Immunohistochemical and molecular characterizations in urothelial carcinoma of bladder in patients less than 45 years

Bladder tumours in early-onset patients are rare and seem to exhibit unique clinicopathological features. Only few studies have investigated somatic alterations in this specific age of onset group and evidence is accumulating of a distinct molecular behaviour of early-onset bladder tumours. We collected the largest cohort of early-onset tumours of patients 45 years old or younger and aimed to test genomic alterations typically found in bladder cancer. Tumours of 118 early-onset patients were compared with a consecutive group of 113 cases. Immunohistochemistry of TP53, CK20 and Ki-67 was carried out. Molecular analysis was conducted to test for loss of heterozygosity of chromosome 9 and 17, as well as TP53 and FGFR3 mutations. Fisheŕs exact and chi-squared test were appropriately used. No differences in grade/stage characteristics were observed. Overexpressed TP53 was differentially distributed between the two groups. TP53 nuclear accumulation was significantly more frequent in early-onset papillomas, PUNLMPs and pTa low-grade tumours compared to the consecutive cohort (p=0.005). Moreover, chromosome 9 deletions (29.5% vs. 44.6%) and FGFR3 mutations (34.5% vs. 63.7%) were less often detected in early-onset patients (p=0.05 and p<0.0001). By comparing the largest cohort of early-onset bladder cancer patients with an unselected group, we demonstrated that the typical molecular features are not independent of age at diagnosis. Our study supports the hypothesis of a distinct biological behaviour in early-onset tumours

Global Functional Analyses of Cellular Responses to Pore-Forming Toxins

Here we present the first global functional analysis of cellular responses to pore-forming toxins (PFTs). PFTs are uniquely important bacterial virulence factors, comprising the single largest class of bacterial protein toxins and being important for the pathogenesis in humans of many Gram positive and Gram negative bacteria. Their mode of action is deceptively simple, poking holes in the plasma membrane of cells. The scattered studies to date of PFT-host cell interactions indicate a handful of genes are involved in cellular defenses to PFTs. How many genes are involved in cellular defenses against PFTs and how cellular defenses are coordinated are unknown. To address these questions, we performed the first genome-wide RNA interference (RNAi) screen for genes that, when knocked down, result in hypersensitivity to a PFT. This screen identifies 106 genes (∼0.5% of genome) in seven functional groups that protect Caenorhabditis elegans from PFT attack. Interactome analyses of these 106 genes suggest that two previously identified mitogen-activated protein kinase (MAPK) pathways, one (p38) studied in detail and the other (JNK) not, form a core PFT defense network. Additional microarray, real-time PCR, and functional studies reveal that the JNK MAPK pathway, but not the p38 MAPK pathway, is a key central regulator of PFT-induced transcriptional and functional responses. We find C. elegans activator protein 1 (AP-1; c-jun, c-fos) is a downstream target of the JNK-mediated PFT protection pathway, protects C. elegans against both small-pore and large-pore PFTs and protects human cells against a large-pore PFT. This in vivo RNAi genomic study of PFT responses proves that cellular commitment to PFT defenses is enormous, demonstrates the JNK MAPK pathway as a key regulator of transcriptionally-induced PFT defenses, and identifies AP-1 as the first cellular component broadly important for defense against large- and small-pore PFTs

Mediating effects of body mass index, physical activity, and emotional distress on the relationship between short sleep and cardiovascular disease

The current study investigated the mediating effects of body mass index (BMI), physical activity, and emotional distress on the association between short sleep duration (<7 hours per 24-hour period) and cardiovascular disease (CVD) and risk factors. We used data from the National Health Interview Survey, an ongoing nationally representative cross-sectional study of noninstitutionalized US adults (>= 18 years) from 2004 to 2013 (N=206,049). Participants provided information about anthropometric features (height and weight), sociodemographic factors, health behaviors (smoking and physical activity), emotional distress, and physician-diagnosed health conditions, including hypertension, coronary heart disease, diabetes, heart attack, stroke, kidney disease, and cancer. Structural equation modeling was used to assess the mediating effects of physical activity, BMI, and emotional distress on the relationship between short sleep and CVDs and risk factors (coronary heart disease, hypertension, diabetes, chronic kidney disease, heart attack, and stroke). Of the sample, 54.7% were female, 60.1% identified as white, 17.7% as Hispanic, and 15.4% as black. The mean age of the respondents was 46.75 years (SE=0.12), with a mean BMI of 27.11kg/m(2) (SE=0.02) and approximately 32.5% reported short sleep duration. The main relationship between short sleep and CVD and risk factors was significant (beta=0.08, P<.001), as was the mediated effect via BMI (indirect effect=0.047, P<.001), emotional distress (indirect effect=0.022, P<.001), and physical activity (indirect effect=-0.022, P=.035), as well as after adjustment for covariates, including age, race, sex, marital status, and income: short sleep and CVD (B=0.15; SE=0.01; P<.001), BMI (B=0.05; SE=0.00; P<.001), emotional distress (B=0.02; SE=0.00; P<.001), and physical activity (B=0.01; SE=0.00; P<.001). Our findings indicate that short sleep is a risk factor for CVD and that the relationship between short sleep and CVD and risk factors may be mediated by emotional distress and obesity, and negatively mediated by physical activity