Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma.

Posterior fossa A (PFA) ependymomas are lethal malignancies of the hindbrain in infants and toddlers. Lacking highly recurrent somatic mutations, PFA ependymomas are proposed to be epigenetically driven tumors for which model systems are lacking. Here we demonstrate that PFA ependymomas are maintained under hypoxia, associated with restricted availability of specific metabolites to diminish histone methylation, and increase histone demethylation and acetylation at histone 3 lysine 27 (H3K27). PFA ependymomas initiate from a cell lineage in the first trimester of human development that resides in restricted oxygen. Unlike other ependymomas, transient exposure of PFA cells to ambient oxygen induces irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3, and, paradoxically, inhibition of H3K27 methylation specifically disrupts PFA tumor growth. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.

The Latest Evidence on Bempedoic Acid: Meta-Analysis of Safety and Efficacy in High Cardiovascular Risk Patients With Hypercholesterolemia⋆.

Background: Bempedoic Acid (BA) is a novel drug that has a potential to serve as an alternative to statins to decrease lipid levels and improve cardiovascular disease (CVD) outcomes, particularly for statin-intolerant individuals. However, insufficient statistical power has limited our understanding of the efficacy and safety of BA. This meta-analysis utilizes the latest data to improve our knowledge of BA's effects on lipids and CVD with increased statistical power. Methods: MEDLINE, Embase, Cochrane Central, Clinicaltrials.gov, abstracts of national and international conferences, and reference lists of studies were searched for relevant studies. Rayyan was used to screen the search results, and Revman 5.3 was used for the meta-analysis and sensitivity analysis. Results: Our final analysis included seven randomized control trials (RCTs) with 17,782 participants, 53.6 % in the BA group (n = 9535) and 46.4 % in the placebo group (n = 8247). BA significantly decreased major adverse cardiovascular events (MACE) (OR: 0.86; 95 % CI 0.78-0.95; p = 0.03), non-fatal myocardial infarction (OR 0.72; 95 % CI 0.61-0.85; p = 0.0001), and new onset/worsening diabetes (OR:0.55; 95 % CI 0.30-0.98, p = 0.04), while reducing low-density lipoprotein cholesterol (LDL-C) levels by 22.5 % (MD: -22.53 %; 95 % CI -25.54 to -19.52, p < 0.00001). Conclusion: The findings of this meta-analysis suggest that BA is a promising and effective alternative to statin therapy, particularly for statin-intolerant and high CVD-risk patients. However, further studies with diverse populations are needed to quantify the long-term efficacy and safety endpoints.

In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer.

How the genetic landscape governs a tumor's response to immunotherapy remains poorly understood. To assess the immune-modulatory capabilities of 573 genes associated with altered cytotoxicity in human cancers, here we perform CRISPR/Cas9 screens directly in mouse lung cancer models. We recover the known immune evasion factors Stat1 and Serpinb9 and identify the cancer testis antigen Adam2 as an immune modulator, whose expression is induced by KrasG12D and further elevated by immunotherapy. Using loss- and gain-of-function experiments, we show that ADAM2 functions as an oncogene by restraining interferon and TNF cytokine signaling causing reduced presentation of tumor-associated antigens. ADAM2 also restricts expression of the immune checkpoint inhibitors PDL1, LAG3, TIGIT and TIM3 in the tumor microenvironment, which might explain why ex vivo expanded and adoptively transferred cytotoxic T-cells show enhanced cytotoxic efficacy in ADAM2 overexpressing tumors. Together, direct in vivo CRISPR/Cas9 screens can uncover genetic alterations that control responses to immunotherapies.

A bibliometric analysis of global research performance on tuberculosis (2011-2020): Time for a global approach to support high-burden countries.

BACKGROUND: Tuberculosis (TB) is a persistent public health issue requiring consistent global effort for its eradication and control. Research on the subject plays a vital role in combatting the disease, giving future directions, and meeting the sustainable development goals (SDGs). This study aimed to evaluate the global TB research trends and performance from 2011 to 2020. MATERIALS AND METHODS: All the data for TB-related research publications from 2011 to 2020 were extracted from the Web of Science database and a comprehensive analysis was performed on the R-bibliometrix package. RESULTS: An increasing number of publications with an annual growth rate of 6.32% and a plateau in production from 2015 to 2018 was observed. Of 145 countries, the United States of America (USA), China, India, the United Kingdom, and South Africa led and made up half of the global contribution. Out of 91,862 authors, Zhang Y was the most productive with 205 articles and Barry CE had the highest H-index of 45. Only seven of the top 20 authors were from high-burden countries. The University of Cape Town was the leading institutional affiliation, followed by Stellenbosch University and the London School of Hygiene and Tropical Medicine. The most frequent international collaboration was between the USA and South Africa, occurring on 1203 instances. Only five of the top 30 high-burden countries were present in the top 30 collaborations. PLOS ONE, disseminating 2271 articles, was the most productive out of 3500 sources. CONCLUSION: The past decade has seen a steady increase in global TB research. Prominent authors, affiliations, and countries showed collaborative trends, but publications were found to be mostly from developed, low-burden countries except China, India, and South Africa. To meet the goals set by the SDGs and the WHO End TB Strategy, high-burden countries need to explore feasible opportunities and global support to enhance their expected TB-related research contributions.

Hand hygiene knowledge and attitude of medical students in western Saudi Arabia.

BACKGROUND: The practice of hand hygiene (HH) has prime importance among Health Care Professionals (HCPs) and non-compliance could cause adverse consequences. By keeping the importance of HH in mind, this study aims at investigating the knowledge and attitudes towards HH among medical students and interns at King Abdulaziz University (KAU), Jeddah, Saudi Arabia (SA). METHODS: The study includes 453 medical students and interns (189 males & 264 females). This study was completed in three months; from September to November 2017. The World Health Organization (WHO) HH questionnaire was used and data were analyzed on SPSS-21. RESULTS: Two-third of the participants 292 (64.2%) had formal training in HH in the last three years. Almost half of the participants 254 (56.1%) had correct knowledge regarding the major course of transmission of potentially detrimental microbes among patients in the healthcare premises. Just 124 (27.4%) of the respondents had the correct knowledge about the most common basis of germs accountable for healthcare-related infections. Females had significantly better knowledge than males regarding the type of HH technique needed before palpation of the abdomen (177(54%) Vs. 151(46%); P < 0.002), before an injection (175(54.5%) Vs. 146(45.5%); P < 0.007), after emptying a bedpan (207(64.7%) Vs. 113(35.3%); P < 0.001), following discarding examination gloves (256(60.4% Vs. 168(39.6%); P < 0.001] and after exposure to blood (200(64.1%) Vs. 112(35.%); P < 0.001). Female participants had better knowledge than males regarding the type of HH actions. Females also had a significantly better attitude towards the importance of HH than males (240(62.5%) Vs. 144(37.5%); P < 0.001). CONCLUSION: The majority of the participants' knowledge regarding HH was not up to the mark; however, female students had better knowledge compared to male students. The medical students and interns' knowledge and positive attitude towards HH can play a pivotal role in preventing HCPs associated infections and it would overall decrease the infection-related burden on the hospital and governmental budgets. It is suggested that multi-dimensional plans are required to change this low compliance to a higher rate.

Genome Analysis of Conserved Dehydrin Motifs in Vascular Plants.

Dehydrins, a large family of abiotic stress proteins, are defined by the presence of a mostly conserved motif known as the K-segment, and may also contain two other conserved motifs known as the Y-segment and S-segment. Using the dehydrin literature, we developed a sequence motif definition of the K-segment, which we used to create a large dataset of dehydrin sequences by searching the Pfam00257 dehydrin dataset and the Phytozome 10 sequences of vascular plants. A comprehensive analysis of these sequences reveals that lysine residues are highly conserved in the K-segment, while the amino acid type is often conserved at other positions. Despite the Y-segment name, the central tyrosine is somewhat conserved, but can be substituted with two other small aromatic amino acids (phenylalanine or histidine). The S-segment contains a series of serine residues, but in some proteins is also preceded by a conserved LHR sequence. In many dehydrins containing all three of these motifs the S-segment is linked to the K-segment by a GXGGRRKK motif (where X can be any amino acid), suggesting a functional linkage between these two motifs. An analysis of the sequences shows that the dehydrin architecture and several biochemical properties (isoelectric point, molecular mass, and hydrophobicity score) are dependent on each other, and that some dehydrin architectures are overexpressed during certain abiotic stress, suggesting that they may be optimized for a specific abiotic stress while others are involved in all forms of dehydration stress (drought, cold, and salinity).