Epithelial-to-mesenchymal transition supports ovarian carcinosarcoma tumorigenesis and confers sensitivity to microtubule-targeting with eribulin

Ovarian carcinosarcoma (OCS) is an aggressive and rare tumour type with limited treatment options. OCS is hypothesised to develop via the combination theory, with a single progenitor resulting in carcinomatous and sarcomatous components, or alternatively via the conversion theory, with the sarcomatous component developing from the carcinomatous component through epithelial-to-mesenchymal transition (EMT). In this study, we analysed DNA variants from isolated carcinoma and sarcoma components to show that OCS from 18 women is monoclonal. RNA sequencing indicated the carcinoma components were more mesenchymal when compared with pure epithelial ovarian carcinomas, supporting the conversion theory and suggesting that EMT is important in the formation of these tumours. Preclinical OCS models were used to test the efficacy of microtubule-targeting drugs, including eribulin, which has previously been shown to reverse EMT characteristics in breast cancers and induce differentiation in sarcomas. Vinorelbine and eribulin more effectively inhibited OCS growth than standard-of-care platinum-based chemotherapy, and treatment with eribulin reduced mesenchymal characteristics and N-MYC expression in OCS patient-derived xenografts (PDX). Eribulin treatment resulted in an accumulation of intracellular cholesterol in OCS cells, which triggered a down-regulation of the mevalonate pathway and prevented further cholesterol biosynthesis. Finally, eribulin increased expression of genes related to immune activation and increased the intratumoral accumulation of CD8+ T cells, supporting exploration of immunotherapy combinations in the clinic. Together, these data indicate EMT plays a key role in OCS tumourigenesis and support the conversion theory for OCS histogenesis. Targeting EMT using eribulin could help improve OCS patient outcomes

Increase in diagnoses of recently acquired HIV in people who inject drugs.

An increase in recently acquired HIV in PWID has been noted in Dublin since early 2015. We have defined recently acquired HIV infections as those in which the person tests positive using a combined HIV antigen/antibody screening assay, negative or indeterminate on a confirmatory immunoblot assay and is p24 antigen positive, or has had a HIV negative test within the 12 months prior to the positive test or who suffers an acute HIV sero-conversion illness. A multidisciplinary incident team has been set up by the Director of Public Health in Dublin to investigate and respond to the increase. The team includes public health and HIV Physicians, GPs providing services for drug users and homeless populations, HSE social inclusion, addiction clinicians, clinical virologist and HPSC. An epidemiological investigation is underway. Clinicians from the drug services are concerned that the increase is linked to injection of a synthetic cathinone PVP, street name Snow Blow, with consequent more frequent injecting, and unsafe sexual and needle sharing practices. This has mainly been seen in chaotic drug users, who report polydrug use, and are often homeless. Evidence to date indicates that the increase has been occurring since June 2014. Fifteen cases of recently acquired HIV infection (confirmed cases) and one case with epidemiological link to a recently acquired HIV infection (probable case) have been diagnosed in PWID in Dublin from June 2014 to June 2015. Of the 15 cases, seven are p24 antigen positive indicating very recent infection. A further 16 possible cases in PWID are currently under investigation and new cases continue to be detected. Amongst the 16 confirmed and probable cases, 11 are male and five are female, and the mean age is 35 years (range; 24 to 51 years). A case control study is underway to identify any association between use of Snow Blow leading to an increase in unsafe injecting practices, and at-risk sexual behaviour, and acquisition of HIV.....

Injection of new psychoactive substance snow blow associated with recently acquired HIV infections among homeless people who inject drugs in Dublin, Ireland, 2015.

In February 2015, an outbreak of recently acquired HIV infections among people who inject drugs (PWID) was identified in Dublin, following similar outbreaks in Greece and Romania in 2011. We compared drug and risk behaviours among 15 HIV cases and 39 controls. Injecting a synthetic cathinone, snow blow, was associated with recent HIV infection (AOR: 49; p = 0.003). Prevention and control efforts are underway among PWID in Dublin, but may also be needed elsewhere in Europe