Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma.

IDH1 mutations are common in low-grade gliomas and secondary glioblastomas and cause overproduction of (R)-2HG. (R)-2HG modulates the activity of many enzymes, including some that are linked to transformation and some that are probably bystanders. Although prior work on (R)-2HG targets focused on 2OG-dependent dioxygenases, we found that (R)-2HG potently inhibits the 2OG-dependent transaminases BCAT1 and BCAT2, likely as a bystander effect, thereby decreasing glutamate levels and increasing dependence on glutaminase for the biosynthesis of glutamate and one of its products, glutathione. Inhibiting glutaminase specifically sensitized IDH mutant glioma cells to oxidative stress in vitro and to radiation in vitro and in vivo. These findings highlight the complementary roles for BCATs and glutaminase in glutamate biosynthesis, explain the sensitivity of IDH mutant cells to glutaminase inhibitors, and suggest a strategy for maximizing the effectiveness of such inhibitors against IDH mutant gliomas.

Altered chromosomal topology drives oncogenic programs in SDH-deficient GISTs.

Epigenetic aberrations are widespread in cancer, yet the underlying mechanisms and causality remain poorly understood1-3. A subset of gastrointestinal stromal tumours (GISTs) lack canonical kinase mutations but instead have succinate dehydrogenase (SDH) deficiency and global DNA hyper-methylation4,5. Here, we associate this hyper-methylation with changes in genome topology that activate oncogenic programs. To investigate epigenetic alterations systematically, we mapped DNA methylation, CTCF insulators, enhancers, and chromosome topology in KIT-mutant, PDGFRA-mutant and SDH-deficient GISTs. Although these respective subtypes shared similar enhancer landscapes, we identified hundreds of putative insulators where DNA methylation replaced CTCF binding in SDH-deficient GISTs. We focused on a disrupted insulator that normally partitions a core GIST super-enhancer from the FGF4 oncogene. Recurrent loss of this insulator alters locus topology in SDH-deficient GISTs, allowing aberrant physical interaction between enhancer and oncogene. CRISPR-mediated excision of the corresponding CTCF motifs in an SDH-intact GIST model disrupted the boundary between enhancer and oncogene, and strongly upregulated FGF4 expression. We also identified a second recurrent insulator loss event near the KIT oncogene, which is also highly expressed across SDH-deficient GISTs. Finally, we established a patient-derived xenograft (PDX) from an SDH-deficient GIST that faithfully maintains the epigenetics of the parental tumour, including hypermethylation and insulator defects. This PDX model is highly sensitive to FGF receptor (FGFR) inhibition, and more so to combined FGFR and KIT inhibition, validating the functional significance of the underlying epigenetic lesions. Our study reveals how epigenetic alterations can drive oncogenic programs in the absence of canonical kinase mutations, with implications for mechanistic targeting of aberrant pathways in cancers.

Photoprotective measures among adolescents stratified by region: An analysis utilizing the National College Health Assessment.

BACKGROUND/PURPOSE: Exposure to sunlight has been shown to cause pigmentary alterations, photoaging and photocarcinogenesis. Understanding photoprotective patterns in adolescent populations is beneficial to public health initiatives. We utilized data provided by the American College Health Association's National College Health Assessment to evaluate photoprotective behaviors among adolescent populations. METHODS: Behavioral questions related to photoprotection were analyzed from the American College Health Association (ACHA) National College Health Assessment (NCHA) (Version III). RESULTS: When comparing races, Black/African American respondents had the lowest association of practicing photoprotective behaviors in comparison to white respondents (p < .05). When comparing US geographic regions, the south had the lowest association of photoprotective measures (p < .05). LIMITATIONS: The response rate of each institution varied, although there was still a large quantity of respondents. Finally, we cannot discern the specific reasoning for adolescent populations not using sunscreen. CONCLUSION: These data identify demographics where efforts to enhance education on photoprotective behaviors, specifically among skin of color and southern population, to support public health initiatives.

Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation.

Cancer cells frequently depend on chromatin regulatory activities to maintain a malignant phenotype. Here, we show that leukemia cells require the mammalian SWI/SNF chromatin remodeling complex for their survival and aberrant self-renewal potential. While Brg1, an ATPase subunit of SWI/SNF, is known to suppress tumor formation in several cell types, we found that leukemia cells instead rely on Brg1 to support their oncogenic transcriptional program, which includes Myc as one of its key targets. To account for this context-specific function, we identify a cluster of lineage-specific enhancers located 1.7 Mb downstream from Myc that are occupied by SWI/SNF as well as the BET protein Brd4. Brg1 is required at these distal elements to maintain transcription factor occupancy and for long-range chromatin looping interactions with the Myc promoter. Notably, these distal Myc enhancers coincide with a region that is focally amplified in ∼3% of acute myeloid leukemias. Together, these findings define a leukemia maintenance function for SWI/SNF that is linked to enhancer-mediated gene regulation, providing general insights into how cancer cells exploit transcriptional coactivators to maintain oncogenic gene expression programs.

Acute myeloid leukemia ontogeny is defined by distinct somatic mutations.

Acute myeloid leukemia (AML) can develop after an antecedent myeloid malignancy (secondary AML [s-AML]), after leukemogenic therapy (therapy-related AML [t-AML]), or without an identifiable prodrome or known exposure (de novo AML). The genetic basis of these distinct pathways of AML development has not been determined. We performed targeted mutational analysis of 194 patients with rigorously defined s-AML or t-AML and 105 unselected AML patients. The presence of a mutation in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 was >95% specific for the diagnosis of s-AML. Analysis of serial samples from individual patients revealed that these mutations occur early in leukemogenesis and often persist in clonal remissions. In t-AML and elderly de novo AML populations, these alterations define a distinct genetic subtype that shares clinicopathologic properties with clinically confirmed s-AML and highlights a subset of patients with worse clinical outcomes, including a lower complete remission rate, more frequent reinduction, and decreased event-free survival. This trial was registered at www.clinicaltrials.gov as #NCT00715637.

Availability of Cranial Prostheses for Black Patients at Comprehensive Cancer Centers.

PURPOSE: For patients who seek to camouflage cancer-related hair loss, cranial prostheses such as wigs and hair pieces exist. We sought to determine the availability of yaki-textured, type IV curls, and afro wigs at boutiques in Comprehensive Cancer Centers (CCCs). METHODS: The 56 CCCs in the United States were surveyed to see whether they had an affiliated wig boutique for patients experiencing hair loss. Boutique workers were then asked a series of seven questions regarding cranial prostheses options for patients seeking yaki-textured, type IV curls, and afro wigs. The availability of wigs was compared with US Census data on population size and density of Black residents. RESULTS: Of the 56 CCCs, 27 (46%) institutions had active affiliated hair boutiques. We were able to reach 19 (70%) of the 27 boutiques, of which 53% (n = 10) offered yaki-textured wigs, 37% (n = 7) offered type IV curls or afro wigs, and 47% (n = 9) offered neither. Two additional boutiques offered in-store catalogs for Black patients who were interested in naturally appearing wigs. Although two institutions offered a wig bank that was free to all patients, neither had yaki-textured or afro wigs in stock. There was no significant relationship between population size or density of Black residents and availability of these wigs. CONCLUSION: Many Black patients undergoing cancer treatment interested in cranial prosthesis do not have consistent access to wigs with textures comparable with type IV hair at CCCs. With increased inventory of racially inclusive wigs, partnerships with third-party vendors, and support for the previous authorization process, we can better support Black patients experiencing cancer-related hair loss.

Association of retinal optical coherence tomography metrics and polygenic risk scores with cognitive function and future cognitive decline.

PURPOSE: To evaluate the potential of retinal optical coherence tomography (OCT) measurements and polygenic risk scores (PRS) to identify people at risk of cognitive impairment. METHODS: Using OCT images from 50 342 UK Biobank participants, we examined associations between retinal layer thickness and genetic risk for neurodegenerative disease and combined these metrics with PRS to predict baseline cognitive function and future cognitive deterioration. Multivariate Cox proportional hazard models were used to predict cognitive performance. P values for retinal thickness analyses are false-discovery-rate-adjusted. RESULTS: Higher Alzheimer's disease PRS was associated with a thicker inner nuclear layer (INL), chorio-scleral interface (CSI) and inner plexiform layer (IPL) (all p<0.05). Higher Parkinson's disease PRS was associated with thinner outer plexiform layer (p<0.001). Worse baseline cognitive performance was associated with thinner retinal nerve fibre layer (RNFL) (aOR=1.038, 95% CI (1.029 to 1.047), p<0.001) and photoreceptor (PR) segment (aOR=1.035, 95% CI (1.019 to 1.051), p<0.001), ganglion cell complex (aOR=1.007, 95% CI (1.002 to 1.013), p=0.004) and thicker ganglion cell layer (aOR=0.981, 95% CI (0.967 to 0.995), p=0.009), IPL (aOR=0.976, 95% CI (0.961 to 0.992), p=0.003), INL (aOR=0.923, 95% CI (0.905 to 0.941), p<0.001) and CSI (aOR=0.998, 95% CI (0.997 to 0.999), p<0.001). Worse future cognitive performance was associated with thicker IPL (aOR=0.945, 95% CI (0.915 to 0.999), p=0.045) and CSI (aOR=0.996, 95% CI (0.993 to 0.999) 95% CI, p=0.014). Prediction of cognitive decline was significantly improved with the addition of PRS and retinal measurements. CONCLUSIONS AND RELEVANCE: Retinal OCT measurements are significantly associated with genetic risk of neurodegenerative disease and may serve as biomarkers predictive of future cognitive impairment.

Applying to dermatology residency without a home program: Advice to medical students in the COVID-19 pandemic and beyond.

Dermatology has historically been one of the most competitive residencies to match into. One commonly overlooked factor is the importance of having mentors in the field, as they have experience guiding successful applicants and can provide great insight into what residency programs are looking for. Given that many students without home dermatology programs may struggle to find mentors in the field, we share advice on how these students can obtain the mentorship and guidance needed to match into dermatology.

Extended-representation bisulfite sequencing of gene regulatory elements in multiplexed samples and single cells.

The biological roles of DNA methylation have been elucidated by profiling methods based on whole-genome or reduced-representation bisulfite sequencing, but these approaches do not efficiently survey the vast numbers of non-coding regulatory elements in mammalian genomes. Here we present an extended-representation bisulfite sequencing (XRBS) method for targeted profiling of DNA methylation. Our design strikes a balance between expanding coverage of regulatory elements and reproducibly enriching informative CpG dinucleotides in promoters, enhancers and CTCF binding sites. Barcoded DNA fragments are pooled before bisulfite conversion, allowing multiplex processing and technical consistency in low-input samples. Application of XRBS to single leukemia cells enabled us to evaluate genetic copy number variations and methylation variability across individual cells. Our analysis highlights heterochromatic H3K9me3 regions as having the highest cell-to-cell variability in their methylation, likely reflecting inherent epigenetic instability of these late-replicating regions, compounded by differences in cell cycle stages among sampled cells.

Susceptibility of ABO blood group to COVID-19 infections: clinico-hematological, radiological, and complications analysis.

ABSTRACT: In the wake of the COVID-19 pandemic, research indicates that the COVID-19 disease susceptibility varies among individuals depending on their ABO blood groups. Researchers globally commenced investigating potential methods to stratify cases according to prognosis depending on several clinical parameters. Since there is evidence of a link between ABO blood groups and disease susceptibility, it could be argued that there is a link between blood groups and disease manifestation and progression. The current study investigates whether clinical manifestation, laboratory, and imaging findings vary among ABO blood groups of hospitalized confirmed COVID-19 patients.This retrospective cohort study was conducted between March 1, 2020 and March 31, 2021 in King Faisal Specialist Hospital and Research Centre Riyadh and Jeddah, Saudi Arabia. Demographic information, clinical information, laboratory findings, and imaging investigations were extracted from the data warehouse for all confirmed COVID-19 patients.A total of 285 admitted patients were included in the study. Of these, 81 (28.4%) were blood group A, 43 (15.1%) were blood group B, 11 (3.9%) were blood group AB, and 150 (52.6%) were blood group O. This was almost consistent with the distribution of blood groups among the Saudi Arabia community. The majority of the study participants (79.6% [n = 227]) were asymptomatic. The upper respiratory tract infection (P = .014) and shortness of breath showed statistically significant differences between the ABO blood group (P = .009). Moreover, the incidence of the symptoms was highly observed in blood group O followed by A then B except for pharyngeal exudate observed in blood group A. The one-way ANOVA test indicated that among the studied hematological parameters, glucose (P = .004), absolute lymphocyte count (P = .001), and IgA (P = .036) showed statistically significant differences between the means of the ABO blood group. The differences in both X-ray and computed tomography scan findings were statistically nonsignificant among the ABO age group. Only 86 (30.3%) patients were admitted to an intensive care unit, and the majority of them were blood groups O 28.7% (n = 43) and A 37.0% (n = 30). However, the differences in complications' outcomes were statistically nonsignificant among the ABO age group.ABO blood groups among hospitalized COVID-19 patients are not associated with clinical, hematological, radiological, and complications abnormality.

Lingual Osseous Choristoma: A Comprehensive Systematic Review of Lesion Presentation, Histology, and Morphology.

INTRODUCTION: Osseous choristomas of the tongue are rare, benign tumor-like lesions composed of abnormally placed bone and cartilage tissue. The few publications to date concerning this condition have been primarily limited to case reports. This systematic review aimed to clarify the clinical presentations of osseous choristomas and how to delineate them from other oral pathologies. METHODS: The authors utilized PubMed, Embase, and Cochrane Library reference databases from 1971 to mid-2020. Search terms were "osseous choristoma," "oral cavity," and "lingual." Preferred Reporting Systems for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were used to aggregate relevant data from each study. The authors specifically collected data regarding patient demographics, clinical findings, symptoms, treatments, and subsequent outcomes relating to lingual osseous choristomas. RESULTS: A total of 35 (14.6% of total identified) publications that met inclusion criteria were identified concerning a total of 69 lingual osseous choristoma cases. Results were compiled focusing on sex and age, presenting symptoms, histology, appearance of the lesion base being most commonly pedunculated (e.g., stalk or stem-like), the lesion's location on the tongue, and subsequent treatments. Osseous choristomas had a higher rate of occurrence in females, 48 (70%) and those under the age of 40. Symptomatic presentations occurred in 38 (55%) patients, with the most common presenting symptoms being gagging/globus (i.e., lump or foreign body) sensation (n = 47, 68%) and dysphagia (n = 20, 29%). Identified masses were pedunculated in 33 (80%) of cases and eight (20%) were identified as sessile (i.e., immobile). A total of 41 (59%) lesions were more commonly located in the posterior one third of the tongue compared to 28 (41%) in the anterior two thirds of the tongue. Of those 49 (71%) cases requiring surgical mass excisions, recurrence was reported in 0% of cases. CONCLUSIONS: Although osseous choristomas are benign processes that rarely arise from the tongue, providers should carefully inspect patients with a gagging/globus sensation and pedunculated mass toward the back of the tongue. Surgical resection remains the best treatment to prevent recurrence.

Pigment epithelium-derived factor and interleukin-6 control prostate neuroendocrine differentiation via feed-forward mechanism.

PURPOSE: PEDF (pigment epithelium-derived factor) promotes the differentiation and survival of neuronal cells, and expands the adult neuronal stem cell niche. In the prostate PEDF is suppressed by androgen with unclear physiological consequences. We report that PEDF induced the neuroendocrine differentiation of prostate cancer cells, which was accompanied by neurite outgrowth and chromogranin A expression. MATERIALS AND METHODS: We performed neuroendocrine differentiation assay, Western blot analysis, immunostaining and reverse transcriptase-polymerase chain reaction in the human prostate cancer cell lines LNCaP, PC-3 and DU145, and the prostate epithelial strain RWPE-1 (ATCC). RESULTS: Ectopic and endogenous PEDF caused neuroendocrine differentiation of prostate cancer cells, as manifested by neurite-like outgrowths and chromogranin A expression. The transdifferentiated cells expressed axonal and dendritic markers, as ascertained by immunoblotting for specific markers. Neuroendocrine cells formed multiple synaptophysin positive protrusions resembling dendritic spines and vesicles containing serotonin, pointing to possible synapse formation. The known transdifferentiating agent interleukin-6 induced PEDF secretion. Moreover, PEDF neutralizing antibodies abolished the transdifferentiation of interleukin-6 treated cells, suggesting an autocrine loop. Neurogenic events were independent of cyclic adenosine monophosphate. Instead, PEDF activated in this order RhoA, nuclear factor kappaB and Stat3. Inhibitors of the Rho, nuclear factor kappaB and STAT pathways abolished differentiation and synapse formation. Additionally, nuclear factor kappaB activation caused interleukin-6 expression. CONCLUSIONS: We discovered that nuclear factor kappaB controls the formation of neuronal communications in the prostate due to PEDF. We defined a feed-forward loop, in which nuclear factor kappaB induction elicits Stat3 activation and pro-differentiating interleukin-6 expression causes the further expansion of neuroendocrine communications. Our findings point to the role of nuclear factor kappaB and PEDF in coordinated prostate development.

Adaptive Chromatin Remodeling Drives Glioblastoma Stem Cell Plasticity and Drug Tolerance.

Glioblastoma, the most common and aggressive malignant brain tumor, is propagated by stem-like cancer cells refractory to existing therapies. Understanding the molecular mechanisms that control glioblastoma stem cell (GSC) proliferation and drug resistance may reveal opportunities for therapeutic interventions. Here we show that GSCs can reversibly transition to a slow-cycling, persistent state in response to targeted kinase inhibitors. In this state, GSCs upregulate primitive developmental programs and are dependent upon Notch signaling. This transition is accompanied by widespread redistribution of repressive histone methylation. Accordingly, persister GSCs upregulate, and are dependent on, the histone demethylases KDM6A/B. Slow-cycling cells with high Notch activity and histone demethylase expression are present in primary glioblastomas before treatment, potentially contributing to relapse. Our findings illustrate how cancer cells may hijack aspects of native developmental programs for deranged proliferation, adaptation, and tolerance. They also suggest strategies for eliminating refractory tumor cells by targeting epigenetic and developmental pathways.

Simvastatin prevents isoproterenol-induced cardiac hypertrophy through modulation of the JAK/STAT pathway.

Simvastatin (SIM) is a lipid-soluble inhibitor of hydroxy-3-methylglutaryl coenzyme A reductase with multiple reported therapeutic benefits. The present study was designed to investigate the effect of pretreatment with SIM on isoproterenol (ISO)-induced cardiac hypertrophy in rats. Twenty-four male albino Wistar rats weighing 180-200 g were divided into four groups. Groups I and III received normal saline while groups II and IV received SIM (10 mg/kg body weight) for 30 days per gavage. In the last 7 days, rats of groups III and IV were administered ISO (5 mg/kg) intraperitoneally to induce cardiac hypertrophy. Administration of ISO induced an increase in heart-to-body weight (HW/BW) ratio, an increase in serum interleukin-6, and elevated systolic and diastolic blood pressure. Serum levels of lipids, cardiovascular risk indices, and cardiac troponin I and creatine phosphokinase-MB showed significant increase in ISO-induced hypertrophic rats. Histopathological examination of heart tissue revealed focal areas of subendocardium degeneration, mononuclear cellular infiltrations, fibrous tissue deposition, and increased thickness of the myocardium of left ventricle. In addition, ISO-administered rats exhibited significant upregulation of cardiac Janus kinase, phosphorylated signal transducer and activator of transcription, and nuclear factor-kappa B. Pretreatment with SIM significantly prevented ISO-induced cardiac hypertrophy, alleviated the altered biochemical parameters, and improved the heart architecture. In conclusion, our study provides evidence that SIM prevented the development of cardiac hypertrophy via modulation of the Janus kinase/signal transducer and activator of transcription-signaling pathway in the heart of ISO-administered animals.