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Management of familial adenomatous polyposis (FAP) is guided by the cumulative risk of colorectal cancer (CRC) and aggressive fibromatosis/desmoid (AF/D). The first non-Caucasian FAP cohort with cumulative risk estimates for CRC and AF/D shows distinct differences with the Caucasian and other Asian cohorts. The strong correlation between the adenomatous polyposis coli (APC) mutation location with the FAP phenotype and the geoethnic differences in APC mutation spectrum, genetic constitution, lifestyle and sporadic CRC rates, mandates the use of population-specific cumulative risk estimates for CRC and desmoid for counselling and risk management. On genotype–phenotype correlation in 83 individuals with classical FAP and a confirmed pathogenic/likely Pathogenic (P/LP) APC variant (n=76) or obligate carrier of the family variant (n=7), we observed a high cumulative CRC risk of 40% and 85% by 40 and 60 years, respectively. The observed 30% cumulative risk by 50 years for desmoids was higher than previous European and Asian cohorts and was significantly associated with prophylactic surgery (OR: 4.58, 95% CI 1.06 to 19.78) and APC mutation 3′ of codon 1309 (OR: 13.07, 95% CI 3.58 to 47.56) and also 3′ of codon 1444 (OR: 8.0, 95% CI 1.83 to 34.94). Global cooperation is required to establish FAP genotype–phenotype associations and population- specific risk estimates to guide genetic counselling and risk management. [ABSTRACT FROM AUTHOR]

The emerging pandemic of COVID-19 caused by the novel pathogenic human coronavirus SARS-CoV-2 has caused significant morbidity and mortality across the globe, prompting the scientific world to search for preventive measures to interrupt the disease process. Demographic data indicates gender-based differences in COVID-19 morbidity with better outcome amongst females. Disparity in sex-dependent morbidity and mortality in COVID-19 patients may be attributed to difference in levels of sex steroid hormones -androgens and estrogens. Evidence suggests that apart from the regulation of viral host factors, immunomodulatory and cardioprotective roles exerted by estrogen and progesterone may provide protection to females against COVID-19. Exploring the underlying mechanisms and beneficial effects of these hormones as an adjuvant to existing therapy may be a step towards improving the outcomes. This article aims to review studies demonstrating the role of sex steroidal hormones in modulating SARS-CoV-2 host factors and summarize plausible biological reasons for sex-based differences seen in COVID-19 mortality. [ABSTRACT FROM AUTHOR]

The immunosuppressive nature of the tumor microenvironment poses a significant challenge to effective immunotherapies against glioblastoma (GB). Boosting the immune response is critical for successful therapy. Here, we adopted a cancer gene therapy approach to induce T‐cell‐mediated killing of the tumor through increased activation of the immune system. Patient‐based three‐dimensional (3D) GB models were infected with a replication‐deficient adenovirus (AdV) armed with the class II major histocompatibility complex (MHC‐II) transactivator (CIITA) gene (Ad‐CIITA). Successful induction of surface MHC‐II was achieved in infected GB cell lines and primary human GB organoids. Infection with an AdV carrying a mutant form of CIITA with a single amino acid substitution resulted in cytoplasmic accumulation of CIITA without subsequent MHC‐II expression. Co‐culture of infected tumor cells with either peripheral blood mononuclear cells (PBMCs) or isolated T‐cells led to dramatic breakdown of GB organoids. Intriguingly, both wild‐type and mutant Ad‐CIITA, but not unarmed AdV, triggered immune‐mediated tumor cell death in the co‐culture system, suggesting an at least partially MHC‐II‐independent process. We further show that the observed cancer cell killing requires the presence of either CD8+ or CD4+ T‐cells and direct contact between GB and immune cells. We did not, however, detect evidence of activation of canonical T‐cell‐mediated cell death pathways. Although the precise mechanism remains to be determined, these findings highlight the potential of AdV‐mediated CIITA delivery to enhance T‐cell‐mediated immunity against GB. [ABSTRACT FROM AUTHOR]