bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A064: Mass spectrometry-based proteomics study makes apolipoprotein E a potential risk factor for prostate cancer
Authors: Bizzotto Juan , Vickers Sofia Lage , Paez Alejandra , Scorticati Carlos , Cotignola Javier , Valacco Pia , Mazza Osvaldo , Vazquez Elba , Gueron Geraldine 
Published: February 2019

Abstract
Proteomics represents an important tool for the identification of new molecular targets for prostate cancer (PCa) tailored therapy. Innovative high-throughput proteomic platforms are now identifying and quantifying new specific and sensitive biomarkers for PCa detection, stratification, and treatment. Formalin-fixed and paraffin-embedded (FF-PE) sections mounted on microscope slides are hard to achieve given the low peptide yield obtained from the slides. Here we performed an innovative protocol for an in-depth quantitative mass spectrometry-based proteomics analysis of FF-PE PCa and benign prostate hyperplasia (BPH) sections, using phase-transfer surfactant-aided extraction/tryptic digestion of FF-PE proteins. Results yielded a list of 50 differential proteins only expressed in PCa samples. Of note, apolipoprotein E (APOE) was highly present in carcinoma samples. Furthermore, to evaluate the clinical significance of APOE in PCa we performed a bioinformatics analysis using the Oncomine database. We identified 16 publicly available gene expression microarray datasets comparing prostate adenocarcinoma versus normal prostate, which met our eligibility criteria. We carried out meta-analysis combining the data from the independent datasets. APOE was ranked by its P-value for every analysis scoring a gene rank and then we obtained a median rank (median P-value rank across datasets). APOE showed a significant upregulation (fold change &gt;1.5, P&lt;0.05) comparing prostate adenocarcinoma vs. normal prostate gland. Accordingly, when extending the bioinformatics analysis to evaluate whole-exome and RNA-seq data using cBioportal, the most frequent genetic alteration found for APOE was amplification. RNA-seq data also confirmed a significant upregulation for APOE (P&lt;0.05). We thus identify APOE as a key target in PCa, ascertaining it as a potential risk factor for this disease.
Citation Format: Juan Bizzotto, Sofia Lage Vickers, Alejandra Paez, Carlos Scorticati, Javier Cotignola, Pia Valacco, Osvaldo Mazza, Elba Vazquez, Geraldine Gueron. Mass spectrometry-based proteomics study makes apolipoprotein E a potential risk factor for prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A064.
Abstract A081: Activation of sphingosine kinase 1 by lipopolysaccharide promotes prostate cancer cell invasion via matriptase
Authors: Lee Cheng-Fan , Chen Benjamin , Hsieh Jer-Tsong , Lee Ming-Shyue 
Published: February 2019

Abstract
A 15-year cohort study indicates that bacterial-induced prostatitis is correlated to prostate cancer (PCa) incidence. Several gram-negative bacteria have been identified in PCa patient specimens and inflammatory cytokines derived from bacterial infection have been involved in PCa tumorigenesis. However, the direct effect of lipopolysaccharide (LPS), a potent inflammatory substance from gram-negative bacteria, on PCa development is not well studied. In this study, we examine the effect of LPS on the growth (MTT assay) and invasion (Transwell assay) of several PCa cells lines including LNCaP, PC3, and DU145. Although LPS does not change the cell growth, our results reveal that LPS can enhance the PCa cell invasiveness and increase pericellular proteolytic activities. Using protease inhibitor screening and proteolytic analyses, we have identified that matriptase (MTX), a member of the membrane-anchored serine protease family, plays a key role in LPS-induced PCa cell invasiveness. The activated levels of MTX can be detected in the cells and the conditioned medium (CM) from LPS-treated cells. Indeed, the elevation of MTX expression is associated with high-grade PCa in archival specimens. Knowing LPS as a ligand for toll-like receptor 4 (TLR4), specific antagonists and shRNA knockdown methodology were used to delineate the mechanism by which TLR4/sphingosine kinase 1 (SphK1) signaling cascade plays a role in LPS-induced PCa cell invasion. The results show that SphK1 was important for MTX activation and PCa cell invasion. Moreover, we found that LPS could induce the activation of SphK1 based on an elevated phosphorylation level and SphK1 translocation to plasma membrane for the production of sphingosine 1-phosphate (S1P). S1P can subsequently induce MTX activation and PCa cell invasion through S1P receptor 4 (S1PR4) in a paracrine or autocrine manner. S1PR4 is further identified as an important receptor for S1P to mediate MAPK signaling. Furthermore, there is a significant correlation between the elevated expression of SphK1 and the Gleason scores of PCa specimens. The phenomenon was further corroborated by the fact that LPS could induce SphK1 activation in patient-derived explant model (PDeX). Taken together, we have unveiled a novel LPS-elicited pathway leading to PCa cell invasion. Our results provide not only the potential impact of bacterial infection on PCa progression but also several therapeutic target(s) against PCa metastasis.
Citation Format: Cheng-Fan Lee, Benjamin Chen, Jer-Tsong Hsieh, Ming-Shyue Lee. Activation of sphingosine kinase 1 by lipopolysaccharide promotes prostate cancer cell invasion via matriptase [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A081.
Abstract A089: Challenging the free hormone hypothesis for vitamin D in the prostate has implications for the prostate cancer disparity in African American men
Authors: Richards Zachary , Nonn Larisa 
Published: February 2019

Abstract
African American (AA) men are disproportionately at risk for both prostate cancer (PCa) and vitamin D (vitD) deficiency compared to European American (EA) men. Based on the numerous chemopreventative properties of vitD and its status with PCa aggressiveness and mortality, vitD deficiency has been hypothesized as a biologic contributor to the PCa disparity in AA men. We recently reported that despite having deficient levels of vitD in the serum, AAs have higher levels of vitD in their prostate tissue compared to EAs. This suggests a mechanism of active vitD transport across the membrane and challenges the longstanding free hormone hypothesis, which asserts that the activity of a hormone is due to the bioavailable fraction and its passive diffusion across the membrane. The majority of VitD circulates bound to D binding protein (DBP) and is sequestered in the serum, rendering it unavailable for passive diffusion. A mechanism of active DBP-vitD endocytosis has been well characterized in the kidney by the extracellular receptor megalin. We hypothesized that megalin is functional in prostate epithelium and facilitates adequate prostatic vitD levels in AAs with vitD deficiency. Here, we report megalin protein expression in prostate tissue, LNCaP, and primary human prostate cells. Megalin function was further assessed in primary human-derived organoids treated with 25D in the presence or absence of DBP. Surprisingly, vitD import and metabolism occurred faster in +DBP conditions and suggests that DBP-vitD active transport is more efficient than passive diffusion of vitD alone. VDR activation was diminished in a dose-responsive manner by addition of a megalin antagonist. Additionally, megalin protein levels in PCa were significantly lower compared to benign (p&lt;0.05) on a tissue microarray quantified by immunofluorescent staining. In summary, our data support a model of megalin-mediated active transport for vitD in the prostate and demonstrate ancestry-related and PCa differences in megalin regulation. These findings challenge the free hormone hypothesis and postulate that vitD deficiency is more complex than previously thought.
Citation Format: Zachary Richards, Larisa Nonn. Challenging the free hormone hypothesis for vitamin D in the prostate has implications for the prostate cancer disparity in African American men [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A089.
Abstract B004: A combination of two chemically distinct inhibitors of class I HDACs is highly effective to suppress AR signaling and in vivo growth of prostate cancer xenograft
Authors: Tian Guimei , Mahmud Iqbal , Stowe Ryan , Zhang Yushan , Purayil Hamsa Thayek , Roush William , Daaka Yehia , Liao Daiqing 
Published: February 2019

Abstract
Class I HDACs 1-3 are critical for the AR-mediated transcriptional program. Thus, targeting class I HDACs is a promising strategy for treating prostate cancer. However, several FDA-approved HDAC inhibitors (HDACi) broadly inhibiting different HDACs have been shown to be ineffective and overtly toxic for treating castration-resistant prostate cancer in clinical trials. These observations suggest that HDACi selective for class I HDACs may be more effective but less toxic for treating prostate cancer than pan HDACi. Notably, we and others have shown that HDACi of different chemical classes individually exhibit nonoverlapping but limited effects on the acetylome in cancer cells. We hypothesize that a combination treatment strategy with class I HDAC-selective HDACi of different chemical classes is more effective to block AR signaling and prostate tumor growth than such HDACi individually. We have recently discovered the novel benzoylhydrazide chemo-type of class I HDAC-selective HDACi with a unique pharmacologic profile. Medicinal chemistry effort led to an optimized analog, SR-4370, with 6 nM potency to HDAC3. In support of our hypothesis, SR-4370 in combination with the clinical class I HDACi entinostat markedly suppressed AR signaling, prostate cancer cell proliferation in vitro, and tumor growth in vivo, and the tumor-suppressive effects by the HDACi combination were more pronounced than by SR-4370 and entinostat individually. Gene expression profiling experiments revealed that the SR-4370/entinostat combination profoundly downregulated AR, AR-V7, and AR target genes, while activating immune and cell death signaling pathways. In a C4-2 xenograft model using athymic nude mice, the SR-4370/entinostat combination was highly effective in suppressing tumor growth. Importantly, these HDACi alone or in combination did not cause observable adverse effects judged by body weight and blood chemistry tests of treated mice. Overall, our data suggest that the SR-4370/entinostat combination may be a translatable treatment for castration-resistant prostate cancer.
Citation Format: Guimei Tian, Iqbal Mahmud, Ryan Stowe, Yushan Zhang, Hamsa Thayek Purayil, William Roush, Yehia Daaka, Daiqing Liao. A combination of two chemically distinct inhibitors of class I HDACs is highly effective to suppress AR signaling and in vivo growth of prostate cancer xenograft [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B004.
Abstract B005: Ginger consumption inhibits β-arrestin-2 expression and functions in melanoma and prostate cancer cells
Authors: Mowart Tonelia A. , Adekoya Timothy , Smith Nikia , Lane Tonya S. , Richardson Ricardo M. 
Published: February 2019

Abstract
Ginger active components are widely known for being a potent antioxidant and recently as a potential anticancer agent. [6]-Gingerol, the most abundant and pungent bioactive component of ginger, was shown to inhibit angiogenesis and tumorigenesis in xenograph models of both prostate cancer (PCa) and melanoma. To date, the precise mechanism(s) for the antitumor effect of ginger is not well understood. The adaptor proteins, β-arrestins, have been shown to modulate tumor development and metastasis in both PCa and melanoma. In this study, we sought to determine the role of [6]-gingerol in β-arrestin (βarr) 1 and 2-mediated PCa and melanoma development, progression, and metastasis. To that end, the PCa cells PC-3 and the melanoma B16-F10 cells were treated with different concentrations of [6]-gingerol for 48 hours. Cell lysates were assayed by Western blot analysis for βarr-1 and βarr-2, CXCR1, and CXCR2 expression, as well as MAP kinase and transcription factors activation. The data demonstrated that pretreatment with [6]-gingerol caused a dose-dependent inhibition of βarr-2, but not βarr-1, in both cell lines, which correlated with significant decrease in Akt and NF-κB activation. [6]-Gingerol pretreatment decreased CXCR1 and CXCR2 expression, CXCL-8-induced intracellular calcium mobilization; and delayed wound closure. [6]-Gingerol exposure also decreased PC-3 and B16 metastasis in zebrafish. Altogether the data indicated that the protective effect of [6]-gingerol in tumorigenesis is likely mediated via a βarr-2-dependent mechanism.
Citation Format: Tonelia A. Mowart, Timothy Adekoya, Nikia Smith, Tonya S. Lane, Ricardo M. Richardson. Ginger consumption inhibits β-arrestin-2 expression and functions in melanoma and prostate cancer cells [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B005.
Abstract B014: Simulating prostate cancer stem cell dynamics to predict patient-specific sensitivity or resistance to intermittent androgen-deprivation therapy
Authors: Brady Renee , Nagy John , Nagy John , Enderling Heiko 
Published: February 2019

Abstract
Intermittent androgen suppression is an attractive treatment approach for biochemically recurrent locally advanced prostate cancer to delay evolution of treatment resistance (PMID: 16783817). We developed a mathematical model of prostate cancer stem cell dynamics during therapy as a plausible mechanism of resistance evolution. We simulate division dynamics of cancer stem cells, non-stem cancer cells, and PSA concentration and generate highly accurate model fits to the longitudinal data of 55 patients undergoing 2-4 cycles of intermittent androgen suppression. We analyze model dynamics to identify cancer stem cell proliferation patterns that correlate with patient outcomes, and score model predictive power to accurately forecast evolution of resistance in individual patients. The presented framework may contribute to identifying patients who do and do not develop resistance to intermittent androgen suppression. The obtained predictive power on a retrospective data set warrants prospective evaluation in a clinical setting.
Citation Format: Renee Brady, John Nagy, John Nagy, Heiko Enderling. Simulating prostate cancer stem cell dynamics to predict patient-specific sensitivity or resistance to intermittent androgen-deprivation therapy [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B014.
Abstract B024: Family history of prostate cancer and the incidence of ERG- and PTEN-defined prostate cancer
Authors: Hashim Dana , Gonzalez-Feliciano Amparo G. , Ahearn Thomas U. , Pettersson Andreas , Barber Lauren , Pernar Claire H. , Ebot Ericka M. , Finn Stephen , Giovannucci Edward L. , Lis Rosina T. , Loda Massimo , Parmigiani Giovanni , Penney Kathryn L. , Lotan Tamara , Kantoff Philip W. , Mucci Lorelei A. , Graff Rebecca E. 
Published: February 2019

Abstract
Introduction: Family history is among the strongest known risk factors for prostate cancer. Emerging data suggest unique molecular subtypes of disease, including common somatic genetic aberrations: fusions of androgen-regulated promoters with ERG and, separately, PTEN loss. We examined associations between family history and incidence of these subtypes under the hypothesis that family history could be differentially associated with their occurrence.
Methods: We studied 47,115 men in the prospective Health Professionals Follow-up Study from 1986 to 2009. ERG and PTEN status were assessed with immunohistochemistry. Multivariable competing risk models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between self-reported family history of prostate cancer and disease defined by molecular subtypes.
Results: During a median follow-up of 22.3 years, 5,606 prostate cancer cases were diagnosed. Among them, 889 and 711 were assayed for ERG status (48% ERG+) and PTEN loss (14% PTEN null), respectively. Prostate cancer family history was positively associated with both ERG+ (HR=1.85; 95% CI: 1.47-2.33) and ERG- (HR=2.20; 95% CI: 1.78-2.72) disease (P-heterogeneity=0.29). High-grade ERG+ disease suggested a pronounced association (HR=2.58; 95% CI: 1.85-3.61; P-heterogeneity versus high-grade ERG-: 0.08). Family history was also positively associated with PTEN null (HR=2.39; 95% CI: 1.53-3.71) and PTEN intact (HR=1.88; 95% CI: 1.54-2.28) prostate cancer (P-heterogeneity=0.34).
Conclusion: Prostate cancer family history is positively associated with prostate cancer defined by ERG and PTEN, suggesting a similar role of genetic susceptibility for these subtypes. It is possible that high-grade ERG+ disease could be uniquely associated with positive family history.
Citation Format: Dana Hashim, Amparo G. Gonzalez-Feliciano, Thomas U. Ahearn, Andreas Pettersson, Lauren Barber, Claire H. Pernar, Ericka M. Ebot, Stephen Finn, Edward L. Giovannucci, Rosina T. Lis, Massimo Loda, Giovanni Parmigiani, Kathryn L. Penney, Tamara Lotan, Philip W. Kantoff, Lorelei A. Mucci, Rebecca E. Graff. Family history of prostate cancer and the incidence of ERG- and PTEN-defined prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B024.
Abstract B032: Inappropriate AR reactivation-induced redox stress as a novel therapeutic target in castration-resistant prostate cancer
Authors: Samaranayake Govindi J. , Troccoli Clara I. , Huynh Mai Q. , Lyles Rolando D.Z. , Kwon Deukwoo , Ban Yuguang , Chen Steven Xi , Jorda Merce , Burnstein Kerry , Rai Priyamvada 
Published: February 2019

Abstract
Androgen deprivation therapy (ADT) initially suppresses prostate cancer (PC) progression. However, castration-resistant PC (CRPC) cells inevitably emerge, resulting in incurable disease. We recently demonstrated that AD produces a form of cellular senescence leading to outgrowth of CRPC subpopulations from the AD-sensitive parental cells. Gene expression profiling studies comparing the parental LNCaP line to the senescence-resistant, early CRPC variant, LNCaP SB5, revealed an enrichment of redox-protective proteins in the latter under AD conditions. This finding suggests that redox stress due to hyperactivated mitogenic/survival signaling or metabolic stresses may be an important and understudied Achilles heel in the progression to CRPC. Here we present the effects of inhibiting thioredoxin-1 (TRX1), a redox-protective protein that was identified as being elevated in our early CRPC LNCaP SB5 model as well as in human CRPC vs. AD-responsive PC datasets. Suppression of TRX1 expression via shRNA led to profound growth suppression of CRPC cells, relative to their AD-sensitive counterparts, and significantly reduced CRPC xenograft tumor growth. Furthermore, under AD, TRX1 suppression promoted p53-induced cell death, which was accompanied by increased reactive oxygen species (ROS). Curiously, TRX1 inhibition led to increased AR and Sp1 expression under AD, and the oxidative stress effects associated with TRX1 inhibition could be mitigated by depleting AR expression. These in vitro and in vivo results were recapitulated using PX-12 a phase I-approved pharmacologic TRX1 inhibitor. Thus our results point to TRX1 as a critical requirement for protecting against redox stress evoked by the inappropriate reactivation of AR in a low-androgen environment in CRPC. Our work provides a rationale for using TRX1 inhibitors in conjunction with ADT to limit CRPC.
Citation Format: Govindi J. Samaranayake, Clara I. Troccoli, Mai Q. Huynh, Rolando D.Z. Lyles, Deukwoo Kwon, Yuguang Ban, Steven Xi Chen, Merce Jorda, Kerry Burnstein, Priyamvada Rai. Inappropriate AR reactivation-induced redox stress as a novel therapeutic target in castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B032.