infiltrating lymphocytes reveals TH17 and Treg skewing. Clinical Cancer Research, 14:3254-3261, 2008.

Sfanos K.S., Wilson B.A., De Marzo A.M., Isaacs W.B. Acute inflammatory proteins constitute the organic matrix of prostatic corpora amylacea and calculi in men with prostate cancer. Proceedings of the National Academy of Sciences (PNAS) U.S.A., 106:3443-3448, 2009.

Aloia A.L., Sfanos K.S.*, Isaacs W.B., Zheng Q., Maldarelli F., De Marzo A.M., Rein A. XMRV: A new virus in prostate cancer? Cancer Research, 70:10028-10033, 2010.

Shinohara D.B., Vaghasia A., Yu S-H., Mak T.N., Brüggemann H., Nelson W.G., De Marzo A.M., Yegnasubramanian S., Sfanos K.S. A mouse model of chronic prostatic inflammation using a human prostate cancer-derived isolate of Propionibacterium acnes. Prostate, 73(9):1007-1015, 2013.

Sfanos K.S., Canene-Adams K., Hempel H., Yu S.-H., Simons B.W., Schaeffer A.J., Schaeffer E.M., Nelson W.G., De Marzo A.M. Bacterial prostatitis enhances 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced cancer at multiple sites. Cancer Prevention Research, Online AOP, 2015. doi: 10.1158/1940-6207

Yu S.-H., Zheng Q., Esopi D., Luo J., Macgregor-Das A., Antonarakis E.S., Vessella R., Morrissey C., De Marzo A.M., Sfanos K.S. A paracrine role for IL-6 in prostate cancer patients: Lack of production by primary or metastatic tumor cells. Cancer Immunology Research, Online AOP, 2015. doi: 10.1158/2326-6066



 


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