Outcomes of Donation After Circulatory Death Heart Transplantation in Australia

Background

Transplantation of hearts retrieved from donation after circulatory death (DCD) donors is an evolving clinical practice.

Screening for Inhibition of Vibrio cholerae VipA-VipB Interaction Identifies Small-Molecule Compounds Active against Type VI Secretion

The type VI secretion system (T6SS) is the most prevalent bacterial secretion system and an important virulence mechanism utilized by Gram-negative bacteria, either to target eukaryotic cells or to combat other microbes. The components show much variability, but some appear essential for the function, and two homologues, denoted VipA and VipB in Vibrio cholerae, have been identified in all T6SSs described so far. Secretion is dependent on binding of an α-helical region of VipA to VipB, and in the absence of this binding, both components are degraded within minutes and secretion is ceased. The aim of the study was to investigate if this interaction could be blocked, and we hypothesized that such inhibition would lead to abrogation of T6S. A library of 9,600 small-molecule compounds was screened for their ability to block the binding of VipA-VipB in a bacterial two-hybrid system (B2H). After excluding compounds that showed cytotoxicity toward eukaryotic cells, that inhibited growth of Vibrio, or that inhibited an unrelated B2H interaction, 34 compounds were further investigated for effects on the T6SS-dependent secretion of hemolysin-coregulated protein (Hcp) or of phospholipase A₁ activity. Two compounds, KS100 and KS200, showed intermediate or strong effects in both assays. Analogues were obtained, and compounds with potent inhibitory effects in the assays and desirable physicochemical properties as predicted by in silico analysis were identified. Since the compounds specifically target a virulence mechanism without affecting bacterial replication, they have the potential to mitigate the virulence with minimal risk for development of resistance.     

Cholecystectomy and the risk of colorectal cancer by tumor mismatch repair deficiency status

Purpose

Gallbladder diseases and cholecystectomy may play a role in the development of colorectal cancer (CRC). Our aim was to investigate the association between cholecystectomy and CRC risk overall and by sex, family history, anatomical location, and tumor mismatch repair (MMR) status.

Methods

This study comprised 5847 incident CRC cases recruited from population cancer registries in Australia, Canada, and the USA into the Colon Cancer Family Registry between 1997 and 2012 and 4970 controls with no personal history of CRC who were either randomly selected from the general population or were spouses of the cases. The association between cholecystectomy and CRC was estimated using logistic regression, after adjusting for confounding factors.

Results

Overall, there was no evidence for an association between cholecystectomy and CRC (odds ratio [OR] = 0.88, 95 % confidence interval 0.73, 1.08). In the stratified analyses, there was no evidence for a difference in the association between women and men (P = 0.54), between individuals with and without family history of CRC in first-degree relative (P = 0.64), between tumor anatomical locations (P = 0.45), or between MMR-proficient and MMR-deficient cases (P = 0.54).

Conclusion

Cholecystectomy is not a substantial risk factor for CRC, regardless of sex, family history, anatomical location, or tumor MMR status.

     

Fecal Steroid 21-Dehydroxylase, a Potential Marker for Colorectal Cancer

Eubacterium lentum and phenotypically similar organisms synthesize a steroid 21-dehydroxylase which converts biliary tetrahydrodeoxycorticosterone to pregnanolone. Tetrahydrodeoxycorticosterone, in contrast to pregnanolone, is carcinogenic for hamster embryonic cells (HECT test). In patients with recently diagnosed, untreated sigmoidal or rectal cancer the fecal concentration of 21-dehydroxylating organisms is reduced by more than 99% as compared with age-matched controls. The lack of fecal 21-dehydroxylating organisms, therefore, is a potential marker for the disorder. The role of steroid 21-dehydroxylase in the pathogenesis of colorectal cancer is unknown.