LGBTQIA health in medical education: a national survey of Australian medical students.

PURPOSE: Lesbian, gay, bisexual, transgender, queer, intersex and asexual (LGBTQIA) individuals experience poorer health outcomes than other individuals. Insufficient LGBTQIA health education of doctors in existing medical curricula contributes to these outcomes. We sought to explore medical students' experiences of content coverage and mode of delivery, as well as their preparedness, attitudes and learning needs regarding LGBTQIA health education in Australia. METHODS: Using a conceptual framework specific to curricular development, we adapted a previous cross-sectional national survey. This included 28 questions (analysed statistically) and 5 free text responses (analysed deductively using Braun and Clarke's thematic analysis framework). Data was compared between LGBTQIA and non-LGBTQIA respondents, and clinical and preclinical students. RESULTS: There were 913 participants from 21 of 23 medical schools, with most preclinical (55%) and clinical (89%) students reporting no teaching specific to LGBTQIA health. Reported content coverage was highest for sexual history taking (30%), and especially low for transgender and intersex health (< 16%), and intersectional LGBTQIA health (< 7%). Participants had positive attitudes towards LGBTQIA health, with 89% agreeing LGBTQIA topics were important and need to be covered in detail. Students desired longitudinal integration of LGBTQIA content, and LGBTQIA community involvement and case-based teaching that allows for interaction and questions. Self-perceived competency was low in all LGBTQIA health topics, although LGBTQIA participants reported higher preparedness than non-LGBTQIA participants. CONCLUSIONS: Majority of survey participants reported limited teaching of LGBTQIA health-specific content, highlighting the limited coverage of LGBTQIA health in Australian medical schools. Participants expressed positive attitudes towards LGBTQIA content and broadly agreed with statements supporting increased integration of LGBTQIA health content within medical curricula.

Clinical MDR1 inhibitors enhance Smac-mimetic bioavailability to kill murine LSCs and improve survival in AML models.

The specific targeting of inhibitor of apoptosis (IAP) proteins by Smac-mimetic (SM) drugs, such as birinapant, has been tested in clinical trials of acute myeloid leukemia (AML) and certain solid cancers. Despite their promising safety profile, SMs have had variable and limited success. Using a library of more than 5700 bioactive compounds, we screened for approaches that could sensitize AML cells to birinapant and identified multidrug resistance protein 1 inhibitors (MDR1i) as a class of clinically approved drugs that can enhance the efficacy of SM therapy. Genetic or pharmacological inhibition of MDR1 increased intracellular levels of birinapant and sensitized AML cells from leukemia murine models, human leukemia cell lines, and primary AML samples to killing by birinapant. The combination of clinical MDR1 and IAP inhibitors was well tolerated in vivo and more effective against leukemic cells, compared with normal hematopoietic progenitors. Importantly, birinapant combined with third-generation MDR1i effectively killed murine leukemic stem cells (LSCs) and prolonged survival of AML-burdened mice, suggesting a therapeutic opportunity for AML. This study identified a drug combination strategy that, by efficiently killing LSCs, may have the potential to improve outcomes in patients with AML.

Multiple ABCB1 transcriptional fusions in drug resistant high-grade serous ovarian and breast cancer.

ABCB1 encodes Multidrug Resistance protein (MDR1), an ATP-binding cassette member involved in the cellular efflux of chemotherapeutic drugs. Here we report that ovarian and breast samples from chemotherapy treated patients are positive for multiple transcriptional fusions involving ABCB1, placing it under the control of a strong promoter while leaving its open reading frame intact. We identified 15 different transcriptional fusion partners involving ABCB1, as well as patients with multiple distinct fusion events. The partner gene selected depended on its structure, promoter strength, and chromosomal proximity to ABCB1. Fusion positivity was strongly associated with the number of lines of MDR1-substrate chemotherapy given. MDR1 inhibition in a fusion positive ovarian cancer cell line increased sensitivity to paclitaxel more than 50-fold. Convergent evolution of ABCB1 fusion is therefore frequent in chemotherapy resistant recurrent ovarian cancer. As most currently approved PARP inhibitors (PARPi) are MDR1 substrates, prior chemotherapy may precondition resistance to PARPi.