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Passions will be tested and young hearts will be broken. Ultimately, talent, dedication and hard work will triumph. Centers around a group of dancers, singers, musicians and actors at the New York City High School of Performing Arts, and their spirited drive to live out their dreams of stardom. In an incredibly competitive atmosphere, each student must shine amidst the tumult of school work, deep friendships, budding romance and self-discovery.

Background Vitamin D3 (VitD) deficiency is linked to increased incidence and worse survival in bladder cancer (BCa). In addition to cystectomy, patients are treated with cisplatin‐based chemotherapy, however 30%‐50% of patients do not benefit from this treatment. The effects of VitD deficiency on response to chemotherapy remain unknown. Methods To test effects of VitD supplementation on the response to cisplatin we analyzed patient serum VitD levels and correlated that with survival. In vivo, VitD deficient mice were treated with cisplatin, with or without pretreatment with the active VitD metabolite, 1,25 dihydroxyvitamin D3 (1,25D3). Lastly, using BCa cell lines, T24 and RT‐112, the mechanism of action of 1,25D3 and cisplatin combination treatment was determined by apoptosis assays, as well as western blot and RT‐PCR. Results In this study, we determined that low serum 25 hydroxyvitamin D3 (25D3) levels was significantly associated with worse response to cisplatin. Pretreating deficient mice with 1,25D3, reduced tumor volume compared to cisplatin monotherapy. In vitro, 1,25D3 pretreatment increased the apoptotic response to cisplatin. 1,25D3 pretreatment increased expression of TAp73 and its pro‐apoptotic targets, in a VDR dependent manner. VDR and its transcriptional targets were induced after 1,25D3 treatment and further increased after the combination of 1,25D3 and cisplatin in a TAp73 dependent manner. Conclusions Our data suggest that VitD deficiency could be a biomarker for poor response to cisplatin, and pretreating with VitD can increase the apoptotic response to cisplatin through VDR and TAp73 signaling crosstalk. In this article, we investigated the effects of vitamin D deficiency and sufficiency on the response to cisplatin in bladder cancer. We determined that increased vitamin D status, through either dietary intervention or treating with the active vitamin D metabolite, is associated with a increase in response to cisplatin. Finally, we determined the mechanism of action was due to crosstalk between VDR and TAp73 siganling.

Using complete genome analysis, we sequenced five bladder tumors accrued from patients with muscle-invasive transitional cell carcinoma of the urinary bladder (TCC-UB) and identified a spectrum of genomic aberrations. In three tumors, complex genotype changes were noted. All three had tumor protein p53 mutations and a relatively large number of single-nucleotide variants (SNVs; average of 11.2 per megabase), structural variants (SVs; average of 46), or both. This group was best characterized by chromothripsis and the presence of subclonal populations of neoplastic cells or intratumoral mutational heterogeneity. Here, we provide evidence that the process of chromothripsis in TCC-UB is mediated by nonhomologous end-joining using kilobase, rather than megabase, fragments of DNA, which we refer to as “stitchers,” to repair this process. We postulate that a potential unifying theme among tumors with the more complex genotype group is a defective replication–licensing complex. A second group (two bladder tumors) had no chromothripsis, and a simpler genotype, WT tumor protein p53, had relatively few SNVs (average of 5.9 per megabase) and only a single SV. There was no evidence of a subclonal population of neoplastic cells. In this group, we used a preclinical model of bladder carcinoma cell lines to study a unique SV (translocation and amplification) of the gene glutamate receptor ionotropic N-methyl D-aspertate as a potential new therapeutic target in bladder cancer.

African Americans (AAs) have lower circulating 25-hydroxyvitamin D3 [25(OH)D3] concentrations and higher prostate cancer (CaP) aggressiveness than other racial/ethnic groups. The purpose of the current study was to examine the relationship between plasma 25(OH)D3, African ancestry and CaP aggressiveness among AAs and European Americans (EAs). Plasma 25(OH)D3 was measured using LC-MS/MS (Liquid Chromatography Tandem Mass Spectrometry) in 537 AA and 663 EA newly-diagnosed CaP patients from the North Carolina-Louisiana Prostate Cancer Project (PCaP) classified as having either 'high' or 'low' aggressive disease based on clinical stage, Gleason grade and prostate specific antigen at diagnosis. Mean plasma 25(OH)D3 concentrations were compared by proportion of African ancestry. Logistic regression was used to calculate multivariable adjusted odds ratios (OR) and 95% confidence intervals (95%CI) for high aggressive CaP by tertile of plasma 25(OH)D3. AAs with highest percent African ancestry (>95%) had the lowest mean plasma 25(OH)D3 concentrations. Overall, plasma 25(OH)D3 was associated positively with aggressiveness among AA men, an association that was modified by calcium intake (ORT 3vs.T1: 2.23, 95%CI: 1.26-3.95 among men with low calcium intake, and ORT 3vs.T1: 0.19, 95%CI: 0.05-0.70 among men with high calcium intake). Among EAs, the point estimates of the ORs were <1.0 for the upper tertiles with CIs that included the null. Among AAs, plasma 25(OH)D3 was associated positively with CaP aggressiveness among men with low calcium intake and inversely among men with high calcium intake. The clinical significance of circulating concentrations of 25(OH)D3 and interactions with calcium intake in the AA population warrants further study.

Background A low Glycaemic Index (GI) diet may decrease some long-term health risks in Polycystic Ovary Syndrome (PCOS) such as endometrial cancer. This study was performed to assess compliance to a low GI diet in women with PCOS. Food diaries prospectively collected over 6 months from women on a low GI diet or healthy eating diet were analysed retrospectively. The women were recruited for a pilot randomised control trial investigating whether a low GI diet decreased the risk of Endometrial Cancer. Nine women with PCOS completed 33 food diaries (17 from women on a low GI diet and 16 from women on a healthy eating diet) recording 3023 food items (low GI group:n = 1457; healthy eating group:n = 1566). Data was analysed using Foster-Powell international values inserted into an SPSS database as no scientifically valid established nutrition software was found. The main outcome measures were mean item GI and Glyacemic Load (GL), mean meal GL, percentage high GI foods and mean weight loss. Findings Women allocated the low GI diet had a statistically significant lower GI of food items (33.67 vs 36.91, p < 0.05), lower percentage of high GI foods (4.3% vs 12.1%, p < 0.05) and lower GL of food items and meals. Conclusion Women with PCOS on a low GI diet consumed food items with a significantly lower mean GI and GL compared to the healthy eating diet group. Longer term compliance needs evaluation in subsequent studies to ascertain that this translates to reduced long term health risks. Trial Registration ISRCTN: ISRCTN86420258

Aberrant DNA methylation observed in cancer can provide survival benefits to cells by silencing genes essential for anti-tumor activity. DNA-demethylating agents such as Decitabine (DAC)/Azacitidine (AZA) activate otherwise silenced tumor suppressor genes, alter immune response and epigenetically reprogram tumor cells. In this study, we show that non-cytotoxic nanomolar DAC concentrations modify the bladder cancer transcriptome to activate NOTCH1 at the mRNA and protein level, increase double-stranded RNA sensors and CK5-dependent differentiation. Importantly, DAC treatment increases ICN1 expression (the active intracellular domain of NOTCH1) significantly inhibiting cell proliferation and causing changes in cell size inducing morphological alterations reminiscent of senescence. These changes were not associated with β-galactosidase activity or increased p16 levels, but instead were associated with substantial IL-6 release. Increased IL-6 release was observed in both DAC-treated and ICN1 overexpressing cells as compared to control cells. Exogenous IL-6 expression was associated with a similar enlarged cell morphology that was rescued by the addition of a monoclonal antibody against IL-6. Treatment with DAC, overexpression with ICN1 or addition of exogenous IL-6 showed CK5 reduction, a surrogate marker of differentiation. Overall this study suggests that in MIBC cells, DNA hypomethylation increases NOTCH1 expression and IL-6 release to induce CK5-related differentiation.

Objective To determine whether dietary intervention or knee strengthening exercise, or both, can reduce knee pain and improve knee function in overweight and obese adults in the community.Design Pragmatic factorial randomised controlled trial.Setting Five general practices in Nottingham.Participants 389 men and women aged 45 and over with a body mass index (BMI) of ≥28.0 and self reported knee pain.Interventions Participants were randomised to dietary intervention plus quadriceps strengthening exercises; dietary intervention alone; quadriceps strengthening exercises alone; advice leaflet only (control group). Dietary intervention consisted of individualised healthy eating advice that would reduce normal intake by 2.5 MJ (600 kcal) a day. Interventions were delivered at home visits over a two year period.Main outcome measures The primary outcome was severity of knee pain scored with the Western Ontario McMaster (WOMAC) osteoarthritis index at 6, 12, and 24 months. Secondary outcomes (all at 24 months) included WOMAC knee physical function and stiffness scores and selected domains on the SF-36 and the hospital anxiety and depression index.Results 289 (74%) participants completed the trial. There was a significant reduction in knee pain in the knee exercise groups compared with those in the non-exercise groups at 24 months (percentage risk difference 11.61, 95% confidence interval 1.81% to 21.41%). The absolute effect size (0.25) was moderate. The number needed to treat to benefit from a ≥30% improvement in knee pain at 24 months was 9 (5 to 55). In those randomised to knee exercise improvement in function was evident at 24 months (mean difference −3.64, −6.01 to −1.27). The mean difference in weight loss at 24 months in the dietary intervention group compared with no dietary intervention was 2.95 kg (1.44 to 4.46); for exercise versus no exercise the difference was 0.43 kg (−0.82 to 1.68). This difference in weight loss was not associated with improvement in knee pain or function but was associated with a reduction in depression (absolute effect size 0.19).Conclusions A home based, self managed programme of simple knee strengthening exercises over a two year period can significantly reduce knee pain and improve knee function in overweight and obese people with knee pain. A moderate sustained weight loss is achievable with dietary intervention and is associated with reduced depression but is without apparent influence on pain or function.Trial registration Current Controlled Trials ISRCTN 93206785.

Prostate cancer (PCa) cells display abnormal expression of cytoskeletal proteins resulting in an augmented capacity to resist chemotherapy and colonize distant organs. We have previously shown that heme oxygenase 1 (HO-1) is implicated in cell morphology regulation in PCa. Here, through a multi 'omics' approach we define the HO-1 interactome in PCa, identifying HO-1 molecular partners associated with the integrity of the cellular cytoskeleton. The bioinformatics screening for these cytoskeletal-related partners reveal that they are highly misregulated in prostate adenocarcinoma compared with normal prostate tissue. Under HO-1 induction, PCa cells present reduced frequency in migration events, trajectory and cell velocity and, a significant higher proportion of filopodia-like protrusions favoring zippering among neighboring cells. Moreover forced expression of HO-1 was also capable of altering cell protrusions in transwell co-culture systems of PCa cells with MC3T3 cells (pre-osteoblastic cell line). Accordingly, these effects were reversed under siHO. Transcriptomics profiling evidenced significant modulation of key markers related to cell adhesion and cell–cell communication under HO-1 induction. The integration from our omics-based research provides a four molecular pathway foundation (ANXA2/HMGA1/POU3F1; NFRSF13/GSN; TMOD3/RAI14/VWF; and PLAT/PLAU) behind HO-1 regulation of tumor cytoskeletal cell compartments. The complementary proteomics and transcriptomics approaches presented here promise to move us closer to unravel the molecular framework underpinning HO-1 involvement in the modulation of cytoskeleton pathways, pushing toward a less aggressive phenotype in PCa.

An abrupt increase in metastatic growth as a consequence of the removal of primary tumors suggests that the concomitant resistance (CR) phenomenon might occur in human cancer. CR occurs in murine tumors and ROS-damaged phenylalanine, meta-tyrosine (m-Tyr), was proposed as the serum anti-tumor factor primarily responsible for CR. Herein, we demonstrate for the first time that CR happens in different experimental human solid tumors (prostate, lung anaplastic, and nasopharyngeal carcinoma). Moreover, m-Tyr was detected in the serum of mice bearing prostate cancer (PCa) xenografts. Primary tumor growth was inhibited in animals injected with m-Tyr. Further, the CR phenomenon was reversed when secondary implants were injected into mice with phenylalanine (Phe), a protective amino acid highly present in primary tumors. PCa cells exposed to m-Tyr in vitro showed reduced cell viability, downregulated NFκB/STAT3/Notch axis, and induced autophagy; effects reversed by Phe. Strikingly, m-Tyr administration also impaired both, spontaneous metastasis derived from murine mammary carcinomas (4T1, C7HI, and LMM3) and PCa experimental metastases. Altogether, our findings propose m-Tyr delivery as a novel approach to boost the therapeutic efficacy of the current treatment for metastasis preventing the escape from tumor dormancy.