Rucaparib in the landscape of PARP inhibition in ovarian cancer

Introduction: The landscape of poly (ADP-ribose) polymerase (PARP) inhibition in ovarian cancer is rapidly evolving and becoming increasingly complex. Ovarian cancer is leading therapeutic innovation by providing the proof of concept for DNA repair as a target. Three different PARP inhibitors have now received approvals in the US and Europe in different indications. Subtle but crucial differences can be found among the licensed indications for each PARP inhibitor in terms of histology, type of BRCA mutation (germline and/or somatic), number of prior lines of chemotherapy and whether the indication is in the treatment or maintenance settings.

Areas covered: We review the latest clinical data regarding the PARP inhibitor rucaparib in ovarian cancer, provide an update on the evolving landscape of PARP inhibition in ovarian cancer, and summarize avenues of ongoing and future research.

Expert opinion: All eligible patients should be offered a PARP inhibitor. SOLO1 trial results demonstrated an unprecedented benefit maintenance with PARP inhibitors in first line. Results from trials evaluating PARP inhibitors as maintenance in first line regardless of BRCA status and from trials evaluating combinatorial strategies are eagerly awaited.     

Assessing the impact of blood alcohol concentration on the rate of in-hospital mortality following traumatic motor vehicle crash injury: A matched analysis of the National Trauma Data Bank

Background

The purpose of this study was to compare the outcomes of trauma patients who were injured in a motor vehicle crash and tested positive for alcohol upon hospital arrival versus those who tested negative.

Novel vaccination strategies and approaches against human tuberculosis

Tuberculosis (TB) remains one of a major health problem worldwide. Tuberculosis vaccine research has made an extraordinary progress over the past few years. However, there is still no replacement for the Bacillus Calmette‐Guérin vaccine, the only TB vaccine licensed for human use. Therefore, the discovery and development of new TB vaccines remains a priority. This article discusses current strategies used to diversify TB vaccines and includes discussion of the status of efforts to improve protection against Mycobacterium tuberculosis (M tb) infection or TB disease by developing new and safe TB vaccines. This article also highlights the current research efforts in immune‐enhancing approaches to improve vaccination efficacy. The development of more effective TB vaccines might have significant impact on global TB control.     

Application of the adverse outcome pathway framework to genotoxic modes of action

In May 2017, the Health and Environmental Sciences Institute's Genetic Toxicology Technical Committee hosted a workshop to discuss whether mode of action (MOA) investigation is enhanced through the application of the adverse outcome pathway (AOP) framework. As AOPs are a relatively new approach in genetic toxicology, this report describes how AOPs could be harnessed to advance MOA analysis of genotoxicity pathways using five example case studies. Each of these genetic toxicology AOPs proposed for further development includes the relevant molecular initiating events, key events, and adverse outcomes (AOs), identification and/or further development of the appropriate assays to link an agent to these events, and discussion regarding the biological plausibility of the proposed AOP. A key difference between these proposed genetic toxicology AOPs versus traditional AOPs is that the AO is a genetic toxicology endpoint of potential significance in risk characterization, in contrast to an adverse state of an organism or a population. The first two detailed case studies describe provisional AOPs for aurora kinase inhibition and tubulin binding, leading to the common AO of aneuploidy. The remaining three case studies highlight provisional AOPs that lead to chromosome breakage or mutation via indirect DNA interaction (inhibition of topoisomerase II, production of cellular reactive oxygen species, and inhibition of DNA synthesis). These case studies serve as starting points for genotoxicity AOPs that could ultimately be published and utilized by the broader toxicology community and illustrate the practical considerations and evidence required to formalize such AOPs so that they may be applied to genetic toxicity evaluation schemes. Environ. Mol. Mutagen. 61:114–134, 2020. © 2019 Wiley Periodicals, Inc.     

Prevalence,Risk Factors,and Transmission Dynamics of Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae: a National Survey of Cattle Farms in Israel in 2013

Our objectives were to study the prevalence, risk factors for carriage, and transmission dynamics of extended-spectrum-β-lactamase (ESBL)-producing Enterobacteriaceae (ESBLPE) in a national survey of cattle. This was a point prevalence study conducted from July to October 2013 in Israel. Stool samples were collected from 1,226 cows in 123 sections on 40 farms of all production types. ESBLPE were identified in 291 samples (23.7%): 287 contained Escherichia coli and 4 contained Klebsiella pneumoniae. The number of ESBLPE-positive cows was the highest in quarantine stations and on fattening farms and was the lowest on pasture farms (P = 0.03). The number of ESBLPE-positive cows was the lowest in sections containing adult cows (age, >25 months) and highest in sections containing calves (age, <4 months) (P < 0.001). Infrastructure variables that were significant risk factors for ESBLPE carriage included crowding, a lack of manure cleaning, and a lack of a cooling (P < 0.001 for each), all of which were more common in sections containing calves. Antimicrobial prophylaxis was given almost exclusively to calves and was associated with a high number of ESBLPE carriers (P < 0.001). The 287 E. coli isolates were typed into 106 repetitive extragenic palindromic (REP)-PCR types and mostly harbored bla_CTX-M-1 or bla_CTX-M-9 group genes. The isolates on the six farms with ≥15 isolates of ESBLPE were of 4 to 7 different REP-PCR types, with one dominant type being harbored by about half of the isolates. Fourteen types were identified on more than one farm, with only six of the farms being adjacent to each other. The prevalence of ESBLPE carriage is high in calves in cowsheds where the use of antimicrobial prophylaxis is common. ESBLPE disseminate within cowsheds mainly by clonal spread, with limited intercowshed transmission occurring.