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UNLABELLED: Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. SIGNIFICANCE: The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293.

From identification of SARS-CoV-2 in December 2019 through September 22, 2022, [approximately equal to] 612 million confirmed cases and 6.5 million confirmed deaths were reported worldwide (1). During the COVID-19 [...]

ObjectiveThe authors conducted a genome-wide association study of anorexia nervosa and calculated genetic correlations with a series of psychiatric, educational, and metabolic phenotypes.MethodFollowing uniform quality control and imputation procedures using the 1000 Genomes Project (phase 3) in 12 case-control cohorts comprising 3,495 anorexia nervosa cases and 10,982 controls, the authors performed standard association analysis followed by a meta-analysis across cohorts. Linkage disequilibrium score regression was used to calculate genome-wide common variant heritability (single-nucleotide polymorphism [SNP]-based heritability [h2SNP]), partitioned heritability, and genetic correlations (rg) between anorexia nervosa and 159 other phenotypes.ResultsResults were obtained for 10,641,224 SNPs and insertion-deletion variants with minor allele frequencies >1% and imputation quality scores >0.6. The h2SNP of anorexia nervosa was 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability arises from common genetic variation. The authors identified one genome-wide significant locus on chromosome 12 (rs4622308) in a region harboring a previously reported type 1 diabetes and autoimmune disorder locus. Significant positive genetic correlations were observed between anorexia nervosa and schizophrenia, neuroticism, educational attainment, and high-density lipoprotein cholesterol, and significant negative genetic correlations were observed between anorexia nervosa and body mass index, insulin, glucose, and lipid phenotypes.ConclusionsAnorexia nervosa is a complex heritable phenotype for which this study has uncovered the first genome-wide significant locus. Anorexia nervosa also has large and significant genetic correlations with both psychiatric phenotypes and metabolic traits. The study results encourage a reconceptualization of this frequently lethal disorder as one with both psychiatric and metabolic etiology.

Introduction: Like other forms of neuropathology, gliomas appear to spread along neural pathways. Accordingly, our group and others have previously shown that brain network connectivity is highly predictive of glioma survival. In this study, we aimed to examine the molecular mechanisms of this relationship via imaging transcriptomics. Methods: We retrospectively obtained presurgical, T1-weighted MRI datasets from 669 adult patients, newly diagnosed with diffuse glioma. We measured brain connectivity using gray matter networks and coregistered these data with a transcriptomic brain atlas to determine the spatial co-localization between brain connectivity and expression patterns for 14 proto-oncogenes and 3 neural network construction genes. Results: We found that all 17 genes were significantly co-localized with brain connectivity (p < 0.03, corrected). The strength of co-localization was highly predictive of overall survival in a cross-validated Cox Proportional Hazards model (mean area under the curve, AUC = 0.68 +/- 0.01) and significantly (p < 0.001) more so for a random forest survival model (mean AUC = 0.97 +/- 0.06). Bayesian network analysis demonstrated direct and indirect causal relationships among gene-brain co-localizations and survival. Gene ontology analysis showed that metabolic processes were overexpressed when spatial co-localization between brain connectivity and gene transcription was highest (p < 0.001). Drug-gene interaction analysis identified 84 potential candidate therapies based on our findings. Discussion: Our findings provide novel insights regarding how gene-brain connectivity interactions may affect glioma survival. [ABSTRACT FROM AUTHOR]

This essay explores the semantics of skin, constructs of whiteness and bodies with albinism in Eudora Welty's fiction. Topics discussed include Welty's deconstruction of socially engendered hierarchies of identity and parameters of womanhood, albinism through the lens of feminist disability theory, social taboos and prejudice and racial difference in "Shower of Gold," disruption of the normalization of ableism, sexism and racism, and the power of innate otherness to undermine white discourse.

Nipah virus targets human endothelial cells via NiV-F and NiV-G envelope glycoproteins, resulting in endothelial syncytia formation and vascular compromise. Endothelial cells respond to viral infection by releasing innate immune effectors, including galectins, which are secreted proteins that bind to specific glycan ligands on cell surface glycoproteins. We demonstrate that galectin-1 reduces NiV-F mediated fusion of endothelial cells, and that endogenous galectin-1 in endothelial cells is sufficient to inhibit syncytia formation. Galectin-1 regulates NiV-F mediated cell fusion at three distinct points, including retarding maturation of nascent NiV-F, reducing NiV-F lateral mobility on the plasma membrane, and directly inhibiting the conformational change in NiV-F required for triggering fusion. Characterization of the NiV-F N-glycome showed that the critical site for galectin-1 inhibition is rich in glycan structures known to bind galectin-1. These studies identify a unique set of mechanisms for regulating pathophysiology of NiV infection at the level of the target cell.

Background: Collaborative relationships between academic oncology and industry (pharmaceutical, biotechnology, "omic," and medical device companies) are essential for therapeutic development in oncology; however, limited research on engagement in and perceptions of these relationships has been done. Methods: Survey questions were developed to evaluate relationships between academic oncology and industry. An electronic survey was delivered to 1000 randomly selected members of the American Society of Clinical Oncology, a professional organization for oncologists, eliciting respondents' views around oncology‐industry collaborations. The responses were analyzed according to prespecified plans. Results: There were 225 survey respondents. Most were from the United States (70.0%), worked at an academic institution (60.1%), worked in medical oncology (81.2%), and had an active relationship with industry (85.8%). One quarter (26.7%) of respondents reported difficulty establishing a relationship with industry collaborators, and most respondents (75%) did not report having had mentorship in developing these relationships. The majority (85.3%) of respondents considered these collaborations important to their careers. Respondents generally thought that scientific integrity was preserved (92%), and most respondents (95%) had little concern over the quality of the collaborative product. Many (60%) shared concerns over potential conflict of interest if an individual with a compensated relationship promoted an industry product for clinical care/research, yet most respondents (67%) stated these relationships did not shape their interactions with patients. Conclusions: This study provides novel data characterizing the nature of collaborative relationships between clinicians, researchers, and industry in oncology. Although respondents considered these collaborations an important part of clinical and academic oncology, formal education or mentorship around these relationships was rare. Conflicting findings around conflict of interest highlight the importance of more dedicated research in this area. Plain Language Summary: Business enterprises in health care play a central role in cancer research and care, driving the development of new medical testing, drugs, and devices. Effective working relationships among clinicians, researchers, and these industry partners can promote innovative research and enhance patient care. Study of these collaborations has been limited to date. Through distribution of a questionnaire to cancer clinicians and researchers, we found that most participants consider these relationships valuable, though they find establishing such relationships challenging partly because of gaps in educational programs in this area. Our findings also highlight the need for further policy around the potential bias these relationships can introduce. Oncology‐industry collaborations can be mutually beneficial relationships that contribute to both scientific and clinical innovation. Despite their value, a deficit of education and policy around these collaborations is recognized by cancer clinicians and researchers. [ABSTRACT FROM AUTHOR]

Background and Aims: The impacts of the COVID‐19 pandemic have not been equal, with a disproportionate impact among ethnic minority communities. Structural inequalities in social determinants of health such as housing and employment have contributed to COVID‐19's impact on deprived communities, including many ethnic minority communities. To compare (1) how the UK government's "social distancing" restrictions and guidance were perceived and implemented by ethnic minority populations compared to white populations, (2) the impact of restrictions and guidance upon these groups. Methods: An explanatory sequential mixed methods study incorporated a quantitative survey and qualitative semi‐structured interviews to explore individual perceptions and experiences of COVID‐19 and the national restrictions. Survey participants (n = 1587) were recruited from North West England; 60 (4%) participants were from ethnic minority communities. Forty‐nine interviews were conducted; 19 (39%) participants were from ethnic minority communities. Interviews were transcribed verbatim and analysed using a thematic approach. Data collection was between April and August 2020. Results: Significant differences in demographics and household overcrowding were observed between white vs ethnic minority survey respondents, who were also significantly less confident in their knowledge of COVID‐19, less likely to be high‐risk drinkers, and marginally more likely to have experienced job loss and/or reduced household income. There were no group differences in wellbeing, perceptions, or nonfinancial impacts. Two inter‐related themes included: (1) government guidance, incorporating people's knowledge and understanding of the guidance and their confusion/frustration over messaging; (2) the impacts of restrictions on keyworkers, home‐schooling, working from home and changes in lifestyle/wellbeing. Conclusions: Further research is needed on the long‐term impacts of COVID‐19 on ethnic minority communities. If policy responses to COVID‐19 are to benefit ethnic minority communities, there is a need for future studies to consider fundamental societal issues, such as the role of housing and economic disadvantage. Highlights: What is known about this topic? The COVID‐19 pandemic has impacted the entire world, however it has had disproportionate impacts on ethnic minority communities.'Social distancing' is a public health intervention that has been utilised in previous pandemics where measures are put in place to encourage individuals to undertake a number of changes to their social behaviours to increase physical distance from others and to reduce number of contacts with other people.Living conditions such as overcrowding are a risk factor for ill health, including from COVID‐19. What this paper add? Ethnic minority respondents were significantly more concerned about the educational impacts on their children.Living in overcrowded homes significantly affected the ethnic minority respondents with regard to increased risk within their home environment, less space for privacy for working from home and education/welfare needs of children.More practical and relevant government guidance is needed for ethnic minority communities and future policy should consider the economic and societal impacts for ethnic minority workers. [ABSTRACT FROM AUTHOR]