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Item Dietary factors and risk for advanced prostate cancer(Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2014-03) Gathirua-Mwangi, Wambui G.; Zhang, Jianjun; Department of Epidemiology, Richard M. Fairbanks School of Public HealthProstate cancer is the second most common cancer among men worldwide. Although some nutrients have been linked to the development of total prostate cancer, it remains unclear whether these nutrients modulate the risk of its clinically significant form - advanced tumor. Therefore, this study sought to perform a systematic review of the literature on this topic. The papers reviewed were identified from PubMed using keywords diet and advanced, metastatic, or lethal prostate cancer. A total of 46 papers published until September 2012 met our eligibility criteria and thus were evaluated in this review. Epidemiologic studies have shown that, overall, the habitual consumption of a diet high in saturated fat, well-done meats, and calcium is associated with an increased risk for advanced prostate cancer. An inconsistent association was observed for intake of total meat, fruits, and vegetables. Although most case-control studies suggest that intake of these nutrients or foods significantly alters advanced prostate cancer risk, cohort studies yielded mixed results. No apparent effect of fish and zinc intake on advanced prostate cancer was found in most epidemiologic studies. Epidemiologic studies conducted to date have revealed that some dietary factors modulate the risk for advanced prostate cancer. If these findings are confirmed by more adequately powered epidemiologic studies, especially prospective cohort studies that measure the nutrients and their biochemical indicators, the risk of advanced prostate cancer, which is fatal and thus clinically significant, may be reduced by dietary modification or chemoprevention.Item Dramatic polarization in genitourinary expert opinions regarding the clinical utility of positron emission tomography (PET) imaging in prostate cance(SciELO, 2019-01) Sandler, Kiri A.; McClelland, Shearwood, III; Degnin, Catherine; Chen, Yiyi; Mitin, Timur; Radiation Oncology, School of MedicineOBJECTIVES: To ascertain the opinions of North American genitourinary (GU) experts regarding inclusion of technologies such as prostate - specific membrane antigen (PSMA) and C - 11 choline positron emission tomography (PET) into routine practice. MATERIALS AND METHODS: A survey was distributed to North American GU experts. Questions pertained to the role of PSMA and C - 11 PET in PCa management. Participants were categorized as "supporters" or "opponents" of incorporation of novel imaging techniques. Opinions were correlated with practice patterns. RESULTS: Response rate was 54% and we analyzed 42 radiation oncologist respondents. 17 participants (40%) have been in practice for > 20 years and 38 (90%) practice at an academic center. 24 (57%) were supporters of PSMA and 29 (69%) were supporters of C - 11. Supporters were more likely to treat pelvic nodes (88% vs. 56%, p < 01) and trended to be more likely to treat patients with moderate or extreme hypofractionation (58% vs. 28%, p = 065). Supporters trended to be more likely to offer brachytherapy boost (55% vs. 23%, p = 09), favor initial observation and early salvage over adjuvant radiation (77% vs. 55%, p = 09), and to consider themselves expert brachytherapists (69% vs. 39%, p = 09). CONCLUSIONS: There is a polarization among GU radiation oncology experts regarding novel imaging techniques. A correlation emerged between support of novel imaging and adoption of treatment approaches that are clinically superior or less expensive. Pre - existing biases among GU experts on national treatment - decision panels and leaders of cooperative group studies may affect the design of future studies and influence the adoption of these technologies in clinical practice.Item Excess TGF-β mediates muscle weakness associated with bone metastases in mice(SpringerNature, 2015-11) Waning, David L.; Mohammad, Khalid S.; Reiken, Steven; Xie, Wenjun; Andersson, Daniel C.; John, Sutha; Chiechi, Antonella; Wright, Laura E.; Umanskaya, Alisa; Niewolna, Maria; Trivedi, Trupti; Charkhzarrin, Sahba; Khatiwada, Pooja; Wronska, Anetta; Haynes, Ashley; Benassi, Maria Serena; Witzmann, Frank A.; Zhen, Gehua; Wang, Xiao; Cao, Xu; Roodman, G. David; Marks, Andrew R.; Guise, Theresa A.; Department of Medicine, IU School of MedicineCancer-associated muscle weakness is a poorly understood phenomenon, and there is no effective treatment. Here we find that seven different mouse models of human osteolytic bone metastases-representing breast, lung and prostate cancers, as well as multiple myeloma-exhibited impaired muscle function, implicating a role for the tumor-bone microenvironment in cancer-associated muscle weakness. We found that transforming growth factor (TGF)-β, released from the bone surface as a result of metastasis-induced bone destruction, upregulated NADPH oxidase 4 (Nox4), resulting in elevated oxidization of skeletal muscle proteins, including the ryanodine receptor and calcium (Ca(2+)) release channel (RyR1). The oxidized RyR1 channels leaked Ca(2+), resulting in lower intracellular signaling, which is required for proper muscle contraction. We found that inhibiting RyR1 leakage, TGF-β signaling, TGF-β release from bone or Nox4 activity improved muscle function in mice with MDA-MB-231 bone metastases. Humans with breast- or lung cancer-associated bone metastases also had oxidized skeletal muscle RyR1 that is not seen in normal muscle. Similarly, skeletal muscle weakness, increased Nox4 binding to RyR1 and oxidation of RyR1 were present in a mouse model of Camurati-Engelmann disease, a nonmalignant metabolic bone disorder associated with increased TGF-β activity. Thus, pathological TGF-β release from bone contributes to muscle weakness by decreasing Ca(2+)-induced muscle force production.Item Extracellular Signal-Regulated Kinase Signaling Regulates the Opposing Roles of JUN Family Transcription Factors at ETS/AP-1 Sites and in Cell Migration(American Society for Microbiology, 2015-01) Selvaraj, Nagarathinam; Budka, Justin A.; Ferris, Mary W.; Plotnik, Joshua P.; Hollenhorst, Peter C.; Health Sciences, School of Health and Rehabilitation SciencesJUN transcription factors bind DNA as part of the AP-1 complex, regulate many cellular processes, and play a key role in oncogenesis. The three JUN proteins (c-JUN, JUNB, and JUND) can have both redundant and unique functions depending on the biological phenotype and cell type assayed. Mechanisms that allow this dynamic switching between overlapping and distinct functions are unclear. Here we demonstrate that JUND has a role in prostate cell migration that is the opposite of c-JUN's and JUNB's. RNA sequencing reveals that opposing regulation by c-JUN and JUND defines a subset of AP-1 target genes with cell migration roles. cis-regulatory elements for only this subset of targets were enriched for ETS factor binding, indicating a specificity mechanism. Interestingly, the function of c-JUN and JUND in prostate cell migration switched when we compared cells with an inactive versus an active RAS/extracellular signal-regulated kinase (ERK) signaling pathway. We show that this switch is due to phosphorylation and activation of JUND by ERK. Thus, the ETS/AP-1 sequence defines a unique gene expression program regulated by the relative levels of JUN proteins and RAS/ERK signaling. This work provides a rationale for how transcription factors can have distinct roles depending on the signaling status and the biological function in question.Item FHIT expression in prostate tumors(2001) Fouts, Rebecca L.Item A high-throughput screen identifies inhibitors of the interaction between the oncogenic transcription factor ERG and the cofactor EWS(Public Library of Science, 2020-09-11) Nicholas, Taylor R.; Meng, Jingwei; Greulich, Benjamin M.; Morris, Teresa Stevie; Hollenhorst, Peter C.; Biochemistry and Molecular Biology, School of MedicineAberrant expression of the transcription factor ERG is a key driving event in approximately one-half of all of prostate cancers. Lacking an enzymatic pocket and mainly disordered, the structure of ERG is difficult to exploit for therapeutic design. We recently identified EWS as a specific interacting partner of ERG that is required for oncogenic function. In this study, we aimed to target this specific protein-protein interaction with small molecules. A high-throughput screening (HTS) strategy was implemented to identify potential protein-protein interaction inhibitors. Secondary assays verified the function of several hit compounds, and one lead compound inhibited ERG-mediated phenotypes in prostate cells. This is the first study aimed at targeting the ERG-EWS protein-protein interaction for the development of a small molecule-based prostate cancer therapy.Item Interaction with ZMYND11 mediates opposing roles of Ras-responsive transcription factors ETS1 and ETS2(Oxford University Press, 2017-05-05) Plotnik, Joshua P.; Hollenhorst, Peter C.; Biology, School of ScienceAberrant activation of RAS/MAPK signaling is a driver of over one third of all human carcinomas. The homologous transcription factors ETS1 and ETS2 mediate activation of gene expression programs downstream of RAS/MAPK signaling. ETS1 is important for oncogenesis in many tumor types. However, ETS2 can act as an oncogene in some cellular backgrounds, and as a tumor suppressor in others, and the molecular mechanism responsible for this cell-type specific function remains unknown. Here, we show that ETS1 and ETS2 can regulate a cell migration gene expression program in opposite directions, and provide the first comparison of the ETS1 and ETS2 cistromes. This genomic data and an ETS1 deletion line reveal that the opposite function of ETS2 is a result of binding site competition and transcriptional attenuation due to weaker transcriptional activation by ETS2 compared to ETS1. This weaker activation was mapped to the ETS2 N-terminus and a specific interaction with the co-repressor ZMYND11 (BS69). Furthermore, ZMYND11 expression levels in patient tumors correlated with oncogenic versus tumor suppressive roles of ETS2. Therefore, these data indicate a novel and specific mechanism allowing ETS2 to switch between oncogenic and tumor suppressive functions in a cell-type specific manner.Item Is moderate hypofractionation accepted as a new standard of care in north america for prostate cancer patients treated with external beam radiotherapy? Survey of genitourinary expert radiation oncologists(Sociedade Brasileira de Urologia, 2019-03) McClelland, Shearwood; Sandler, Kiri A.; Degnin, Catherine; Chen, Yiyi; Hung, Arthur Y.; Mitin, Timur; Radiation Oncology, School of MedicineINTRODUCTION: Several recent randomized clinical trials have evaluated hypofractionated regimens against conventionally fractionated EBRT and shown similar effectiveness with conflicting toxicity results. The current view regarding hypofractionation compared to conventional EBRT among North American genitourinary experts for management of prostate cancer has not been investigated. MATERIALS AND METHODS: A survey was distributed to 88 practicing North American GU physicians serving on decision - making committees of cooperative group research organizations. Questions pertained to opinions regarding the default EBRT dose and fractionation for a hypothetical example of a favorable intermediate - risk prostate cancer (Gleason 3 + 4). Treatment recommendations were correlated with practice patterns using Fisher's exact test. RESULTS: Forty - two respondents (48%) completed the survey. We excluded from analysis two respondents who selected radical hypofractionation with 5 - 12 fractions as a preferred treatment modality. Among the 40 analyzed respondents, 23 (57.5%) recommend conventional fractionation and 17 (42.5%) recommended moderate hypofractionation. No demographic factors were found to be associated with preference for a fractionation regimen. Support for brachytherapy as a first choice treatment modality for low - risk prostate cancer was borderline significantly associated with support for moderate hypofractionated EBRT treatment modality (p = 0.089). CONCLUSIONS: There is an almost equal split among North American GU expert radiation oncologists regarding the appropriateness to consider moderately hypofractionated EBRT as a new standard of care in management of patients with prostate cancer. Physicians who embrace brachytherapy may be more inclined to support moderate hypofractionated regimen for EBRT. It is unclear whether reports with longer followups will impact this balance, or whether national care and reimbursement policies will drive the clinical decisions. In the day and age of patient - centered care delivery, patients should receive an objective recommendation based on available clinical evidence. The stark division among GU experts may influence the design of future clinical trials utilizing EBRT for patients with prostate cancer.Item Lovastatin enhances adenovirus-mediated TRAIL induced apoptosis by depleting cholesterol of lipid rafts and affecting CAR and death receptor expression of prostate cancer cells(Impact Journals, LLC, 2015-02-20) Liu, Youhong; Chen, Lin; Gong, Zhicheng; Shen, Liangfang; Kao, Chinghai; Hock, Janet M.; Sun, Lunquan; Li, Xiong; Department of Urology, IU school of MedicineOncolytic adenovirus and apoptosis inducer TRAIL are promising cancer therapies. Their antitumor efficacy, when used as single agents, is limited. Oncolytic adenoviruses have low infection activity, and cancer cells develop resistance to TRAIL-induced apoptosis. Here, we explored combining prostate-restricted replication competent adenovirus-mediated TRAIL (PRRA-TRAIL) with lovastatin, a commonly used cholesterol-lowering drug, as a potential therapy for advanced prostate cancer (PCa). Lovastatin significantly enhanced the efficacy of PRRA-TRAIL by promoting the in vivo tumor suppression, and the in vitro cell killing and apoptosis induction, via integration of multiple molecular mechanisms. Lovastatin enhanced PRRA replication and virus-delivered transgene expression by increasing the expression levels of CAR and integrins, which are critical for adenovirus 5 binding and internalization. Lovastatin enhanced TRAIL-induced apoptosis by increasing death receptor DR4 expression. These multiple effects of lovastatin on CAR, integrins and DR4 expression were closely associated with cholesterol-depletion in lipid rafts. These studies, for the first time, show correlations between cholesterol/lipid rafts, oncolytic adenovirus infection efficiency and the antitumor efficacy of TRAIL at the cellular level. This work enhances our understanding of the molecular mechanisms that support use of lovastatin, in combination with PRRA-TRAIL, as a candidate strategy to treat human refractory prostate cancer in the future.Item Nationally representative trends and geographic variation in treatment of localized prostate cancer: the Urologic Diseases in America project(Nature Publishing Group, 2015-06) Cary, K. C.; Punnen, S.; Odisho, A. Y.; Litwin, M. S.; Saigal, C. S.; Cooperberg, M. R.; NIDDK Urologic Diseases in America Project; Department of Urology, IU School of MedicineBACKGROUND: Several treatment options for clinically localized prostate cancer currently exist under the established guidelines. We aim to assess nationally representative trends in treatment over time and determine potential geographic variation using two large national claims registries. METHODS: Men with prostate cancer insured by Medicare (1998-2006) or a private insurer (Ingenix database, 2002-2006) were identified using International Classification of Diseases-9 and Current Procedural Terminology-4 codes. Geographic variation and trends in the type of treatment utilized over time were assessed. Geographic data were mapped using the GeoCommons online mapping platform. Predictors of any treatment were determined using a hierarchical generalized linear mixed model using the logit link function. RESULTS: The use of radical prostatectomy increased, 33-48%, in the privately insured i3 database while remaining stable at 12% in the Medicare population. There was a rapid uptake in the use of newer technologies over time in both the Medicare and i3 cohorts. The use of laparoscopic-assisted prostatectomy increased from 1% in 2002 to 41% in 2006 in i3 patients, whereas the incidence increased from 3% in 2002 to 35% in 2006 for Medicare patients. The use of neoadjuvant/adjuvant androgen deprivation therapy was lower in the i3 cohort and has decreased over time in both i3 and Medicare. Physician density had an impact on the type of primary treatment received in the New England region; however, this trend was not seen in the western or southern regions of the United States. CONCLUSIONS: Using two large national claims registries, we have demonstrated trends over time and substantial geographic variation in the type of primary treatment used for localized prostate cancer. Specifically, there has been a large increase in the use of newer technologies (that is, laparoscopic-assisted prostatectomy and intensity-modulated radiation therapy). These results elucidate the need for improved data collection on prostate cancer treatment outcomes to reduce unwarranted variation in care.