Epigenetic underpinnings of the autistic mind: Histone modifications and prefrontal excitation/inhibition imbalance.

Autism spectrum disorder (ASD) is complex neurobehavioral condition influenced by several cellular and molecular mechanisms that are often concerned with synaptogenesis and synaptic activity. Based on the excitation/inhibition (E/I) imbalance theory, ASD could be the result of disruption in excitatory and inhibitory synaptic transmission across the brain. The prefrontal cortex (PFC) is the chief regulator of executive function and can be affected by altered neuronal excitation and inhibition in the course of ASD. The molecular mechanisms involved in E/I imbalance are subject to epigenetic regulation. In ASD, altered enrichment and spreading of histone H3 and H4 modifications such as the activation-linked H3K4me2/3, H3K9ac, and H3K27ac, and repression-linked H3K9me2, H3K27me3, and H4K20me2 in the PFC result in dysregulation of molecules mediating synaptic excitation (ARC, EGR1, mGluR2, mGluR3, GluN2A, and GluN2B) and synaptic inhibition (BSN, EphA7, SLC6A1). Histone modifications are a dynamic component of the epigenetic regulatory elements with a pronounced effect on patterns of gene expression with regards to any biological process. The excitation/inhibition imbalance associated with ASD is based on the excitatory and inhibitory synaptic activity in different regions of the brain, including the PFC, the ultimate outcome of which is highly influenced by transcriptional activity of relevant genes.

Percutaneous Coronary Intervention Associated with a Higher Risk of Hypoxemia and COVID-19 Severity.

OBJECTIVE: The primary goal of the present study was to measure the implications of hypoxemia in COVID-19 patients with a history of coronary artery disease (CAD). METHODS: A systematic search of the literature published from November 1, 2019 to May 1, 2021, was conducted on PubMed/MEDLINE, Embase, and Web of Science databases. Afterwards, an observational study was designed based on the electronic health records of COVID-19 patients hospitalized in a tertiary referral hospital during the same period. A total of 179 COVID-19 cases were divided into two groups: cases with a history of CAD and percutaneous coronary intervention (CAD/PCI+, n = 89) and controls (n = 90). Clinical data were extracted from the electronic database of the hospital and statistically analyzed. RESULTS: After the application of inclusion/exclusion criteria, only three studies were deemed eligible, one of which was concerned with the impact of CAD on the all-cause mortality of COVID-19. Results from our observational study indicated that the cases were older (median age: 74 vs. 45) and more likely to develop hypoxemia (25.8% vs. 8.8%) than the controls. CAD/PCI+ was correlated with a more severe COVID-19 (11% vs. 1%). Age was a moderately significant independent predictor of increased COVID-19 severity, while hypoxemia was not. CONCLUSION: Considering the negative impact of hypoxemia on the prognosis of COVID-19 and its higher prevalence among COVID-19 patients with underlying CAD, further research is warranted to unravel the negative effects of COVID-19 on the mechanisms of gas exchange and delivery in patients with pre-existing CAD.

Involving stemness factors to improve CAR T-cell-based cancer immunotherapy.

Treatment with chimeric antigen receptor (CAR) T cells indicated remarkable clinical responses with liquid cancers such as hematological malignancies; however, their therapeutic efficacy faced with many challenges in solid tumors due to severe toxicities, antigen evasion, restricted and limited tumor tissue trafficking and infiltration, and, more importantly, immunosuppressive tumor microenvironment (TME) factors that impair the CAR T-cell function adds support survival of cancer stem cells (CSCs), responsible for tumor recurrence and resistance to current cancer therapies. Therefore, in-depth identification of TME and development of more potent CAR platform targeting CSCs may overcome the raised challenges, as presented in this review. We also discuss recent stemness-based innovations in CAR T-cell production and engineering to improve their efficacy in vivo, and finally, we propose solutions and strategies such as oncolytic virus-based therapy and combination therapy to revive the function of CAR T-cell therapy, especially in TME of solid tumors in future.