Summary Cellular senescence entails a stable cell-cycle arrest and a pro-inflammatory secretory phenotype, which contributes to aging and age-related diseases. Obesity is associated with increased senescent cell burden and neuropsychiatric disorders, including anxiety and depression. To investigate the role of senescence in obesity-related neuropsychiatric dysfunction, we used the INK-ATTAC mouse model, from which p16 Ink4a -expressing senescent cells can be eliminated, and senolytic drugs dasatinib and quercetin. We found that obesity results in the accumulation of senescent glial cells in proximity to the lateral ventricle, a region in which adult neurogenesis occurs. Furthermore, senescent glial cells exhibit excessive fat deposits, a phenotype we termed “accumulation of lipids in senescence.” Clearing senescent cells from high fat-fed or leptin receptor-deficient obese mice restored neurogenesis and alleviated anxiety-related behavior. Our study provides proof-of-concept evidence that senescent cells are major contributors to obesity-induced anxiety and that senolytics are a potential new therapeutic avenue for treating neuropsychiatric disorders.
No effective therapy is currently available to promote recovery following ischemic stroke. Stem cells have been proposed as a potential source of new cells to replace those lost due to central nervous system injury, as well as a source of trophic molecules to minimize damage and promote recovery. We undertook a detailed review of data from recent basic science and preclinical studies to investigate the potential application of endogenous and exogenous stem cell therapies for treatment of cerebral ischemia. To date, spontaneous endogenous neurogenesis has been observed in response to ischemic injury, and can be enhanced via infusion of appropriate cytokines. Exogenous stem cells from multiple sources can generate neural cells that survive and form synaptic connections after transplantation in the stroke-injured brain. Stem cells from multiple sources cells also exhibit neuroprotective properties that may ameliorate stroke deficits. In many cases, functional benefits observed are likely independent of neural differentiation, though exact mechanisms remain poorly understood. Future studies of neuroregeneration will require the demonstration of function in endogenously born neurons following focal ischemia. Further, methods are currently lacking to definitively demonstrate the therapeutic effect of newly introduced neural cells. Increased plasticity following stroke may facilitate the functional integration of new neurons, but the loss of appropriate guidance cues and supporting architecture in the infarct cavity will likely impede the restoration of lost circuitry. As such careful investigation of the mechanisms underlying trophic benefits will be essential. Evidence to date suggest that continued development of stem cell therapies may ultimately lead to viable treatment options for ischemic brain injury.
A recent meeting was held on March 22, 2019, among the FDA, clinical scientists, pharmaceutical and biotech companies, clinical trials cooperative groups, and patient advocacy groups to discuss challenges and potential solutions for increasing development of therapeutics for central nervous system metastases. A key issue identified at this meeting was the need for consistent tumor measurement for reliable tumor response assessment, including the first step of standardized image acquisition with an MRI protocol that could be implemented in multicenter studies aimed at testing new therapeutics. This document builds upon previous consensus recommendations for a standardized brain tumor imaging protocol (BTIP) in high-grade gliomas and defines a protocol for brain metastases (BTIP-BM) that addresses unique challenges associated with assessment of CNS metastases. The “minimum standard” recommended pulse sequences include: (i) parameter matched pre- and post-contrast inversion recovery (IR)–prepared, isotropic 3D T1-weighted gradient echo (IR-GRE); (ii) axial 2D T2-weighted turbo spin echo acquired after injection of gadolinium-based contrast agent and before post-contrast 3D T1-weighted images; (iii) axial 2D or 3D T2-weighted fluid attenuated inversion recovery; (iv) axial 2D, 3-directional diffusion-weighted images; and (v) post-contrast 2D T1-weighted spin echo images for increased lesion conspicuity. Recommended sequence parameters are provided for both 1.5T and 3T MR systems. An “ideal” protocol is also provided, which replaces IR-GRE with 3D TSE T1-weighted imaging pre- and post-gadolinium, and is best performed at 3T, for which dynamic susceptibility contrast perfusion is included. Recommended perfusion parameters are given.
Thymidine analogs, including bromodeoxyuridine, chlorodeoxyuridine, iododeoxyuridine, and tritiated thymidine, label dividing cells by incorporating into DNA during S phase of cell division and are widely employed to identify cells transplanted into the central nervous system. However, the potential for transfer of thymidine analogs from grafted cells to dividing host cells has not been thoroughly tested. We here demonstrate that graft-derived thymidine analogs can become incorporated into host neural precursors and glia. Large numbers of labeled neurons and glia were found 3-12 weeks after transplantation of thymidine analog-labeled live stem cells, suggesting differentiation of grafted cells. Remarkably, however, similar results were obtained after transplantation of dead cells or labeled fibroblasts. Our findings reveal for the first time that thymidine analog labeling may not be a reliable means of identifying transplanted cells, particularly in highly proliferative environments such as the developing, neurogenic, or injured brain.
Intracranial hypotension is a disorder of CSF hypovolemia due to iatrogenic or spontaneous spinal CSF leakage. Rarely, positional headaches may progress to coma, with frequent misdiagnosis. The authors review reported cases of verified intracranial hypotension-associated coma, including 3 previously unpublished cases, totaling 29. Most patients presented with headache prior to neurological deterioration, with positional symptoms elicited in almost half. Eight patients had recently undergone a spinal procedure such as lumbar drainage. Diagnostic workup almost always began with a head CT scan. Subdural collections were present in 86%; however, intracranial hypotension was frequently unrecognized as the underlying cause. Twelve patients underwent one or more procedures to evacuate the collections, sometimes with transiently improved mental status. However, no patient experienced lasting neurological improvement after subdural fluid evacuation alone, and some deteriorated further. Intracranial hypotension was diagnosed in most patients via MRI studies, which were often obtained due to failure to improve after subdural hematoma (SDH) evacuation. Once the diagnosis of intracranial hypotension was made, placement of epidural blood patches was curative in 85% of patients. Twenty-seven patients (93%) experienced favorable outcomes after diagnosis and treatment; 1 patient died, and 1 patient had a morbid outcome secondary to duret hemorrhages. The literature review revealed that numerous additional patients with clinical histories consistent with intracranial hypotension but no radiological confirmation developed SDH following a spinal procedure. Several such patients experienced poor outcomes, and there were multiple deaths. To facilitate recognition of this treatable but potentially life-threatening condition, the authors propose criteria that should prompt intracranial hypotension workup in the comatose patient and present a stepwise management algorithm to guide the appropriate diagnosis and treatment of these patients.
Purpose: Glioblastoma is the most frequent and lethal primary brain tumor. Development of novel therapies relies on the availability of relevant preclinical models. We have established a panel of 96 glioblastoma patient-derived xenografts (PDX) and undertaken its genomic and phenotypic characterization.Experimental Design: PDXs were established from glioblastoma, IDH-wildtype (n ¼ 93), glioblastoma, IDH-mutant (n ¼ 2), diffuse midline glioma, H3 K27M-mutant (n ¼ 1), and both primary (n ¼ 60) and recurrent (n ¼ 34) tumors. Tumor growth rates, histopathology, and treatment response were characterized. Integrated molecular profiling was performed by whole-exome sequencing (WES, n ¼ 83), RNAsequencing (n ¼ 68), and genome-wide methylation profiling (n ¼ 76). WES data from 24 patient tumors was compared with derivative models.Results: PDXs recapitulate many key phenotypic and molecular features of patient tumors. Orthotopic PDXs show charac-teristic tumor morphology and invasion patterns, but largely lack microvascular proliferation and necrosis. PDXs capture common and rare molecular drivers, including alterations of TERT, EGFR, PTEN, TP53, BRAF, and IDH1, most at frequencies comparable with human glioblastoma. However, PDGFRA amplification was absent. RNA-sequencing and genome-wide methylation profiling demonstrated broad representation of glioblastoma molecular subtypes. MGMT promoter methylation correlated with increased survival in response to temozolomide. WES of 24 matched patient tumors showed preservation of most genetic driver alterations, including EGFR amplification. However, in four patient-PDX pairs, driver alterations were gained or lost on engraftment, consistent with clonal selection.Conclusions: Our PDX panel captures the molecular heterogeneity of glioblastoma and recapitulates many salient genetic and phenotypic features. All models and genomic data are openly available to investigators.
Glioblastoma (GBM) is uniformly fatal with a median survival of just over 1 year, despite best available treatment including radiotherapy (RT). Impacts of prior brain RT on recurrent tumors are poorly understood, though increasing evidence suggests RT-induced changes in the brain microenvironment contribute to recurrent GBM aggressiveness. The tumor microenvironment impacts malignant cells directly and indirectly through stromal cells that support tumor growth. Changes in extracellular matrix (ECM), abnormal vasculature, hypoxia, and inflammation have been reported to promote tumor aggressiveness that could be exacerbated by prior RT. Prior radiation may have long-term impacts on microglia and brain-infiltrating monocytes, leading to lasting alterations in cytokine signaling and ECM. Tumor-promoting CNS injury responses are recapitulated in the tumor microenvironment and augmented following prior radiation, impacting cell phenotype, proliferation, and infiltration in the CNS. Since RT is vital to GBM management, but substantially alters the tumor microenvironment, we here review challenges, knowledge gaps, and therapeutic opportunities relevant to targeting pro-tumorigenic features of the GBM microenvironment. We suggest that insights from RT-induced changes in the tumor microenvironment may provide opportunities to target mechanisms, such as cellular senescence, that may promote GBM aggressiveness amplified in previously radiated microenvironment.
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