Search

Patients with inflammatory bowel disease (IBD) are susceptible to colitis-associated cancer (CAC). Chronic inflammation promotes the risk for CAC. In contrast, mucosal healing predicts improved prognosis in IBD and reduced risk of CAC. However, the molecular integration among colitis, mucosal healing, and CAC remains poorly understood. Claudin-2 (CLDN2) expression is upregulated in IBD; however, its role in CAC is not known. The current study was undertaken to examine the role for CLDN2 in CAC. The AOM/DSS-induced CAC model was used with WT and CLDN2-modified mice. High-throughput expression analyses, murine models of colitis/recovery, chronic colitis, ex vivo crypt culture, and pharmacological manipulations were employed in order to increase our mechanistic understanding. The Cldn2KO mice showed significant inhibition of CAC despite severe colitis compared with WT littermates. Cldn2 loss also resulted in impaired recovery from colitis and increased injury when mice were subjected to intestinal injury by other methods. Mechanistic studies demonstrated a possibly novel role of CLDN2 in promotion of mucosal healing downstream of EGFR signaling and by regulation of Survivin expression. An upregulated CLDN2 expression protected from CAC and associated positively with crypt regeneration and Survivin expression in patients with IBD. We demonstrate a potentially novel role of CLDN2 in promotion of mucosal healing in patients with IBD and thus regulation of vulnerability to colitis severity and CAC, which can be exploited for improved clinical management., Introduction Patients with inflammatory bowel disease (IBD) have two big fears: (a) developing colon cancer and (b) losing their colon by colectomy because of the heightened risk of colitis-associated cancer [...]

Background: Although studies have provided estimates of premature mortality to either heat or cold in adult populations, and fetal exposure to ambient temperature may be associated with life expectancy, the effects of temperature on aging in early life have not yet been studied. Telomere length (TL) is a marker of biological aging, and a short TL at birth may predict lifespan and disease susceptibility later in life. Objectives: We studied to what extent prenatal ambient temperature exposure is associated with newborn TL. Methods: In the ENVIRONAGE (ENVIRonmental influence ON early AGEing) birth cohort in Flanders, Belgium, we measured cord blood and placental TL in 1,103 mother-newborn pairs (singletons with [greater than or equal to] 36 wk of gestation) using a quantitative real-time polymerase chain reaction (qPCR) method. We associated newborn TL with average weekly exposure to ambient temperature using distributed lag nonlinear models (DLNMs) while controlling for potential confounders. Double-threshold DLNMs were used to estimate cold and heat thresholds and the linear associations between temperature and TL below the cold threshold and above the heat threshold. Results: Prenatal temperature exposure above the heat threshold (19.5[degrees]C) was associated with shorter cord blood TL. The association with a 1[degrees]C increase in temperature was strongest at week 36 of gestation and resulted in a 3.29% [95% confidence interval (CI): - 4.67, -1.88] shorter cord blood TL. Consistently, prenatal temperature exposure below the cold threshold (5.0[degrees]C) was associated with longer cord blood TL. The association with a 1[degrees]C decrease in temperature was strongest at week 10 of gestation with 0.72% (95% CI: 0.46, 0.97) longer cord blood TL. Discussion: Our study supports potential effects of prenatal temperature exposure on longevity and disease susceptibility later in life. Future climate scenarios might jeopardize the potential molecular longevity of future generations from birth onward. https://doi.org/10.1289/EHP5153, Introduction Awareness and concerns regarding global warming worldwide have focused recent research on the evaluation of climate change effects on human health (Patz et al. 2005). Climate change will affect [...]