Discrete bladder cancer molecular subtypes exhibit differential clinical aggressiveness and therapeutic response, which may have significant implications for identifying novel treatments for this common malignancy. However, research is hindered by the lack of suitable models to study each subtype. To address this limitation, we classified bladder cancer cell lines into molecular subtypes using publically available data in the Cancer Cell Line Encyclopedia (CCLE), guided by genomic characterization of bladder cancer by The Cancer Genome Atlas (TCGA). This identified a panel of bladder cancer cell lines which exhibit genetic alterations and gene expression patterns consistent with luminal and basal molecular subtypes of human disease. A subset of bladder cancer cell lines exhibit in vivo histomorphologic patterns consistent with luminal and basal subtypes, including papillary architecture and squamous differentiation. Using the molecular subtype assignments, and our own RNA-seq analysis, we found overexpression of GATA3 and FOXA1 cooperate with PPARɣ activation to drive transdifferentiation of a basal bladder cancer cells to a luminial phenotype. In summary, our analysis identified a set of human cell lines suitable for the study of molecular subtypes in bladder cancer, and furthermore indicates a cooperative regulatory network consisting of GATA3, FOXA1, and PPARɣ drive luminal cell fate.

Increased repolarization heterogeneity can provide the substrate for reentrant ventricular arrhythmias in animal models of cardiomyopathy. We hypothesized that ventricular repolarization heterogeneity is also greater in patients with cardiomyopathy and ventricular arrhythmia vulnerability (inducible ventricular tachycardia or positive microvolt T wave alternans, VT/TWA) compared with a similar patient population without ventricular arrhythmia vulnerability (no VT/TWA). Endocardial and epicardial repolarization heterogeneity was measured in patients with (n = 12) and without (n = 10) VT/TWA by using transvenous 26-electrode catheters placed along the anteroseptal right ventricular endocardium and left ventricular epicardium. Local activation times (AT), activation-recovery intervals (ARI), and repolarization times (RT) were measured from unipolar electrograms. Endocardial RT dispersion along the apicobasal ventricle was greater (P < 0.005) in patients with VT/TWA than in those without VT/TWA because of greater ARI dispersion (P < 0.005). AT dispersion was similar between the two groups. Epicardial RT dispersion along the apicobasal ventricle was greater (P < 0.05) in patients with VT/TWA than in those without VT/TWA because of greater ARI dispersion (P < 0.05). AT dispersion was similar between the two groups. A plot of AT as a function of ARI revealed an inverse linear relationship for no VT/TWA such that progressively later activation was associated with progressively shorter ARI. The AT-ARI relationship was nonlinear in VT/TWA. In conclusion, patients with cardiomyopathy and VT/TWA have greater endocardial and epicardial repolarization heterogeneity than those without VT/TWA without associated conduction slowing. The steep repolarization gradients in VT/TWA may provide the substrate for functional conduction block and reentrant ventricular arrhythmias.

Background: Intensive statin therapy has been shown to improve prognosis in patients with coronary heart disease (CHD). It is unknown whether such benefit is mediated through the reduction of atherosclerotic plaque burden. Aim: To examine the efficacy of high-dose atorvastatin in the reduction of carotid intimal-medial thickness (IMT) and inflammatory markers in patients with CHD. Design: Randomised trial. Setting: Single centre. Patients: 112 patients with angiographic evidence of CHD. Interventions: A high dose (80 mg daily) or low dose (10 mg daily) of atorvastatin was given for 26 weeks. Main outcome measures: Carotid IMT, C-reactive protein (CRP) and proinflammatory cytokine levels were assessed before and after therapy. Conclusions: In patients with CHD, intensive atorvastatin therapy results in regression of carotid atherosclerotic disease, which is associated with reduction in CRP levels. On the other hand, a low-dose regimen only prevents progression of the disease.

Invasive bladder cancer is diverse, and includes several named histomorphologies that differ from conventional urothelial carcinoma, termed "histologic variants." By transcriptional analysis, bladder cancers can be divided into luminal and basal subtypes. In this paper, we study associations between markers of transcriptional subtypes and variant histology in a retrospective cohort of 309 cystectomy specimens. Histology slides were methodically reviewed for all cases, and variant histology was documented. Immunohistochemistry for FOXA1 (luminal marker) and CK14 (basal maker) was performed on histologic variants and their associated conventional urothelial carcinomas. Invasive carcinoma was present in 270 of the cystectomy specimens, 35% of which contained a histologic variant. Squamous carcinomas expressed higher CK14 levels than micropapillary, nested, and plasmacytoid carcinomas (p < 0.001, Kruskal-Wallis), keeping with the basal character of squamous carcinoma. Likewise, squamous carcinomas expressed lower FOXA1 levels than micropapillary, nested, and plasmacytoid carcinomas (p < 0.001, Kruskal-Wallis), keeping with the luminal character of micropapillary carcinoma, and suggesting that nested and plasmacytoid cancers have luminal character. FOXA1 was expressed at lower levels in conventional urothelial carcinoma associated with squamous carcinoma than conventional urothelial carcinoma associated with micropapillary carcinoma (p = 0.0072, Wilcoxon rank sum). CK14 expression did not differ between conventional urothelial carcinomas associated with squamous versus micropapillary carcinoma (p = 0.89, Wilcoxon rank sum). Instead, CK14 expression was higher in squamous carcinoma than conventional urothelial carcinoma present in the same bladder (p = 0.014, Wilcoxon rank sum, paired). Overall, the findings show that squamous and micropapillary cancers have different expression patterns of CK14 and FOXA1 and suggest that they arise from distinct precursors.