Tumor adaptation or selection is thought to underlie therapy resistance in glioma. To investigate longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 132 matched initial and recurrent tumors from patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) glioma. IDHwt gliomas showed a stable epigenome over time with relatively low levels of global methylation. The epigenome of IDHmut gliomas showed initial high levels of genome-wide DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. Integration of epigenomics, gene expression, and functional genomics identified HOXD13 as a master regulator of IDHmut astrocytoma evolution. Furthermore, relapse of IDHmut tumors was accompanied by histologic progression that was associated with survival, as validated in an independent cohort. Finally, the initial cell composition of the tumor microenvironment varied between IDHwt and IDHmut tumors and changed differentially following treatment, suggesting increased neoangiogenesis and T-cell infiltration upon treatment of IDHmut gliomas. This study provides one of the largest cohorts of paired longitudinal glioma samples with epigenomic, transcriptomic, and genomic profiling and suggests that treatment of IDHmut glioma is associated with epigenomic evolution toward an IDHwt-like phenotype. Significance: Standard treatments are related to loss of DNA methylation in IDHmut glioma, resulting in epigenetic activation of genes associated with tumor progression and alterations in the microenvironment that resemble treatment-naïve IDHwt glioma.

Inactivating mutations in the Methyl-CpG Binding Protein 2 (MECP2) gene are the main cause of Rett syndrome (RTT). Despite extensive research into MECP2 function, no treatments for RTT are currently available. Here, we used an evolutionary genomics approach to construct an unbiased MECP2 gene network, using 1028 eukaryotic genomes to prioritize proteins with strong co-evolutionary signatures with MECP2. Focusing on proteins targeted by FDA-approved drugs led to three promising targets, two of which were previously linked to MECP2 function (IRAK, KEAP1) and one that was not (EPOR). The drugs targeting these three proteins (Pacritinib, DMF, and EPO) were able to rescue different phenotypes of MECP2 inactivation in cultured human neural cell types, and appeared to converge on Nuclear Factor Kappa B (NF-κB) signaling in inflammation. This study highlights the potential of comparative genomics to accelerate drug discovery, and yields potential new avenues for the treatment of RTT.

Objectives: To determine if patients with coronavirus disease 2019 had a greater number of unplanned extubations resulting in reintubations than in patients without coronavirus disease 2019. Design: Retrospective cohort study comparing the frequency of unplanned extubations resulting in reintubations in a group of coronavirus disease 2019 patients to a historical (noncoronavirus disease 2019) control group. Setting: This study was conducted at Henry Ford Hospital, an academic medical center in Detroit, MI. The historical noncoronavirus disease 2019 patients were treated in the 68 bed medical ICU. The coronavirus disease 2019 patients were treated in the coronavirus disease ICU, which included the 68 medical ICU beds, 18 neuro-ICU beds, 32 surgical ICU beds, and 40 cardiovascular ICU beds, as the medical ICU was expanded to these units at the peak of the pandemic in Detroit, MI. Patients: The coronavirus disease 2019 cohort included patients diagnosed with coronavirus disease 2019 who were intubated for respiratory failure from March 12, 2020, to April 13, 2020. The historic control (noncoronavirus disease 2019) group consisted of patients who were admitted to the medical ICU in the year spanning from November 1, 2018 to October 31, 2019, with a need for mechanical ventilation that was not related to surgery or a neurologic reason. Interventions: None. Measurements and Main Results: To identify how many patients in each cohort had unplanned extubations, an electronic medical records query for patients with two intubations within 30 days was performed, in addition to a review of our institutional quality and safety database of reported self-extubations. Medical charts were manually reviewed by board-certified anesthesiologists to confirm each event was an unplanned extubation followed by a reintubation within 24 hours. There was a significantly greater incidence of unplanned extubations resulting in reintubation events in the coronavirus disease 2019 cohort than in the noncoronavirus disease 2019 cohort (coronavirus disease 2019 cohort: 167 total admissions with 22 events—13.2%; noncoronavirus disease 2019 cohort: 326 total admissions with 14 events—4.3%; p < 0.001). When the rate of unplanned extubations was expressed per 100 intubated days, there was not a significant difference between the groups (0.88 and 0.57, respectively; p = 0.269). Conclusions: Coronavirus disease 2019 patients have a higher incidence of unplanned extubation that requires reintubation than noncoronavirus disease 2019 patients. Further study is necessary to evaluate the variables that contribute to this higher incidence and clinical strategies that can reduce it.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor. GBM contains a small subpopulation of glioma stem cells (GSCs) that are implicated in treatment resistance, tumor infiltration, and recurrence, and are thereby considered important therapeutic targets. Recent clinical studies have suggested that the choice of general anesthetic (GA), particularly propofol, during tumor resection, affects subsequent tumor response to treatments and patient prognosis. In this study, we investigated the molecular mechanisms underlying propofol’s anti-tumor effects on GSCs and their interaction with microglia cells. Propofol exerted a dose-dependent inhibitory effect on the self-renewal, expression of mesenchymal markers, and migration of GSCs and sensitized them to both temozolomide (TMZ) and radiation. At higher concentrations, propofol induced a large degree of cell death, as demonstrated using microfluid chip technology. Propofol increased the expression of the lncRNA BDNF-AS, which acts as a tumor suppressor in GBM, and silencing of this lncRNA partially abrogated propofol’s effects. Propofol also inhibited the pro-tumorigenic GSC-microglia crosstalk via extracellular vesicles (EVs) and delivery of BDNF-AS. In conclusion, propofol exerted anti-tumor effects on GSCs, sensitized these cells to radiation and TMZ, and inhibited their pro-tumorigenic interactions with microglia via transfer of BDNF-AS by EVs.

Table S6: Deconvolution cell proportions and probe-signature matrix S6A: Methylcibersort cell proportions S6B: Methylcibersort cell reference mixture

Table S2: List of 132 pairs (ID of Initial and Recurrent samples)