ABSTRACT
Glioblastoma (GBM) diffusely infiltrates the brain and intermingles with non-neoplastic brain cells, including astrocytes, neurons and microglia/myeloid cells. This complex mixture of cell types forms the biological context for therapeutic response and tumor recurrence. We used single-nucleus RNA sequencing and spatial transcriptomics to determine the cellular composition and transcriptional states in primary and recurrent glioma and identified three compositional 'tissue-states' defined by cohabitation patterns between specific subpopulations of neoplastic and non-neoplastic brain cells. These tissue-states correlated with radiographic, histopathologic, and prognostic features and were enriched in distinct metabolic pathways. Fatty acid biosynthesis was enriched in the tissue-state defined by the cohabitation of astrocyte-like/mesenchymal glioma cells, reactive astrocytes, and macrophages, and was associated with recurrent GBM and shorter survival. Treating acute slices of GBM with a fatty acid synthesis inhibitor depleted the transcriptional signature of this pernicious tissue-state. These findings point to therapies that target interdependencies in the GBM microenvironment.
Subject(s)
Brain Neoplasms , Glioblastoma , Glioma , Humans , Glioblastoma/pathology , Prognosis , Brain Neoplasms/pathology , Glioma/genetics , Astrocytes/metabolism , Tumor Microenvironment/geneticsABSTRACT
Introduction: For elderly adults in the United States, stroke is the fifth leading cause of death of which ischemic strokes comprise a vast majority. Optimal pharmacological management of elderly ischemic stroke patients involves both reperfusion and supportive care. Recent research into pharmacological management has focused on vascular, immunomodulatory, cytoprotective, and alternative agents, some of which have shown limited success in clinical trials. However, no treatments have been established as a reliable mode for management of cerebral ischemia for elderly adults beyond acute thrombolysis.Areas covered: The authors conducted a literature search for ischemic stroke management in the elderly and a search for human drug studies for managing ischemic stroke on clinicaltrials.gov. Here, they describe recent progress in the pharmacological management of cerebral ischemia in the elderly.Expert opinion: Many drug classes (antihypertensive, cytoprotective and immunomodulatory, and alternative agents) have been explored with limited success in managing ischemic stroke, though some have shown preventative benefits. We generally observed a broad gap in evidence on elderly patients from studies across all drug classes, necessitating further studies to gain an understanding of effective management of ischemic stroke in this large demographic of patients.
Subject(s)
Brain Ischemia , Stroke , Aged , Brain Ischemia/drug therapy , Cerebral Infarction/drug therapy , Fibrinolytic Agents/therapeutic use , Humans , Stroke/drug therapy , Thrombolytic TherapyABSTRACT
BACKGROUND: Inflammatory bowel disease (IBD) patients who have Clostridioides difficile infection (CDI) have worse outcomes. AIMS: We aimed to determine whether such outcomes are the result of CDI or whether CDI occurs in patients who have more severe IBD. METHODS: This was a retrospective study of patients hospitalized for ≥ 2 IBD flares from 2010 to 2019. The primary outcome was time to IBD flare between hospitalizations. First, time to flare was compared between patients who were hospitalized for a flare complicated by CDI and subsequently for a CDI-negative flare (cohort A, denoted +/-) versus patients who were hospitalized for two CDI-negative flares (cohort B, -/-). Second, time between flares was compared within the subset of cohort A patients who had three flares (cohort C, -/+/-) before and after CDI. RESULTS: Time between flares was a median of 4 months (IQR 1-9) among 51 cohort A patients versus 12 months (IQR 6-38) among 51 cohort B patients (log-rank P < 0.01). In contrast, the median time between flares was similar within cohort C before and after CDI (log-rank P = 0.54). At time of the second IBD flare, patients in cohort A (+/-) were more likely to have moderate or severe disease compared to patients in cohort B (-/-). CONCLUSIONS: Patients with prior CDI had shorter time to subsequent IBD flare relative to their CDI-negative counterparts. This is not likely due to CDI itself because there was no difference in time between flares before versus after acquiring CDI. Rather, patients who acquire CDI may have more severe IBD.
Subject(s)
Clostridioides difficile/isolation & purification , Clostridium Infections , Inflammatory Bowel Diseases , Adult , Causality , Clostridium Infections/diagnosis , Clostridium Infections/epidemiology , Clostridium Infections/physiopathology , Female , Hospitalization/statistics & numerical data , Humans , Inflammatory Bowel Diseases/diagnosis , Inflammatory Bowel Diseases/epidemiology , Inflammatory Bowel Diseases/microbiology , Inflammatory Bowel Diseases/therapy , Male , Outcome and Process Assessment, Health Care , Patient Acuity , Prevalence , Recurrence , Retrospective Studies , Severity of Illness Index , Symptom Assessment , Symptom Flare Up , United States/epidemiologyABSTRACT
The fabrication of extracellular matrix-mimic hydrogels that can nurture and direct differentiation of embryonic stem cells is an important target for pattern-printed tissue replacement. Another desirable feature for such materials is their ability to be injected and recover their rheological features post-injection, allowing for facile non-invasive implantation. In this report, we demonstrate the ability of a self-assembling peptide hydrogel to support the culture of embryonic stem cells with the potential to direct differentiation. We also show that we can write a functional tissue replacement with a predetermined pattern using our formulation. Our results may lead to in vivo replacement of diseased tissue with a spatially resolved pattern of a regenerative hydrogel.
