bluuebunny/crossref_metadata_2025_split huggingface dataset:
Capsaicin, a novel radiosensitizer, acts via a TRPV6 mediated phenomenon.
Authors: Klotz L. , Venier N. , Colquhoun A. J. , Sasaki H. , Loblaw D. A. , Fleshner N. , Venkateswaran V. 
Published: February 2017

23 Background: Radiosensitizing agents sensitize cells to the lethal effects of ionizing radiation (IR). This permits use of lower doses of radiation to achieve equivalent cancer control thereby minimizing adverse effects to normal tissues. Given their lack of toxicity compounds occurring naturally in the diet make ideal potential radiosensitizing agents. Capsaicin, a compound found in the Capsicum sp. of plants, is a widely consumed food additive in areas with low PCa incidence. Traditionally capsaicin is used to treat chronic pain syndromes; however, recently evidence using in vitro PCa models describes its anti-carcinogenic potential. The transient receptor potential vanilloid-receptor (TRPV)-1 and TRPV6 cation selective channels are thought to be partly responsible for mediating these effects. TRPV-1 and TRPV-6 expression is up-regulated in PCa tissue correlating directly with increasing tumor grade. This suggests TRPV1 and/or TRPV6 may be potential therapeutic targets for capsaicin mediated interventions in PCa patients. As IR and capsaicin both promote apoptosis and inhibit cell cycle progression in vitro we hypothesize an at least additive effect of combining these two therapies. Methods: Using clonogenic assays we assessed the effect of ionizing radiation (1-8 Gy) and/or capsaicin (1-10μ M) on colony formation rates in 4 human PCa cell lines (LNCaP, PC3, PC3AR2, DU145). Proliferative, apoptotic, TRPV-6 protein markers were assessed using Western blot analyses. Results: Exposure of cells to capsaicin (1-10μ M) or IR (1-8Gy) caused significant dose-dependent inhibition of colony formation (p<0.001). Combining capsaicin with IR resulted in further significant inhibition of colony formation rates (P<0.001). Western blot analyses showed LNCaP cells treated with capsaicin and/or IR to have increased expression of pro- apoptotic proteins BAX and Bad, tumor-suppressor proteins p21 and p27 and reduced androgen-receptor. Additionally, capsaicin monotherapy caused a dramaticalteration in TRPV1 and TRPV6 expression. Conclusions: These studies confirm the radiosensitizing capacity of capsaicin in PCa cells in vitro. Ongoing studies are further delineating the mechanism of interaction of these treatment modalities. No significant financial relationships to disclose.
Alterations in genes regulating cell cycle and apoptosis in high-grade urothelial carcinoma.
Authors: Al-Ahmadie H. , Iyer G. , Lin O. , Gopalan A. , Fine S. , Tickoo S. , Reuter V. E. , Bajorin D. F. , Milowsky M. I. , Solit D. B. 
Published: February 2017

237 Background: Dysregulations of cell cycle and inhibition of apoptosis are crucial factors in tumorigenesis of multiple malignancies, including urothelial carcinoma (UC). Deletions of TP53 and CDKN2A and amplification of MDM2 have been observed in UC, but their exact frequency and functional consequence is less known. We sought to determine the frequency of copy number alteration (CNA) and mutations of genes that regulate cell cycle or apoptosis in a panel of 96 cases of high-grade UC (HGUC) of bladder. Methods: 96 frozen cases of HGUC were studied, including 11 bladder small cell carcinomas. DNA was isolated and analyzed for CNA by comparative genomic hybridization (CGH) using a one million oligonucleotide probe array from Agilent. The targeted genes included TP53, MDM2, CCND1, CCNE1, CDKN2A/B, E2F3 and Rb1. Traditional Sanger sequencing for mutations within TP53, Rb1, and CDKN2A was also performed. Results: The frequency of CNA and mutations are listed in the table. Overall, 54 of 96 cases (56%) showed CNA (45) or mutation (13). Deletion of CDKN2A/B and amplification of E2F3 were the most common alterations in cell cycle regulatory genes (13 cases each, 14%), followed by amplification of CCND1 (11 cases, 11%). There was no co-amplification of CCND1 and CCNE1 in any sample. Rb1 deletion was present in five cases. CNA in E2F3 and Rb1 were mutually exclusive in 14 of 16 cases (88%) and were both present in two cases only. Mutations in TP53 were noted in 13 cases and deletions in nine. Amplification of MDM2 was noted in four cases, none of which overlapped with TP53 deletions or mutations. Overexpression of E2F3 was significantly more common in small cell carcinoma (5/11) compared to conventional UC (8/85, p = 0.006). Conclusions: Regulators of cell cycle and apoptosis are amplified, deleted or mutated in more than half of cases (56%) of high-grade urothelial carcinoma. The overwhelming majority of these abnormalities are nonoverlapping. Amplification of E2F3 seems to be overrepresented in small cell carcinoma of bladder. [Table: see text] No significant financial relationships to disclose.
Use of immunocytology to predict bladder cancer presence in patients with asymptomatic hematuria.
Authors: Cha E. K. , Tirsar L. , Shariat S. F. , Christos P. J. , Mazumdar M. , Hennenlotter J. , Schwentner C. , Mian C. , Lodde M. , Schmitz-Drager B. J. 
Published: February 2017

242 Background: The uCyt immunocytology assay detects cellular biomarkers for bladder cancer (BCa) in exfoliated urothelial cells. We assessed the performance of uCy for detecting BCa in patients undergoing initial evaluation for asymptomatic hematuria. Methods: Data from 1,182 subjects without a history of BCa undergoing evaluation for hematuria were collected at three centers: EuromedClinic/Urologie24, University of Tübingen, and Central Hospital of Bolzano. All subjects underwent standard workup (i.e., voided cytology, upper tract imaging, and cystoscopy) and immunocytology. Results: Overall, 245 subjects had BCa (20.7%). The sensitivity/specificity/negative predictive value for uCyt and cytology were 82.4%/86.6%/95.0% and 46.5%/94.9%/87.2%, respectively. uCyt (OR 18.3, p<0.001) and cytology (OR 2.9, p<0.001) were associated with BCa in a multivariable analysis. The base model (age, gender, smoking status, type of hematuria) predicted BCa with an accuracy of 74.1%. Addition of cytology to the base model improved predictive accuracy (PA) to 83.5% (p<0.001), while addition of uCyt to the base model improved PA to 90.1% (p<0.001). Addition of uCyt to Model 1 significantly improved PA (+7.6%, p<0.001), but addition of cytology to Model 2 did not (+1.0%, p=0.057). uCyt performed equally well in patients with microscopic and gross hematuria (OR 30 vs. 27), while cytology did not (OR 18 vs. 12). Conclusions: uCyt is a strong, independent predictor of BCa in patients with hematuria; it outperforms cytology. uCyt may help with patient counseling, quality of care optimization (referral prioritization), and possibly sparing unnecessary hematuria workup in patients at extremely low risk of BCa. [Table: see text] No significant financial relationships to disclose.
Meta-analysis of randomized trials comparing cisplatin versus carboplatin-based regimens for the first-line therapy of metastatic transitional cell carcinoma of the urothelium (TCCU).
Authors: Sonpavde G. , Galsky M. D. , Chen G. J. , Bellmunt J. , Roth B. J. , Petrioli R. , Hutson T. E. , Dogliotti L. , Dreicer R. , Oh W. K. 
Published: February 2017

247 Background: Cisplatin-based chemotherapy is the first-line treatment standard for metastatic TCCU, although carboplatin is substituted for cisplatin-ineligibility, tolerability, and ease of administration. Since definitive data comparing cisplatin- versus carboplatin-based chemotherapy are lacking, a meta-analysis of published randomized trials was performed. Methods: PubMed was searched for articles published in the English language from 1966 until 2010 and abstracts presented at the American Society of Clinical Oncology Annual Meeting between 2000 and 2010 were searched to identify relevant trials. Eligible studies included prospective randomized trials evaluating cisplatin- versus carboplatin-based regimens in cisplatin-eligible patients with metastatic TCCU. Individual patient data were not available and progression and survival data were inconsistently reported. Therefore, the analysis focused on overall (OR) and complete response (CR). The Mantel-Haenszel method was used for combining trials and calculating pooled risk ratios (RR). Results: A total of 286 patients with metastatic TCCU from 4 randomized trials (3 phase II and 1 phase III trial) were included. Chemotherapy regimens included MVEC (methotrexate, vinblastine, epirubicin, cisplatin) vs. MVECa (methotrexate, vinblastine, epirubicin, carboplatin), MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) vs. MCAVI (methotrexate, carboplatin, vinblastine), MVAC vs. paclitaxel plus carboplatin, and gemcitabine plus cisplatin vs. gemcitabine plus carboplatin. Cisplatin-based chemotherapy was associated with a significant improvement in the likelihood of CR (RR=3.973 [95%CI: 1.562 – 10.110], p =0.004) and OR (RR=1.336 [95%CI: 1.043 – 1.712], p=0.025). Conclusions: Cisplatin-based as compared with carboplatin-based combination chemotherapy significantly increases the likelihoods of both OR and CR, in patients with metastatic TCCU. In the absence of definitive phase 3 trials, these results support cisplatin-based regimens as the preferred first-line treatment for cisplatin-eligible patients with metastatic TCCU. No significant financial relationships to disclose.
Androgen-regulated metabolome in prostate cancer.
Authors: Putluri N. , Zhang Y. , Putluri V. , Vareed S. , Vasu V. T. , Fischer S. M. , Chad C. , Sreekumar A. 
Published: February 2017

25 Background: Prostate cancer (PC) is the second most prevalent cancer among American men which is primarily treated by androgen ablation therapy. Although a number of patients respond to this regimen, a significant subset fail and the tumor invariably progresses into a hormone refractory metastatic state, which is lethal. Earlier we had reported the first unbiased metabolomic signature for localized and metastatic prostate cancer tissues. Advancing further, we attempt to delineate the subset of metabolome in prostate cancer which is regulated by androgen-action. Methods: Androgen responsive (R22V1, LnCap and VCAP) and independent (PC3, DU145) PC cells and benign prostate epithelial cells (RWPE) were profiled for their metabolomic alterations using mass spectrometry. Extracted metabolome from these cells were profiles using a combination quadrupole-time-of-flight (Q-TOF) and triple quadrupole (QQQ) mass spectrometers coupled to reverse phase and aqueous normal phase chromatography. The metabolomic profiles were analyzed to delineate class-specific signatures which were interrogated for altered bioprocesses using Oncomine Concept Map (OCM, www.oncomine.org ). The androgen receptor (AR) regulated metabolome was verified using treatment of PC cells with synthetic androgen, R1881. Results: A total of 3,092 metabolites (113 named) were detected across the 4 cells lines, of which 869 compounds were significantly (ANOVA P<0.01) different between androgen responsive and non-responsive cells. The differential compendia included 28 named metabolites, including sarcosine which was earlier shown to be elevated during PC development and progression. Bioprocess mapping of AR-regulated metabolome revealed enrichment of amino acid metabolism and methylation potential, both of which were earlier defined to be the hallmarks of PC development and progression. Conclusions: The study defines AR-regulated metabolic signature which portrays enrichment of amino acid metabolism and methylation potential that are hallmarks of PC development and progression. No significant financial relationships to disclose.
Risk-specific intensity of surveillance practices in non-muscle-invasive bladder cancer: Results from the BCAN/SUO/AUA/LUGPA electronic survey.
Authors: Smith A. , Nielsen M. E. , Ferguson J. , Manvar A. , Pruthi R. , Wallen E. , Lotan Y. 
Published: February 2017

251 Background: The ideal surveillance regimen for patients with non-muscle-invasive bladder cancer (NMIBC) is uncertain. Given different grade- and stage-specific risks of recurrence and progression, there is some question whether it might be acceptable to pursue less intensive surveillance practices for patients with lower risk disease, and there is a paucity of data on current patterns of care in this area of practice. Methods: An electronic survey was developed by the Bladder Cancer Advocacy Network (BCAN) to elicit self-reported practices of cystoscopy, cytology, and radiographic testing in the setting of surveillance for patients with a history of NMIBC. The survey was circulated to urologists via the AUA, SUO and LUGPA distribution lists. 512 respondents completed the survey. Results: Among respondents, 66% report performing cystoscopy every 3 months on all patients for at least the first two years following diagnosis of NMIBC. The remaining 33% report performing surveillance cystoscopy less frequently, 95% of whom report doing so in the setting of low grade pathology. Similarly, 51% report using cytology with every cystoscopy, 23% do so for all high grade cases, and 30% report not using cytology with every cystoscopy. In the absence of recurrence for patients with an initial high grade diagnosis, upper tract reimaging is performed annually in 48%, biannually in 37% and never in 3%. The corresponding figures for patients with an index diagnosis of low grade disease are 14%, 37% and 28%, respectively. In the event of a recurrence in the bladder, 80% of respondents report reimaging the upper tracts for patients with high grade disease, versus 45% in the event of a low grade recurrence. Conclusions: A substantial number of urologists responding to a survey report using relatively less intensive surveillance practices in patients with lower risk NMIBC. These results suggest a lack of consensus on the ideal intensity of evaluation in this setting, and provide a basis for prospective studies to validate the safest and most cost-effective strategies for surveillance. No significant financial relationships to disclose.
Evaluation of the insulin-like growth factor receptor I and Pyk2 kinase in urothelial carcinomas and effect on motility and invasion of urothelial carcinoma-derived cells.
Authors: Morrione A. , Genua M. , Iozzo R. V. , Gomella L. G. 
Published: February 2017

254 Background: We have recently demonstrated that the IGF-IR is overexpressed in invasive bladder cancer tissues and promotes motility and invasion of urothelial-carcinoma-derived cells without affecting cell proliferation, suggesting that the IGF-IR may play a more prominent role in promoting the transition to the invasive phenotype in bladder cancer. Methods: IGF-IR levels in cancer and normal bladder tissues were analyzed by immunohistochemistry. IGF-IR and Pyk2 signaling pathways were studied in several urothelial carcinoma-derived cancer cells using biochemical assays and siRNA approaches. Pyk2 expression in a bladder tissue array was analyzed by immunofluorescence and by AQUA (Automated Quantitative Analysis). Results: In this studywe demonstrated by immunohistochemical analysis that the IGF-IR expression increased with grade in bladder cancer tissues compared to non-malignant controls. Increased IGF-IR expression in non-tumorigenic T24 urothelial carcinoma cells promoted anchorage independent growth, while IGF-IR targeting in metastatic T24T cells inhibited colony formation in soft-agar. We also discovered that the focal adhesion protein Pyk2 is activated by IGF-I in urothelial carcinoma-derived cells. Using siRNA approaches, we demonstrated that Pyk2 is critical for IGF-IR-dependent motility and invasion and regulates IGF-I-dependent activation of the Akt and MAPK pathways in urothelial cancer cells. Using immunofluorescence and AQUA analysis we also discovered that Pyk2 is overexpressed in bladder cancer tissues compared to normal tissue controls. In urothelial carcinoma-derived tissues there is also increased Pyk2 localization in the nucleus compared to normal tissue controls. Conclusions: Our results provide the first evidence for a role of the IGF-IR and Pyk2 in motility and invasion of bladder cancer cells, and support the hypothesis that the IGF-IR and Pyk2 may play a critical role in the establishment of the invasive phenotype in urothelial neoplasia. The IGF-IR and Pyk2 could also serve as novel tumor biomarkers for diagnosis and possibly prognosis of bladder tumors. No significant financial relationships to disclose.
Investigating the Nrf2 transcription factor as a regulator of cisplatin resistance in urothelial carcinoma (UC) cells.
Authors: Crabb S. J. , Hayden A. , Gould K. , Andrews L. , Packham G. 
Published: February 2017

256 Background: Nrf2 controls expression of multiple target genes, each containing an antioxidant response element (ARE). These targets mediate cellular protection through antioxidant response, cellular detoxification (including glutathione conjugation), and altered drug uptake/efflux. Some targets (e.g., metallothionein, glutathione reductase) are associated with UC characteristics, outcomes, and chemotherapy resistance. Nrf2 regulation is partially understood and includes negative regulation by Keap1 and phosphorylation. De-novo or acquired cisplatin resistance is a problem in UC. We hypothesised that it might be mediated by Nrf2. Methods: Nrf2 expression was assessed in UC clinical samples by immunohistochemistry. We then utilised a panel of UC cell lines, including a cisplatin resistant RT112 sub-line (RT112CP), to test Nrf2 axis expression and activation correlated to cisplatin sensitivity/resistance. Effects of AKT or HER2 kinase activity on Nrf2 activation were tested by chemical inhibition. Results: In UC clinical samples we detected Nrf2 over-expression in 64% of cancers compared to surrounding normal tissue. Varied Nrf2 expression levels were also detected in different UC cell lines whereas Keap1 demonstrated an inverse profile of both RNA and protein expression. Nrf2 expression was 4 fold greater in RT112CP cells which exhibited comparative cisplatin resistance (10 fold greater IC50 in proliferation assays) compared to parental cells. Nrf2 over expression was functional in this model system as indicated by increased activity in ARE luciferase reporter assays, raised expression of Nrf2 transcriptional targets (metallothionein, glutathione reductase) and glutathione levels. Furthermore, depletion of Nrf2 in RT112CP cells by siRNA or transfection of a dominant negative Nrf2 construct partially restored cisplatin sensitivity. Finally chemical inhibition of AKT or HER2 reduced Nrf2 activation in ARE reporter assays. Conclusions: Nrf2 is overexpressed in a subset of UC. In cell line models it is functionally activated and contributes to cisplatin resistance, which is reversible. This might be amenable to detection and therapeutic reversal in the clinic. No significant financial relationships to disclose.
Can we reliably identify patients for radical cystectomy without neoadjuvant chemotherapy?
Authors: Dickstein R. J. , Grossman H. B. , Pretzsch S. M. , Karam J. A. , Millikan R. E. , Dinney C. P. , Kamat A. M. 
Published: February 2017

258 Background: When neoadjuvant chemotherapy is administered prior to radical cystectomy in patients with muscle-invasive urothelial cancer, the patients who benefit most are those with pathologic T3-4 or N+ disease. Thus, some advocate reserving neoadjuvant chemotherapy for patients considered high risk based on presence of the following clinical parameters: lymphovascular invasion, hydroureteronephrosis, presence of a palpable or visible mass on exam under anesthesia or imaging (suggesting cT3 disease), and/or variant histology. The goal of this study was to report the outcome of patients who were classified as “not high risk” (i.e., lacking the above-mentioned criteria) and underwent radical cystectomy without neoadjuvant chemotherapy. Methods: On retrospective review of 858 patients who underwent radical cystectomy from 2000 to 2008, we identified 174 patients with muscle-invasive disease (cT2) who were classified as “not high risk” (i.e., did not have lymphovascular invasion, hydroureteronephrosis, variant histology, and/or palpable or visible mass on imaging studies) and underwent radical cystectomy without neoadjuvant chemotherapy. Endpoints of interest included pathologic upstaging (≥ pT3), pathologic lymph node positivity, need for adjuvant or salvage chemotherapy, disease recurrence, and disease specific survival (DSS). Results: Of the 174 patients, 155 (88.6%) were male and the median age was 67.6 years (range 39-86). At radical cystectomy, 75 patients (42.9%) were upstaged (pT3N0: 45; pT4N0: 6; pTxN+: 24). Thirteen patients (7.4%) received adjuvant chemotherapy for adverse pathology. After a median interval of 27 months, 38 patients (21.7%) developed recurrent disease; isolated pelvic recurrences: 4, distant recurrences: 34, and 2 had both. Eighteen patients with recurrent disease went on to receive salvage chemotherapy. Overall, 25 patients (14.3%) died of disease with a 5-year DSS of 82.3%. Conclusions: Although clinical understaging remains a problem in the management of patients with muscle-invasive urothelial cancer, our criteria for selection of patients for primary radical cystectomy without neoadjuvant chemotherapy results in a cohort with a 5-year DSS of 83%. No significant financial relationships to disclose.
Radiosensitization of MYC-overexpressing prostate cancer cells by statins.
Authors: Salih T. , Aziz K. , Thiyagarajan S. , Armour M. , Shanmugam B. , Zeng J. , Adam S. J. , Felsher D. W. , DeWeese T. L. , Tran P. T. 
Published: February 2017

26 Background: Studies have shown a link between HMG-CoA reductase inhibitors (statins) and decreased cancer risk in various cancers including prostate cancer. Recent clinical studies have shown improved outcome for men on statin therapy receiving definitive radiation therapy compared to radiation therapy alone for prostate cancer. The oncogene Ras can be inhibited by statin treatment and in turn also result in targeted downregulation of Myc. Inactivation of Myc has been shown to induce tumor regression in transgenic mouse models of different cancers. Methods: Utilizing both in vitro and in vivo models, we studied in MYC over-expressing prostate cancer cells statin induced cytotoxicity and radiosensitization. We studied the effect of statin treatment with and without radiation treatment on in vitro cell death and clonogenic survival and correlated effects to levels of MYC and phospho-MYC. We constructed mutant cell lines to specifically examine the MYC-dependent effects of statins on prostate cancer cell cytotoxicity and radiosensitization. We performed similar studies in vivo using subcutaneous tumor grafts. Results: Statin treatment alone of prostate cancer cells resulted in increased cell death and decreased clonegenic survival. Statin treatment further sensitized prostate cancer cells to ionizing radiation as shown through colony formation assays. These cellular effects were associated with decreased levels of active MYC as confirmed by western and phospho-western analysis. Statin-induced cell death and decreased MYC levels could be rescued with the HMG-CoA bypass product mevalonate. Finally, flank tumor graft experiments demonstrated the ability of statins and radiation to delay tumor growth in vivo. Conclusions: Our preliminary data have implicated MYC as a potential critical target for the cytotoxic effects of statins on prostate cancer cells. The prevalence of MYC overexpression in human prostate cancers is as high as 80%. Thus the ability of statins to radiosensitize MYC overexpressing prostate cancer cells may provide a mechanistic explanation to the improved outcomes for men taking statins while on radiation therapy and now may afford us a molecular biomarker to examine this phenomenon in the clinic. No significant financial relationships to disclose.