Diverse genetic, epigenetic, and developmental programs drive glioblastoma, an incurable and poorly understood tumor, but their precise characterization remains challenging. Here, we use an integrative approach spanning single-cell RNA-sequencing of 28 tumors, bulk genetic and expression analysis of 401 specimens from the The Cancer Genome Atlas (TCGA), functional approaches, and single-cell lineage tracing to derive a unified model of cellular states and genetic diversity in glioblastoma. We find that malignant cells in glioblastoma exist in four main cellular states that recapitulate distinct neural cell types, are influenced by the tumor microenvironment, and exhibit plasticity. The relative frequency of cells in each state varies between glioblastoma samples and is influenced by copy number amplifications of the CDK4, EGFR, and PDGFRA loci and by mutations in the NF1 locus, which each favor a defined state. Our work provides a blueprint for glioblastoma, integrating the malignant cell programs, their plasticity, and their modulation by genetic drivers.

Glioblastomas exhibit a hierarchical cellular organization, suggesting that they are driven by neoplastic stem cells that retain partial yet abnormal differentiation potential. Here, we show that a large subset of patient-derived glioblastoma stem cells (GSCs) express high levels of Achaete-scute homolog 1 (ASCL1), a proneural transcription factor involved in normal neurogenesis. ASCL1hi GSCs exhibit a latent capacity for terminal neuronal differentiation in response to inhibition of Notch signaling, whereas ASCL1lo GSCs do not. Increasing ASCL1 levels in ASCL1lo GSCs restores neuronal lineage potential, promotes terminal differentiation, and attenuates tumorigenicity. ASCL1 mediates these effects by functioning as a pioneer factor at closed chromatin, opening new sites to activate a neurogenic gene expression program. Directing GSCs toward terminal differentiation may provide therapeutic applications for a subset of GBM patients and strongly supports efforts to restore differentiation potential in GBM and other cancers.

The aim of this study was to investigate the clinical characteristics of central nervous system (CNS) aspergillosis in immunocompetent patients.This study enrolled six immunocompetent patients diagnosed with CNS aspergillosis. Additionally, we reviewed the clinical profiles for 28 cases reported in the literature. The age, gender, etiology of Aspergillus infection, clinical manifestations, location of the lesion, treatment, and prognosis were analyzed.There were 19 men (average age, 54.6 ± 14.3 years) and 15 women (average age, 47.0 ± 19.4 years). The clinical manifestations included headache (55.9%; n = 19), visual impairment (32.4%; n = 11), diplopia (32.4%; n = 11), hemiplegia (20.6%; n = 7), fever (17.6%; n = 6), and epilepsy (8.8%; n = 3). According to the radiological features, CNS aspergillosis lesions were divided into two subtypes: parenchymal lesions in the cerebral lobes (n = 11), and meningeal lesions in the meninges (n = 23). The patients with meningeal lesions are easy to be complicated with more serious cerebrovascular diseases, such as subarachnoid hemorrhage and massive infarction. Most of the lesions in brain parenchyma were abscess formation, and magnetic resonance imaging showed ring enhancement. The clinical diagnosis of Aspergillus infection was mainly based on brain biopsy (n = 14), autopsy (n = 8), pathological examination of adjacent brain tissues (n = 7), cerebrospinal fluid (CSF) or tissue culture (n = 3), and second-generation sequencing analysis of the CSF (n = 3). Clinical improvement was achieved in 23 cases, and 11 patients succumbed to the disease. Voriconazole treatment was effective in 24 (70.6%) cases.Immunocompetent subjects are also at risk for Aspergillus infections. Concomitant cerebrovascular diseases are common in patients with CNS aspergillosis, especially in patients with meningeal aspergillosis. Parenchymal aspergillosis lesions are usually localized and manifest as brain abscesses with annular enhancement on magnetic resonance imaging. Biopsy, CSF culture, and next-generation sequencing are mainstream diagnostic modalities. Voriconazole is an effective treatment for Aspergillus infection, and early diagnosis and treatment should be highlighted.

Fatigue and burnout are prevalent among resident physicians across Canada. Shifts exceeding 24 hours are commonly purported as detrimental to resident health and performance. Residency training programs have employed strategies towards understanding and intervening upon the complex issue of resident fatigue, where alternative resident scheduling models have been an area of active investigation. This study sought to characterize drivers and outcomes of fatigue and burnout amongst internal medicine residents across different scheduling models.

Glioblastoma (GBM) is a deadly cancer in which cancer stem cells (CSCs) sustain tumor growth and contribute to therapeutic resistance. Protein arginine methyltransferase 5 (PRMT5) has recently emerged as a promising target in GBM. Using two orthogonal-acting inhibitors of PRMT5 (GSK591 or LLY-283), we show that pharmacological inhibition of PRMT5 suppresses the growth of a cohort of 46 patient-derived GBM stem cell cultures, with the proneural subtype showing greater sensitivity. We show that PRMT5 inhibition causes widespread disruption of splicing across the transcriptome, particularly affecting cell cycle gene products. We identify a GBM splicing signature that correlates with the degree of response to PRMT5 inhibition. Importantly, we demonstrate that LLY-283 is brain-penetrant and significantly prolongs the survival of mice with orthotopic patient-derived xenografts. Collectively, our findings provide a rationale for the clinical development of brain penetrant PRMT5 inhibitors as treatment for GBM.

Glioblastoma (GBM) is a cancer comprised of morphologically, genetically, and phenotypically diverse cells. However, an understanding of the functional significance of intratumoral heterogeneity is lacking. We devised a method to isolate and functionally profile tumorigenic clones from patient glioblastoma samples. Individual clones demonstrated unique proliferation and differentiation abilities. Importantly, naïve patient tumors included clones that were temozolomide resistant, indicating that resistance to conventional GBM therapy can preexist in untreated tumors at a clonal level. Further, candidate therapies for resistant clones were detected with clone-specific drug screening. Genomic analyses revealed genes and pathways that associate with specific functional behavior of single clones. Our results suggest that functional clonal profiling used to identify tumorigenic and drug-resistant tumor clones will lead to the discovery of new GBM clone-specific treatment strategies.

No abstract available

Medulloblastoma (MB) is a neoplasm linked to dysregulated cerebellar development. Previously, we demonstrated that the Sonic Hedgehog (SHH) subgroup grows hierarchically, with Sox2+ cells at the apex of tumor progression and relapse. To test whether this mechanism is rooted in a normal developmental process, we studied the role of Sox2 in cerebellar development. We find that the external germinal layer (EGL) is derived from embryonic Sox2+ precursors and that the EGL maintains a rare fraction of Sox2+ cells during the first postnatal week. Through lineage tracing and single-cell analysis, we demonstrate that these Sox2+ cells are within the Atoh1+ lineage, contribute extensively to adult granule neurons, and resemble Sox2+ tumor cells. Critically, constitutive activation of the SHH pathway leads to their aberrant persistence in the EGL and rapid tumor onset. We propose that failure to eliminate this rare but potent developmental population is the tumor initiation mechanism in SHH-subgroup MB.

Lidocaine, a local anesthetic, is a valuable agent for the treatment of neuronal ischemia/reperfusion (I/R) injury. The aim of the present study was to investigate the role of lidocaine in oxygen-glucose deprivation/reperfusion (OGD/R)-induced cortical neurons and explore the related molecular mechanisms. Cerebral cortical neurons were isolated from Sprague-Dawley rat embryos and stimulated with OGD/R to establish an in vitro I/R injury model. Subsequently, neuronal cell viability, cytotoxicity and apoptosis were evaluated by performing the MTT assay, lactate dehydrogenase (LDH) assay and flow cytometry, respectively. The results suggested that OGD/R exposure significantly decreased cerebral cortical neuron cell viability, accelerated LDH release and induced cell apoptosis compared with control neurons, indicating that cerebral I/R injury was stimulated by OGD/R treatment. Further investigation indicated that 10 µM lidocaine significantly enhanced neuronal cell viability, and reduced LDH release and neuronal cell apoptosis in OGD/R-exposed cells compared with the OGD/R + saline group, which indicated that lidocaine displayed neuroprotective effects against I/R damage. In addition, the findings of the present study suggested that OGD/R exposure significantly decreased Bcl-2 and Bcl-xl protein expression levels, but increased Bax protein expression levels, the Bax/Bcl-2 ratio and caspase-3 activity compared with control neurons. However, lidocaine reversed OGD/R-mediated alterations to apoptosis-related protein expression. Furthermore, the results of the present study indicated that lidocaine increased Wnt3a, β-catenin and cyclin D1 expression levels in OGD/R-exposed cells compared with the OGD/R + saline group, thus activating the Wnt/β-catenin signaling pathway. The findings of the present study suggested that lidocaine served a protective role in OGD/R-triggered neuronal damage by activating the Wnt/β-catenin signaling pathway; therefore, lidocaine may serve as a potential candidate for the treatment of cerebral I/R injury.

Background: There is a strong need for short and effective methods to screen for cognitive impairment. Recent studies have created short forms of the Montreal Cognitive Assessment (s-MoCA) in English-speaking populations. It is also important to develop a validated Chinese short version to detect cognitive impairment. Methods: Item response theory and computerized adaptive testing analytics were used to construct abbreviated MoCAs across a large neurological sample comprising 6,981 community-dwelling Chinese veterans. Results: Six MoCA items with high discrimination and appropriate difficulty were included in the s-MoCA. The Chinese short versions (sensitivity 0.89/0.90, specificity 0.72/0.77) are similar in performance to the full MoCA in identifying cognitive impairment (sensitivity 0.91, specificity 0.82). Conclusions: These short variants of the MoCA may serve as quick and effective instruments when the original MoCA cannot be feasibly administered in clinical services with a high patient burden and limited cognitive testing resources.