Altered cellular metabolism is a hallmark of gliomas. Propelled by a set of recent technological advances, new insights into the molecular mechanisms underlying glioma metabolism are rapidly ...emerging. In this Review, we focus on the dynamic nature of glioma metabolism and how it is shaped by the interaction between tumour genotype and brain microenvironment. Recent advances integrating metabolomics with genomics are discussed, yielding new insight into the mechanisms that drive glioma pathogenesis. Studies that shed light on interactions between the tumour microenvironment and tumour genotype are highlighted, providing important clues as to how gliomas respond to and adapt to their changing tissue and biochemical contexts. Finally, a road map for the discovery of potential new glioma drug targets is suggested, with the goal of translating these new insights about glioma metabolism into clinical benefits for patients.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
This article reports on a noninvasive approach in detecting and following-up individuals who are at-risk or have an existing COVID-19 infection, with a potential ability to serve as an epidemic ...control tool. The proposed method uses a developed breath device composed of a nanomaterial-based hybrid sensor array with multiplexed detection capabilities that can detect disease-specific biomarkers from exhaled breath, thus enabling rapid and accurate diagnosis. An exploratory clinical study with this approach was examined in Wuhan, China, during March 2020. The study cohort included 49 confirmed COVID-19 patients, 58 healthy controls, and 33 non-COVID lung infection controls. When applicable, positive COVID-19 patients were sampled twice: during the active disease and after recovery. Discriminant analysis of the obtained signals from the nanomaterial-based sensors achieved very good test discriminations between the different groups. The training and test set data exhibited respectively 94% and 76% accuracy in differentiating patients from controls as well as 90% and 95% accuracy in differentiating between patients with COVID-19 and patients with other lung infections. While further validation studies are needed, the results may serve as a base for technology that would lead to a reduction in the number of unneeded confirmatory tests and lower the burden on hospitals, while allowing individuals a screening solution that can be performed in PoC facilities. The proposed method can be considered as a platform that could be applied for any other disease infection with proper modifications to the artificial intelligence and would therefore be available to serve as a diagnostic tool in case of a new disease outbreak.
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IJS, KILJ, NUK, PNG, UL, UM
Human exhaled volatile organic compounds (VOCs) are being extensively studied for the purposes of noninvasive cancer diagnoses. This article was primarily to assess the feasibility of utilizing ...exhaled VOCs analysis for gastrointestinal cancer (GIC) diagnosis.
PRISMA-based system searches were conducted for related studies of exhaled VOCs in GIC diagnosis based on predetermined criteria. Relevant articles on colorectal cancer and gastroesophageal cancer were summarized, and meta analysis was performed on articles providing sensitivity and specificity data.
From 2,227 articles, 14 were found to meet inclusion criteria, six of which were on colorectal cancer (CRC) and eight on Gastroesophageal cancer(GEC). Five articles could provide specific data of sensitivity and specificity in GEC, which were used for meta-analysis. The pooled sensitivity, specificity, diagnostic odds ratio (DOR), and area under the curve (AUC) were calculated based on the combination of these data, and were 85.0% 95% confidence interval (CI): 79.0%-90.0%, 89.0% (95%CI: 86.0%-91.0%), 41.30 (21.56-79.10), and 0.93, respectively.
VOCs can distinguish gastrointestinal cancers from other gastrointestinal diseases, opening up a new avenue for the diagnosis and identification of gastrointestinal cancers, and the analysis of VOCs in exhaled breath has potential clinical application in screening. VOCs are promising tumor biomarkers for GIC diagnosis. Furthermore, limitations like the heterogeneity of diagnostic VOCs between studies should be minded.
Dysregulated Th17 cell responses underlie multiple inflammatory and autoimmune diseases, including autoimmune uveitis and its animal model, EAU. However, clinical trials targeting IL-17A in uveitis ...were not successful. Here, we report that Th17 cells were regulated by their own signature cytokine, IL-17A. Loss of IL-17A in autopathogenic Th17 cells did not reduce their pathogenicity and instead elevated their expression of the Th17 cytokines GM-CSF and IL-17F. Mechanistic in vitro studies revealed a Th17 cell-intrinsic autocrine loop triggered by binding of IL-17A to its receptor, leading to activation of the transcription factor NF-κB and induction of IL-24, which repressed the Th17 cytokine program. In vivo, IL-24 treatment ameliorated Th17-induced EAU, whereas silencing of IL-24 in Th17 cells enhanced disease. This regulatory pathway also operated in human Th17 cells. Thus, IL-17A limits pathogenicity of Th17 cells by inducing IL-24. These findings may explain the disappointing therapeutic effect of targeting IL-17A in uveitis.
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•IL-17A deficiency does not reduce the pathogenicity of Th17 cells in uveitis•IL-17A binds to its own receptor on Th17 cells, activating NF-κB•NF-κB induces IL-24 production, repressing the Th17 cytokine program through SOCS1/3•Silencing or depleting IL-24 in Th17 cells exacerbates neuroinflammation
Loss of IL-17A, the signature cytokine of autoreactive Th17 cells, unexpectedly did not diminish the pathogenicity of Th17 cells in neuroinflammatory disease. This report demonstrates that IL-17A represses the Th17 cytokine program, primarily IL-17F and GM-CSF, by inducing autocrine production of IL-24. Thus, IL-17A has a dual role in Th17 cells: pathogenic as well as regulatory.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Advances in DNA sequencing technologies have reshaped our understanding of the molecular basis of cancer, providing a precise genomic view of tumors. Complementary biochemical and biophysical ...perspectives of cancer point toward profound shifts in nutrient uptake and utilization that propel tumor growth and major changes in the structure of the plasma membrane of tumor cells. The molecular mechanisms that bridge these fundamental aspects of tumor biology remain poorly understood. Here, we show that the lysophosphatidylcholine acyltransferase LPCAT1 functionally links specific genetic alterations in cancer with aberrant metabolism and plasma membrane remodeling to drive tumor growth. Growth factor receptor-driven cancers are found to depend on LPCAT1 to shape plasma membrane composition through enhanced saturated phosphatidylcholine content that is, in turn, required for the transduction of oncogenic signals. These results point to a genotype-informed strategy that prioritizes lipid remodeling pathways as therapeutic targets for diverse cancers.
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•Persistent EGFR signaling activates membrane lipid remodeling through LPCAT1•LPCAT1 regulates phospholipid saturation and oncogenic growth factor signaling•LPCAT1 is frequently amplified in cancer and associated with poor patient survival•Membrane phospholipid remodeling generates an actionable dependency across cancers
Persistent growth factor receptor signaling and metabolic reprograming are hallmarks of cancer. Bi et al. show that LPCAT1-mediated phospholipid remodeling supports the sustained oncogenic activity of growth factor receptors on plasma membrane of tumor cells, suggesting an actionable dependency in a wide variety of cancers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Polystyrene nanoplastics (PS-NPs) are typical accumulated nanoplastics in the marine environment and organisms, and have strong potential risks to marine ecological environment and human health. ...MiRNAs could respond to and participate in the response process of environmental stressors. However, the response of miRNAs to nanoplastics has not been fully explored. In this study, miRNA responses of digestive glands in mussels Mytilus galloprovincialis treated by 200 nm PS-NPs (20, 200, 2000 μg/L) for 7 days were characterized by BGISEQ-500 deep sequencing and bioinformatics analysis, along with histopathological quantification with planimetric parameters on hematoxylin and eosin (H&E) staining. Results showed that one novel miRNA (novel_mir63) and seven known miRNAs (miR-34_2, miR-34_5, miR-281_8, let-7–5p_6, miR-10, miR-124, miR-29b-3p) were significantly (adjusted P-value < 0.05) differentially expressed after PS-NPs treatments, and most of them were down-regulated expect for novel_mir63 and miR-34_2. Function analysis of target genes corresponding to these differentially expressed miRNAs indicated that PS-NPs disturbed the process related to metabolism, aging, cardiac function, neural excitation, and repairment. Among them, acetyl-CoA C-acetyltransferase and purine metabolism pathway played vital connection roles. Meanwhile, significantly morphology changes of digestive tubes obtained from H&E stained sections also implied severely disrupted metabolic capability in digestive glands, reflected by significantly increased mean diverticular radius (MDR) and mean luminal radius (MLR) values and the ratio of MLR to mean epithelial thickness (MET), and significantly decreased MET value and MET/MDR. Overall, these findings have revealed new characterization of miRNAs and their target genes in mussel M. galloprovincialis under PS-NPs stress, and provide important clues to further elucidate the toxicity mechanisms of PS-NPs.
•PS-NPs exhibited toxic effects on digestive glands of mussels.•PS-NPs exposure significantly affected morphology of digestive tubes.•miR-34, miR-281–8 and novel_mir63 are the main miRNAs induced by PS-NPs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Extrachromosomal DNA is a common cause of oncogene amplification in cancer. The non-chromosomal inheritance of ecDNA enables tumors to rapidly evolve, contributing to treatment resistance and poor ...outcome for patients. The transcriptional context in which ecDNAs arise and progress, including chromosomally-driven transcription, is incompletely understood. We examined gene expression patterns of 870 tumors of varied histological types, to identify transcriptional correlates of ecDNA. Here, we show that ecDNA-containing tumors impact four major biological processes. Specifically, ecDNA-containing tumors up-regulate DNA damage and repair, cell cycle control, and mitotic processes, but down-regulate global immune regulation pathways. Taken together, these results suggest profound alterations in gene regulation in ecDNA-containing tumors, shedding light on molecular processes that give rise to their development and progression.
Significance Although oncolytic virotherapy is showing great promise in clinical trials, not all patients are benefiting. Identifying predictors of therapeutic effectiveness for each oncolytic virus ...would provide a good chance to increase response rate. Here, we describe an alphavirus (M1) that possesses selective and potent antitumor activity through intravenous infusion, whereas its replication is controlled by the zinc-finger antiviral protein (ZAP) gene. A survey of cancer tissue banks reveals that ZAP is commonly deficient in human cancers, suggesting extensive application prospects of M1. Our work provides an example of a potentially personalized cancer therapy using a targeted oncolytic virus that can be selectively administered to patients with ZAP-deficient tumors. We predict that such agents will form the armamentarium of cancer therapy in the future.
Oncolytic virotherapy is a growing treatment modality that uses replicating viruses as selective antineoplastic agents. Safety and efficacy considerations dictate that an ideal oncolytic agent would discriminate between normal and cancer cells on the basis of common genetic abnormalities in human cancers. Here, we identify a naturally occurring alphavirus (M1) as a novel selective killer targeting zinc-finger antiviral protein (ZAP)-deficient cancer cells. In vitro, in vivo, and ex vivo studies showed potent oncolytic efficacy and high tumor tropism of M1. We showed that the selectivity depends on ZAP deficiency by systematic identification. A large-scale multicenter pathology study using tissue microarrays reveals that ZAP is commonly deficient in human cancers, suggesting extensive application prospects for M1. Additionally, M1 killed cancer cells by inducing endoplasmic reticulum stress-mediated apoptosis. Our report provides novel insights into potentially personalized cancer therapy using oncolytic viruses.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Astrocytomas are the most common and aggressive brain tumors characterized by their highly invasive growth. Gain of chromosome 7 with a hot spot at 7q32 appears to be the most prominent aberration in ...astrocytoma. Previously reports have shown that microRNA-335 (miR-335) resided on chromosome 7q32 is deregulated in many cancers; however, the biological function of miR-335 in astrocytoma has yet to be elucidated.
We report that miR-335 acts as a tumor promoter in conferring tumorigenic features such as growth and invasion on malignant astrocytoma. The miR-335 level is highly elevated in C6 astrocytoma cells and human malignant astrocytomas. Ectopic expression of miR-335 in C6 cells dramatically enhances cell viability, colony-forming ability and invasiveness. Conversely, delivery of antagonist specific for miR-335 (antagomir-335) to C6 cells results in growth arrest, cell apoptosis, invasion repression and marked regression of astrocytoma xenografts. Further investigation reveals that miR-335 targets disheveled-associated activator of morphogenesis 1(Daam1) at posttranscriptional level. Moreover, silencing of endogenous Daam1 (siDaam1) could mimic the oncogenic effects of miR-335 and reverse the growth arrest, proapoptotic and invasion repression effects induced by antagomir-335. Notably, the oncogenic effects of miR-335 and siDAAM1 together with anti-tumor effects of antagomir-335 are also confirmed in human astrocytoma U87-MG cells.
These findings suggest an oncogenic role of miR-335 and shed new lights on the therapy of malignant astrocytomas by targeting miR-335.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Avoiding immune destruction is essential for tumorigenesis. Current research into the interaction between tumor and immunological niches complement tumor pathology beyond cancer genetics. Intrinsic ...host defense immunity is a specialized innate immunity component to restrict viral infection. However, whether intrinsic immunity participates in tumor pathology is unclear. Previously, we identified a zinc-finger antiviral protein ZAP that is commonly downregulated in a panel of clinical cancer specimens. However, whether ZAP has an impact on tumor development was unknown. Here we report ZAP as a genuine tumor suppressor. Pan-caner analysis with TCGA data from 712 patients and large-scale immunohistochemistry in tissue microarrays from 1552 patients reveal that ZAP is prevalently downregulated, and associated with poor survival in liver, colon, and bladder cancer patients. Ectopic over-expression of ZAP inhibits the malignant phenotypes of colorectal tumor by cell cycle arrest. Using RNA immunoprecipitation and RNA decay assays, we demonstrate that ZAP directly and specifically binds to and degrades the transcript of TRAILR4, which in turn represses TRAILR4 expression and inhibits the aggressiveness of colorectal cancer cells. Furthermore, our CRISPR-engineered mice models show that loss-of-function of ZAP synergizes with APC-deficiency to drive malignant colorectal cancer in vivo. Overall, we identify a previously unknown function of the antiviral factor ZAP in colorectal tumorigenesis, linking intrinsic immunity to tumor pathogenetics.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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