Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis.

The gastrointestinal (GI) tract contains much of the body's serotonin (5-hydroxytryptamine, 5-HT), but mechanisms controlling the metabolism of gut-derived 5-HT remain unclear. Here, we demonstrate that the microbiota plays a critical role in regulating host 5-HT. Indigenous spore-forming bacteria (Sp) from the mouse and human microbiota promote 5-HT biosynthesis from colonic enterochromaffin cells (ECs), which supply 5-HT to the mucosa, lumen, and circulating platelets. Importantly, microbiota-dependent effects on gut 5-HT significantly impact host physiology, modulating GI motility and platelet function. We identify select fecal metabolites that are increased by Sp and that elevate 5-HT in chromaffin cell cultures, suggesting direct metabolic signaling of gut microbes to ECs. Furthermore, elevating luminal concentrations of particular microbial metabolites increases colonic and blood 5-HT in germ-free mice. Altogether, these findings demonstrate that Sp are important modulators of host 5-HT and further highlight a key role for host-microbiota interactions in regulating fundamental 5-HT-related biological processes.

Ovarian granulosa cell tumor: A National Cancer Database study.

OBJECTIVE: To provide prognostic information from a large cohort of women with granulosa cell tumor we analyzed the National Cancer Database. METHODS: We performed an observational retrospective cohort analysis of 2680 women with ovarian granulosa cell tumor from the 1998-2013 National Cancer Database. Kaplan-Meier and multivariable Cox proportional-hazards survival analyses were performed for the overall cohort and propensity score matched cohorts to examine the association of surgical staging and adjuvant chemotherapy with survival. A random forest was used to determine important prognostic factors in stages II-IV granulosa cell tumor. RESULTS: Adjuvant chemotherapy, hormonal therapy, and radiotherapy were not associated with survival. Older age, more comorbidities, prior malignancy, higher stage, poor differentiation, larger tumor size, incomplete surgical staging, and residual disease at a surgical margin were independently associated with increased hazard of death. Among women with stage I disease, each one centimeter increase in tumor size was associated with 4% (2-6%) increased hazard of death (P<0.001). By matched cohort analyses, the hazard ratio (HR) (95% CI) for death associated with incomplete surgical staging was 1.77 (1.30-2.41), P<0.001 among women with stage I disease. Receiving adjuvant chemotherapy was not associated with increased survival among women with stages II-IV disease compared to no adjuvant treatment. CONCLUSION: Incomplete surgical staging was associated with increased hazard of death. There was no evidence of increased survival with use of adjuvant chemotherapy. Early and complete surgical resection remains the best evidenced treatment for ovarian granulosa cell tumor.

Arterial spin labeling perfusion in acute Wernicke encephalopathy: a case series discussion.

Wernicke's encephalopathy (WE) is a life-threatening neurologic disorder resulting from thiamine (vitamin B1) deficiency that can be secondary to chronic alcohol abuse, gastrointestinal surgery, systemic infectious and non-infectious diseases, and chemotherapy. WE is classically characterized on MRI by reduced diffusion and T2 prolongation along the mammillothalamic tracts, periaqueductal gray and tectal plate. We present two patients with acute WE who had baseline arterial spin labeling (ASL) perfusion at the time of presentation, demonstrating increase in cerebral blood flow (CBF) within the classically involved brain regions and concurrent global cerebral cortical hypoperfusion. Both patients were successfully treated with intravenous thiamine infusion. Post-treatment MRI demonstrated improvement of reduced diffusion and normalization of CBF within the involved structures. Prior histopathological studies have documented prominent undulation and luminal dilatation of arteries and arterioles in acute WE lesions, likely explaining the increased perfusion shown by imaging. The root of this pathophysiologic process may trace back to thiamine's biochemical role in maintaining osmotic gradients and glucose metabolism, that if failed can lead to arterial hyper-perfusion. Our findings show that ASL-CBF can highlight the underlying pathophysiology in patients with acute WE by demonstrating increased CBF in involved central structures. This luxury perfusion may be a compensatory or protective mechanism by which increased metabolic demand is met in the acute setting and which, if treated timely, will show normalization of CBF on ASL imaging.

Association of increased primary breast tumor AGR2 with decreased disease-specific survival.

OBJECTIVE: Tumor expression of Anterior Gradient 2 (AGR2), an endoplasmic reticulum protein disulfide isomerase, was associated with decreased breast cancer survival. We aimed to validate the association of tumor AGR2 mRNA expression with disease-specific survival (DSS) and identify differentially expressed signaling pathways between high and low AGR2 expression tumor groups. METHODS: Primary tumor mRNA expression data from the METABRIC study was used to evaluate AGR2 expression as a prognostic factor for DSS while adjusting for survival-determining confounders using Cox proportional-hazards regression. Differentially expressed genes and signaling pathway differences between high and low AGR2 groups were determined by modular enrichment analyses using DAVID and Ingenuity Pathway Analysis. RESULTS: Increased tumor AGR2 mRNA expression was associated with decreased DSS among 1,341 women (per each standard deviation increase of AGR2 expression: HR 1.14, 95% CI: 1.01-1.29, P = 0.03). Pathway analyses supported prior experimental studies showing that estrogen receptor 1 (ESR1) regulated AGR2 expression. Canonical signaling pathways significantly differentially represented between high and low AGR2 groups included those involved in inflammation and immunity. CONCLUSION: Increased primary tumor AGR2 expression was associated with decreased DSS. Pathway analyses suggested that increased AGR2 was associated with endoplasmic reticular homeostasis, possibly allowing tumor cells to overcome hypoxic stress and meet the increased protein demand of tumorigenesis, thereby preventing unfolded protein response-mediated apoptosis.