ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97.

The t(X,17) chromosomal translocation, generating the ASPSCR1::TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCCs), frustrating efforts to identify therapeutic targets for these rare cancers. Here, proteomic analysis identifies VCP/p97, an AAA+ ATPase with known segregase function, as strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1::TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1::TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributes with ASPSCR1::TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its enzymatic function orchestrate the oncogenic transcriptional signature of ASPSCR1::TFE3, by facilitating assembly of higher-order chromatin conformation structures demonstrated by HiChIP. Finally, ASPSCR1::TFE3 and VCP demonstrate co-dependence for cancer cell proliferation and tumorigenesis in vitro and in ASPS and RCC mouse models, underscoring VCP's potential as a novel therapeutic target.

ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97.

The t(X,17) chromosomal translocation, generating the ASPSCR1-TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCC), frustrating efforts to identify therapeutic targets for these rare cancers. Proteomic analysis showed that VCP/p97, an AAA+ ATPase with known segregase function, was strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1-TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1-TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributed with ASPSCR1-TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its enzymatic function orchestrated the oncogenic transcriptional signature of ASPSCR1-TFE3, by facilitating assembly of higher-order chromatin conformation structures as demonstrated by HiChIP. Finally, ASPSCR1-TFE3 and VCP demonstrated co-dependence for cancer cell proliferation and tumorigenesis in vitro and in ASPS and RCC mouse models, underscoring VCP's potential as a novel therapeutic target.

Alternative career pathway decision-support job database for international medical graduates in Canada.

OBJECTIVES: Canadian regulations have made it challenging for the international medical graduates (IMGs) to get jobs in their original profession as physicians. Consequently, alternative careers are gaining interest among IMGs to avoid underemployment or unemployment. We conducted research to identify the factors that IMGs consider for taking up an alternative career in Canada. Based on those understandings, we aimed to create a database where information about health-related alternative jobs is presented in a searchable way, which can aid IMGs' strategic job search. DATA DESCRIPTION: We first determined job searching preferences and constraints for IMGs regarding alternative career through focus groups. We used their preferred and constraining factors for collecting job-specific information through systematically reviewing job advertisements. Using this information, we created a database that contains available alternative career pathways for IMGs living in Canada. In total, we have identified 1374 job titles under 192 unique job categories comprising 47 National Occupational Classification (NOC) codes that could be suitable for IMGs seeking an alternative career based on their own short, intermediate, and long-term career goals. We expect that this database will help IMGs in deciding on alternative careers.

Mental Health and Well-Being Needs among Non-Health Essential Workers during Recent Epidemics and Pandemics.

Essential workers, those who work in a variety of sectors that are critical to sustain the societal infrastructure, were affected both physically and mentally by the COVID-19 pandemic. While the most studied group of this population were healthcare workers, other essential non-health workers such as those working in the law enforcement sector, grocery services, food services, delivery services, and other sectors were studied less commonly. We explored both the academic (using MEDLINE, PsycInfo, CINAHL, Sociological Abstracts, and Web of Science databases) and grey literature (using Google Scholar) to identify studies on the mental health effects of the six pandemics in the last 20 years (2000-2020). We identified a total of 32 articles; all of them pertained to COVID-19 except for one about Ebola. We found there was an increase in depression, anxiety, stress, and other mental health issues among non-health essential workers. They were more worried about passing the infection on to their loved ones and often did not have adequate training, supply of personal protective equipment, and support to cope with the effects. Generally, women, people having lower education, and younger people were more likely to be affected by a pandemic. Exploring occupation-specific coping strategies of those whose mental health was affected during a pandemic using more robust methodologies such as longitudinal studies and in-depth qualitative exploration would help facilitate appropriate responses for their recovery.

Author Correction: Smac mimetics and oncolytic viruses synergize in driving anticancer T-cell responses through complementary mechanisms.

The originally published version of this article contained an error in the spelling of the author Pankaj Tailor, which was incorrectly given as Pankaj Taylor. This has now been corrected in both the PDF and HTML versions of the article.

Smac mimetics and oncolytic viruses synergize in driving anticancer T-cell responses through complementary mechanisms.

Second mitochondrial activator of caspase (Smac)-mimetic compounds and oncolytic viruses were developed to kill cancer cells directly. However, Smac-mimetic compound and oncolytic virus therapies also modulate host immune responses in ways we hypothesized would complement one another in promoting anticancer T-cell immunity. We show that Smac-mimetic compound and oncolytic virus therapies synergize in driving CD8+ T-cell responses toward tumors through distinct activities. Smac-mimetic compound treatment with LCL161 reinvigorates exhausted CD8+ T cells within immunosuppressed tumors by targeting tumor-associated macrophages for M1-like polarization. Oncolytic virus treatment with vesicular stomatitis virus (VSVΔM51) promotes CD8+ T-cell accumulation within tumors and CD8+ T-cell activation within the tumor-draining lymph node. When combined, LCL161 and VSVΔM51 therapy engenders CD8+ T-cell-mediated tumor control in several aggressive mouse models of cancer. Smac-mimetic compound and oncolytic virus therapies are both in clinical development and their combination therapy represents a promising approach for promoting anticancer T-cell immunity.Oncolytic viruses (OV) and second mitochondrial activator of caspase (Smac)-mimetic compounds (SMC) synergistically kill cancer cells directly. Here, the authors show that SMC and OV therapies combination also synergize in vivo by promoting anticancer immunity through an increase in CD8+ T-cell response.