Transgenic Expression of Entire Hepatitis B Virus in Mice Induces Hepatocarcinogenesis Independent of Chronic Liver Injury

Hepatocellular carcinoma (HCC), the third leading cause of cancer deaths worldwide, is most commonly caused by chronic hepatitis B virus (HBV) infection. However, whether HBV plays any direct role in carcinogenesis, other than indirectly causing chronic liver injury by inciting the host immune response, remains unclear. We have established two independent transgenic mouse lines expressing the complete genome of a mutant HBV (“preS2 mutant”) that is found at much higher frequencies in people with HCC than those without. The transgenic mice show evidence of stress in the endoplasmic reticulum (ER) and overexpression of cyclin D1 in hepatocytes. These mice do not show any evidence of chronic liver injury, but by 2 years of age a majority of the male mice develop hepatocellular neoplasms, including HCC. Unexpectedly, we also found a significant increase in hepatocarcinogenesis independent of necroinflammation in a transgenic line expressing the entire wildtype HBV. As in the mutant HBV mice, HCC was found only in aged—2-year-old—mice of the wildtype HBV line. The karyotype in all the three transgenic lines appears normal and none of the integration sites of the HBV transgene in the mice is near an oncogene or tumor suppressor gene. The significant increase of HCC incidence in all the three transgenic lines—expressing either mutant or wildtype HBV—therefore argues strongly that in absence of chronic necroinflammation, HBV can contribute directly to the development of HCC

Prenatal bisphenol a exposure and dysregulation of infant hypothalamic-pituitary-adrenal axis function: findings from the APrON cohort study

Abstract Background Animal models show that prenatal bisphenol A (BPA) exposure leads to sexually dimorphic disruption of the neuroendocrine system in offspring, including the hypothalamic-pituitary-adrenal (HPA) neuroendocrine system, but human data are lacking. In humans, prenatal BPA exposure is associated with sex-specific behavioural problems in children, and HPA axis dysregulation may be a biological mechanism. The objective of the current study was to examine sex differences in associations between prenatal maternal urinary BPA concentration and HPA axis function in 3 month old infants. Methods Mother-infant pairs (n = 132) were part of the Alberta Pregnancy Outcomes and Nutrition study, a longitudinal birth cohort recruited (2010–2012) during pregnancy. Maternal spot urine samples collected during the 2nd trimester were analyzed for total BPA and creatinine. Infant saliva samples collected prior to and after a blood draw were analyzed for cortisol. Linear growth curve models were used to characterize changes in infant cortisol as a function of prenatal BPA exposure. Results Higher maternal BPA was associated with increases in baseline cortisol among females (β = 0.13 log μg/dL; 95% CI: 0.01, 0.26), but decreases among males (β = −0.22 log μg/dL; 95% CI: -0.39, −0.05). In contrast, higher BPA was associated with increased reactivity in males (β = .30 log μg/dL; 95% CI: 0.04, 0.56) but decreased reactivity in females (β = −0.15 log μg/dL; 95% CI: -0.35, 0.05). Models adjusting for creatinine yielded similar results. Conclusions Prenatal BPA exposure is associated with sex-specific changes in infant HPA axis function. The biological plausibility of these findings is supported by their consistency with evidence in rodent models. Furthermore, these data support the hypotheses that sexually dimorphic changes in children’s behaviour following prenatal BPA exposure are mediated by sexually dimorphic changes in HPA axis function

Physical function and exercise training in older patients with heart failure

Heart failure (HF) is a common end point for numerous cardiovascular conditions, including coronary artery disease, valvular disease, and hypertension. HF predominantly affects older individuals (aged >= 70 years), particularly those living in developed countries. The pathophysiological sequelae of HF progression have a substantial negative effect on physical function. Diminished physical function in older patients with HF, which is the result of combined disease-related and age-related effects, has important implications on health. A large body of research spanning several decades has demonstrated the safety and efficacy of regular physical activity in improving outcomes among the HF population, regardless of age, sex, or ethnicity. However, patients with HF, especially those who are older, are less likely to engage in regular exercise training compared with the general population. To improve initiation of regular exercise training and subsequent long-term compliance, there is a need to rethink the dialogue between clinicians and patients. This Review discusses the need to improve physical function and exercise habits in patients with HF, focusing on the older population