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Religion and popular culture in America
\"Since 2000, Religion and Popular Culture in America has been one [of the] standard books used in teaching this area of study. Modestly updated in 2005, it continues to be taught in colleges, universities and theological schools across the continent. The basic four-part structure of Religion and Popular Culture in America remains sound and is a feature that appeals to many who have taught the volume. Section One, Religion in Popular Culture, examines the way traditional religious symbols, narratives, and forms of religious practice appear in popular culture. Section Two, Popular Culture in Religion, considers how religion takes on and is reshaped by styles and values of popular culture. Section Three, Popular Culture as Religion, explores the ways that aspects of popular culture and their reception might be considered to be forms of religion. Section Four, Religion and Popular Culture in Dialogue, introduces religiously based critiques of popular culture and ways that popular culture articulates common critiques of religion. The third edition maintains the structure and basic length of the current edition and retains Forbes' introductory framework and update versions of key essay. But they replace many of the more dated subjects with new material drawing on more contemporary examples. A concluding essay by Mahan organizes key insights from the essays and relates them to the theories of popular culture illuminated in the introduction\"--Provided by publisher.
Book
Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma
Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of
PTEN
mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (
PTPN11
,
BRAF
) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor’s clonal evolution during treatment.
Genomic, transcriptomic, and microenvironmental analyses of samples from patients with glioblastoma treated with nivolumab or pembrolizumab identifies features associated with treatment response that may help in refining patient stratification.
Journal Article
Dietary restriction of cysteine and methionine sensitizes gliomas to ferroptosis and induces alterations in energetic metabolism
Ferroptosis is mediated by lipid peroxidation of phospholipids containing polyunsaturated fatty acyl moieties. Glutathione, the key cellular antioxidant capable of inhibiting lipid peroxidation via the activity of the enzyme glutathione peroxidase 4 (GPX-4), is generated directly from the sulfur-containing amino acid cysteine, and indirectly from methionine via the transsulfuration pathway. Herein we show that cysteine and methionine deprivation (CMD) can synergize with the GPX4 inhibitor RSL3 to increase ferroptotic cell death and lipid peroxidation in both murine and human glioma cell lines and in ex vivo organotypic slice cultures. We also show that a cysteine-depleted, methionine-restricted diet can improve therapeutic response to RSL3 and prolong survival in a syngeneic orthotopic murine glioma model. Finally, this CMD diet leads to profound in vivo metabolomic, proteomic and lipidomic alterations, highlighting the potential for improving the efficacy of ferroptotic therapies in glioma treatment with a non-invasive dietary modification.
Diet intervention is emerging as an option to improve cancer therapy. Here, the authors show that a diet with restrictive cysteine and methionine synergizes with a ferroptosis inducer to increase cell death and survival in glioma preclinical models.
Journal Article
HDAC inhibitors elicit metabolic reprogramming by targeting super-enhancers in glioblastoma models
The Warburg effect is a tumor-related phenomenon that could potentially be targeted therapeutically. Here, we showed that glioblastoma (GBM) cultures and patients' tumors harbored super-enhancers in several genes related to the Warburg effect. By conducting a transcriptome analysis followed by ChIP-Seq coupled with a comprehensive metabolite analysis in GBM models, we found that FDA-approved global (panobinostat, vorinostat) and selective (romidepsin) histone deacetylase (HDAC) inhibitors elicited metabolic reprogramming in concert with disruption of several Warburg effect-related super-enhancers. Extracellular flux and carbon-tracing analyses revealed that HDAC inhibitors blunted glycolysis in a c-Myc-dependent manner and lowered ATP levels. This resulted in the engagement of oxidative phosphorylation (OXPHOS) driven by elevated fatty acid oxidation (FAO), rendering GBM cells dependent on these pathways. Mechanistically, interference with HDAC1/-2 elicited a suppression of c-Myc protein levels and a concomitant increase in 2 transcriptional drivers of oxidative metabolism, PGC1α and PPARD, suggesting an inverse relationship. Rescue and ChIP experiments indicated that c-Myc bound to the promoter regions of PGC1α and PPARD to counteract their upregulation driven by HDAC1/-2 inhibition. Finally, we demonstrated that combination treatment with HDAC and FAO inhibitors extended animal survival in patient-derived xenograft model systems in vivo more potently than single treatments in the absence of toxicity.
Journal Article
Re-convolving the compositional landscape of primary and recurrent glioblastoma reveals prognostic and targetable tissue states
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.
Glioblastoma (GBM) cells can infiltrate into the tumour microenvironment (TME) and contribute to recurrence. Here, the authors analyse primary and recurrent GBMs and their TME using single-nucleus and spatial transcriptomics, revealing tissue states defined by the combinations of neoplastic and non-neoplastic cells, which could be therapeutic targets.
Journal Article
A Review of Therapeutic Agents Given by Convection-Enhanced Delivery for Adult Glioblastoma
Glioblastoma remains a devastating disease with a bleak prognosis despite continued research and numerous clinical trials. Convection-enhanced delivery offers researchers and clinicians a platform to bypass the blood–brain barrier and administer drugs directly to the brain parenchyma. While not without significant technological challenges, convection-enhanced delivery theoretically allows for a wide range of therapeutic agents to be delivered to the tumoral space while preventing systemic toxicities. This article provides a comprehensive review of the antitumor agents studied in clinical trials of convection-enhanced delivery to treat adult high-grade gliomas. Agents are grouped by classes, and preclinical evidence for these agents is summarized, as is a brief description of their mechanism of action. The strengths and weaknesses of each clinical trial are also outlined. By doing so, the difficulty of untangling the efficacy of a drug from the technological challenges of convection-enhanced delivery is highlighted. Finally, this article provides a focused review of some therapeutics that might stand to benefit from future clinical trials for glioblastoma using convection-enhanced delivery.
Journal Article
Convection-enhanced drug delivery for glioblastoma: a review
Introduction
Convection-enhanced delivery (CED) is a method of targeted, local drug delivery to the central nervous system (CNS) that bypasses the blood-brain barrier (BBB) and permits the delivery of high-dose therapeutics to large volumes of interest while limiting associated systemic toxicities. Since its inception, CED has undergone considerable preclinical and clinical study as a safe method for treating glioblastoma (GBM). However, the heterogeneity of both, the surgical procedure and the mechanisms of action of the agents studied—combined with the additional costs of performing a trial evaluating CED—has limited the field’s ability to adequately assess the durability of any potential anti-tumor responses. As a result, the long-term efficacy of the agents studied to date remains difficult to assess.
Materials and methods
We searched PubMed using the phrase “convection-enhanced delivery and glioblastoma”. The references of significant systematic reviews were also reviewed for additional sources. Articles focusing on physiological and physical mechanisms of CED were included as well as technological CED advances.
Results
We review the history and principles of CED, procedural advancements and characteristics, and outcomes from key clinical trials, as well as discuss the potential future of this promising technique for the treatment of GBM.
Conclusion
While the long-term efficacy of the agents studied to date remains difficult to assess, CED remains a promising technique for the treatment of GBM.
Journal Article
Glioblastoma Models Reveal the Connection between Adult Glial Progenitors and the Proneural Phenotype
Tumor heterogeneity is a major obstacle for finding effective treatment of Glioblastoma (GBM). Based on global expression analysis, GBM can be classified into distinct subtypes: Proneural, Neural, Classical and Mesenchymal. The signatures of these different tumor subtypes may reflect the phenotypes of cells giving rise to them. However, the experimental evidence connecting any specific subtype of GBM to particular cells of origin is lacking. In addition, it is unclear how different genetic alterations interact with cells of origin in determining tumor heterogeneity. This issue cannot be addressed by studying end-stage human tumors.
To address this issue, we used retroviruses to deliver transforming genetic lesions to glial progenitors in adult mouse brain. We compared the resulting tumors to human GBM. We found that different initiating genetic lesions gave rise to tumors with different growth rates. However all mouse tumors closely resembled the human Proneural GBM. Comparative analysis of these mouse tumors allowed us to identify a set of genes whose expression in humans with Proneural GBM correlates with survival.
This study offers insights into the relationship between adult glial progenitors and Proneural GBM, and allows us to identify molecular alterations that lead to more aggressive tumor growth. In addition, we present a new preclinical model that can be used to test treatments directed at a specific type of GBM in future studies.
Journal Article
Patient-Specific Metrics of Invasiveness Reveal Significant Prognostic Benefit of Resection in a Predictable Subset of Gliomas
Malignant gliomas are incurable, primary brain neoplasms noted for their potential to extensively invade brain parenchyma. Current methods of clinical imaging do not elucidate the full extent of brain invasion, making it difficult to predict which, if any, patients are likely to benefit from gross total resection. Our goal was to apply a mathematical modeling approach to estimate the overall tumor invasiveness on a patient-by-patient basis and determine whether gross total resection would improve survival in patients with relatively less invasive gliomas.
In 243 patients presenting with contrast-enhancing gliomas, estimates of the relative invasiveness of each patient's tumor, in terms of the ratio of net proliferation rate of the glioma cells to their net dispersal rate, were derived by applying a patient-specific mathematical model to routine pretreatment MR imaging. The effect of varying degrees of extent of resection on overall survival was assessed for cohorts of patients grouped by tumor invasiveness.
We demonstrate that patients with more diffuse tumors showed no survival benefit (P = 0.532) from gross total resection over subtotal/biopsy, while those with nodular (less diffuse) tumors showed a significant benefit (P = 0.00142) with a striking median survival benefit of over eight months compared to sub-totally resected tumors in the same cohort (an 80% improvement in survival time for GTR only seen for nodular tumors).
These results suggest that our patient-specific, model-based estimates of tumor invasiveness have clinical utility in surgical decision making. Quantification of relative invasiveness assessed from routinely obtained pre-operative imaging provides a practical predictor of the benefit of gross total resection.
Journal Article
Single-cell transcriptome analysis of lineage diversity in high-grade glioma
Background
Despite extensive molecular characterization, we lack a comprehensive understanding of lineage identity, differentiation, and proliferation in high-grade gliomas (HGGs).
Methods
We sampled the cellular milieu of HGGs by profiling dissociated human surgical specimens with a high-density microwell system for massively parallel single-cell RNA-Seq. We analyzed the resulting profiles to identify subpopulations of both HGG and microenvironmental cells and applied graph-based methods to infer structural features of the malignantly transformed populations.
Results
While HGG cells can resemble glia or even immature neurons and form branched lineage structures, mesenchymal transformation results in unstructured populations. Glioma cells in a subset of mesenchymal tumors lose their neural lineage identity, express inflammatory genes, and co-exist with marked myeloid infiltration, reminiscent of molecular interactions between glioma and immune cells established in animal models. Additionally, we discovered a tight coupling between lineage resemblance and proliferation among malignantly transformed cells. Glioma cells that resemble oligodendrocyte progenitors, which proliferate in the brain, are often found in the cell cycle. Conversely, glioma cells that resemble astrocytes, neuroblasts, and oligodendrocytes, which are non-proliferative in the brain, are generally non-cycling in tumors.
Conclusions
These studies reveal a relationship between cellular identity and proliferation in HGG and distinct population structures that reflects the extent of neural and non-neural lineage resemblance among malignantly transformed cells.
Journal Article