Heterozygous variants in MYH10 associated with neurodevelopmental disorders and congenital anomalies with evidence for primary cilia-dependent defects in Hedgehog signaling

PurposeNonmuscle myosin II complexes are master regulators of actin dynamics that play essential roles during embryogenesis with vertebrates possessing 3 nonmuscle myosin II heavy chain genes, MYH9, MYH10, and MYH14. As opposed to MYH9 and MYH14, no recognizable disorder has been associated with MYH10. We sought to define the clinical characteristics and molecular mechanism of a novel autosomal dominant disorder related to MYH10.MethodsAn international collaboration identified the patient cohort. CAS9-mediated knockout cell models were used to explore the mechanism of disease pathogenesis.ResultsWe identified a cohort of 16 individuals with heterozygous MYH10 variants presenting with a broad spectrum of neurodevelopmental disorders and variable congenital anomalies that affect most organ systems and were recapitulated in animal models of altered MYH10 activity. Variants were typically de novo missense changes with clustering observed in the motor domain. MYH10 knockout cells showed defects in primary ciliogenesis and reduced ciliary length with impaired Hedgehog signaling. MYH10 variant overexpression produced a dominant-negative effect on ciliary length.ConclusionThese data presented a novel genetic cause of isolated and syndromic neurodevelopmental disorders related to heterozygous variants in the MYH10 gene with implications for disrupted primary cilia length control and altered Hedgehog signaling in disease pathogenesis.     

A Review of Labeling Based on Patient-Reported Outcome Endpoints for New Oncology Drugs Approved by the European Medicines Agency (2017-2021)

ObjectiveA review of new oncology indications approved by the European Medicines Agency (EMA) for 2012-2016 showed that 33% of new drugs had labeling based on patient-reported outcomes (PROs). We reviewed labeling text based on PRO endpoints for new oncology indications approved during 2017-2021.MethodsNew oncology drugs approved by EMA to treat indications of cancers during 2017-2021 were identified from the EMA website. PRO-related language reported in EMA summaries of product characteristics (SmPCs) were summarized and compared with similar findings reported for oncology indications approved during 2012-2016.ResultsReview documents by the EMA during 2017-2021 were available for 49 new oncology drugs for 70 cancer indications. Submissions for 52 (74.3%) of the 70 indications included PRO data for EMA review. Of all submissions, 14 (20.0%) approvals contained PRO-related language in the SmPC. Broad concepts such as health-related quality of life were most common and found in 8 of 14 (57.1%) PRO-related labels.ConclusionPRO-related language appeared in SmPCs for 20% of all indications of new oncology drugs approved by EMA during 2017-2021 compared with approximately 33% of EMA approvals during 2012-2016. PRO-related labeling during the same periods showed a greater decline (from 47% to 27%) for indications of new oncology drugs that also included PRO data. One possible reason for this decline may be the increase in open-label studies from 62% between 2012 and 2016 to approximately 79% between 2017 and 2021.     

HIIT is most effective than mict on glycemic control of older people with glucose metabolism impairments: A systematic review and metanalysis

IntroductionPhysical exercise can improve glucose metabolism; however, the best type, volume, intensity, and frequency aren't knowledge. High-Intensity Interval Training (HIIT), an emergent exercise type implicated as a short time-efficient exercise to improve metabolic health, needs more investigation regarding the traditional Moderate-Intensity Continuous Training (MICT).ObjectiveTo identify the effects of MICT and HIIT on glycemic control of older people with glucose metabolism impairments.MethodsOur research question was based on the PICO model and the systematic review of the literature according to the guidelines of the preferred report items for systematic reviews and PRISMA meta-analyses. An extensive search was conducted in the Web of Science, PubMed, and Scielo databases. Only English language papers were included. The keywords used were "HIIT and metabolism of the elderly", "HIIT and glucose metabolism of the elderly", and "MICT and metabolism of the elderly", which were crossed with the Boolean operators "AND" and "OR" or both according to the guidelines of the PRISMA.ResultsSeventy papers were retrieved in the initial search. After applying all inclusions and exclusion parameters, 63 articles were excluded. In the end, six papers were classified as eligible for this study. All data categorically demonstrates that both HIIT and MICT can improve glucose metabolism with a larger effect size towards the HIIT model after the meta-analysis, pointing to HIIT as the most effective strategy.ConclusionBoth modalities can improve glucose metabolism in the elderly with a clear advantage for HIIT over MICT.     

Hypoxic niches attract and sequester tumor-associated macrophages and cytotoxic T cells and reprogram them for immunosuppression

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A prospective study on the prevalence of NAFLD,advanced fibrosis,cirrhosis and hepatocellular carcinoma in people with type 2 diabetes

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Infection induces tissue-resident memory NK cells that safeguard tissue health

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