Frazierwoodward1658

Metabolically quiescent T cells circulate throughout the body in search of antigen. Following engagement of their cognate receptors, T cells undergo metabolic reprogramming to support their activation, differentiation, and ultimately function. In the spirit of Sir Archibald Garrod, this metabolic reprogramming actually imparts a chemical individuality which confers advantage, while in others confers vulnerability, depending upon the milieu. Studying T cell immunometabolism in the context of inborn errors of metabolism allows one to define essential pathways of intermediary metabolism as well metabolic vulnerabilities and plasticity. Inborn errors of metabolism, a class of diseases first named by Garrod, have a long history of being informative for common physiologic and pathologic processes. This endeavor may be accomplished through the study of patients, animal models, and in vitro models of inborn errors of metabolism. In this review, the basics of intermediary metabolism and core metabolic pathways will be discussed, along with their relationship to T cell immunometabolism. Due to their pleiotropic nature, the reader will be specifically directed toward various inborn errors of metabolism which may be helpful for answering important questions about the role of metabolism in T cells. Published 2020. This article is a U.S. Government work and is in the public domain in the USA.INTRODUCTION The most commonly mutated gene in vulvar squamous cell carcinoma (VSCC) is TP53 and its prognostic value, particularly in HPV-independent VSCC, is uncertain. In other tumors, p53 immunohistochemistry (IHC) is an excellent surrogate marker for TP53 mutations. In order to study this in VSCC, we assigned six p53-IHC patterns into two final classes 'wildtype' or 'mutant'. We determined the performance and interobserver variability of this pattern-based p53-IHC approach. METHODS Two experienced gynecologic pathologists scored the predefined p53-IHC patterns of 59 VSCC, independently and blinded for molecular data. Agreement was calculated by Cohen's kappa. All disagreements regarding p53-IHC patterns were resolved by a consensus meeting. After DNA isolation, the presence of pathogenic TP53 variants were determined by next-generation sequencing (NGS). Sensitivity, specificity, and accuracy of p53-IHC as a surrogate marker for TP53 mutation status were calculated. RESULTS Initial p53-IHC pattern interpretation showed substantial agreement between both observers (k=0.71, p less then 0.001). After consensus, 18 cases (30.5%) were assigned a final p53-IHC class as TP53 wildtype and 41 cases (69.5%) as 'mutant'. The accuracy between the p53-IHC class and TP53 mutation status, after the consensus meeting, was 96.6%. Ferrostatin-1 solubility dmso Moreover, the sensitivity and specificity were high 95.3% (95%CI 82.9-99.1%) and 100% (95%CI 75.9-100%)). CONCLUSIONS Pattern-based p53-IHC classification is highly reproducible amongst experienced gynecologic pathologists and accurately reflects TP53 mutations in VSCC. This approach to p53-IHC interpretation offers guidance and provides necessary clarity for resolving the proposed prognostic relevance of final p53-IHC class within HPV-independent VSCC. This article is protected by copyright. All rights reserved.BACKGROUND Most pediatric elevated blood pressure (BP) remains undiagnosed. The American Academy of Pediatrics states "there is limited evidence to support school-based measurement of children's BP." We explored the utility school-based BP screening. METHODS A cross-sectional sample of 4096 students ages 6 to 17 from Title 1 Miami-Dade Public Schools (50% female, 71% non-Hispanic black, 26% Hispanic) had their systolic/diastolic BP (SBP/DBP) and body mass index (BMI) collected over the 2016 to 2017 or 2017 to 2018 school years. Relative risks (RRs) ratios were calculated to estimate normal/elevated SBP/DBP by BMI percentile, ethnicity, and sex. RESULTS Overall, 26.4% had at least one elevated BP measurement, of which 59% were not obese. RR for obese status was significant for all categories of elevated BP (RRs > 1.88, p  less then  .0001). Being either female (RR = 1.34, p = .009) or Hispanic (RR = 1.31, p = .014) was significantly associated with elevated DBP. BMI accounted for less then 10% of the variation in BP (SBP F(1, 4095) = 367.6, adjusted R2  = .08, p  less then  .0001; DBP F(1, 4095) = 93.3, adjusted R2  = .02, p  less then  .0001). CONCLUSION These findings support providing BP screenings in school settings. Low-income and minority students often have limited access to health care, higher obesity rates, and unhealthy behaviors. Our findings support universal school-based BP screening regardless of weight status, particularly among ethnically diverse populations. © 2020, American School Health Association.DNA damage repair within telomeres are suppressed to maintain the integrity of linear chromosomes, but the accidental activation of repairs can lead to genome instability. This review develops the concept that mechanisms to repair DNA damage in telomeres contribute to genetic variability and karyotype evolution, rather than catastrophe. Spontaneous breaks in telomeres can be repaired by telomerase, but in some cases DNA repair pathways are activated, and can cause chromosomal rearrangements or fusions. The resultant changes can also affect subtelomeric regions that are adjacent to telomeres. Subtelomeres are actively involved in such chromosomal changes, and are therefore the most variable regions in the genome. The case of Caenorhabditis elegans in the context of changes of subtelomeric structures revealed by long-read sequencing is also discussed. Theoretical and methodological issues covered in this review will help to explore the mechanism of chromosome evolution by reconstruction of chromosomal ends in nature. © 2020 WILEY Periodicals, Inc.Studies have elucidated that pyrethroids induce adipogenesis. It is also known that macrophages can affect the homeostasis of adipose tissue. However, whether and how the β-cypermethrin (β-CYP)-mediated inhibition of the macrophages affects adipogenesis remain unknown. To explore the effects of β-CYP on adipogenesis through modulating the function of macrophages, 3T3-L1 cells, a preadipocyte cell line, were exposed to culture medium from either RAW 264.7 cells, a macrophage cell line (RM), or β-CYP-treated RAW 264.7 cells (CRM). CRM decreased the inhibitory effects of RM treatment on cell proliferation and adipogenesis, as lipid accumulation, the CEBPA content, and Fasn and Acaca expression in 3T3-L1 cells were higher following CRM treatment than following RM treatment through the higher levels of the demethylated CEBPA promoter in 3T3-L1 cells. However, the medium from β-CYP- and N-acetyl-L-cysteine-cotreated RAW 264.7 cells (CNRM) partially restored the inhibitory effects of RAW 264.7 cells on 3T3-L1 cells that had been reduced by CRM, indicating that β-CYP might reduce the cytotoxicity and inhibitory effects of RAW 264.