202 research outputs found
Whose Line is it Anyway? Examining the Media\u27s Coverage of Cabinet Secretaries\u27 Speeches
Previous research suggests that politicians and the press spin news stories through their remarks and coverage of remarks to their own benefit — but is this also true for remarks made by Cabinet Secretaries? For this project, I compared remarks given by DHS Secretaries with newspaper articles about those remarks. I find that Secretaries’ ability to shape issues is initially limited by the press; however, Secretaries succeed in conveying their message eventually. This is important because citizens should know what government officials are saying and what those statements mean; therefore, media coverage of those statements should be critical and accurate
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Identification of Small Molecule Inhibitors of 3-Phosphoglycerate Dehydrogenase to Target Serine Biosynthesis in Cancers
Cancer cells are known to reprogram their metabolism in order to promote growth and proliferation. The amino acid serine is utilized in a plethora of anabolic reactions and supports the synthesis of all three major macromolecular classes: proteins, lipids, and nucleic acids. Serine can either be synthesized de novo via the phosphoserine pathway or imported from the extracellular space via amino acid transporters. The gene encoding the enzyme 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the first committed step of the phosphoserine pathway, is focally amplified in human cancers suggesting that it is pro-tumorigenic. Cancer cell lines that harbor PHGDH amplifications, or over express PHGDH independently of amplification, are uniquely sensitive to genetic ablation of the pathway. In contrast, cancer cell lines that express little PHGDH, and instead rely on serine import, are resistant to genetic ablation of the pathway. Given these observations, we speculated that PHGDH might be a clinically interesting target in oncology and sought to develop small molecule inhibitors of PHGDH in order to provide tool compounds with which to study the biology of PHGDH and evaluate the efficacy of inhibiting serine synthesis in cancers.
In order to identify inhibitors of PHGDH an in vitro enzymatic assay was developed and libraries of drug-like small molecules were screened. Hit compounds were validated in biochemical assays to determine potency and selectivity for PHGDH. Selected compounds were tested on cells for their ability to inhibit de novo serine synthesis and one lead, CBR-5884, was identified. CBR-5884 was selectively toxic to PHGDH amplified or overexpressing cancer cells but had no effect on cells that express little PHGDH. Mechanistically, CBR-5884 was found to be a non-competitive inhibitor that showed a time dependent onset of inhibition and disrupted the oligomerization state of PHGDH. These results provide a proof-of-concept for targeting PHGDH and suggest that inhibiting PHGDH in cancers addicted to serine synthesis is a potentially viable targeted therapy option.Medical Science
Inflammation and the coagulation system in tuberculosis: Tissue Factor leads the dance
Mycobacterium tuberculosis, the causative agent of tuberculosis, drives the formation of granulomas, structures in which both immune cells and the bacterial pathogen cohabit. The most abundant cells in granulomas are macrophages, which contribute as both cells with bactericidal activity and as targets for M. tuberculosis infection and proliferation during the entire course of infection. The mechanisms and factors involved in the regulation and control of macrophage microenvironment-specific polarization and plasticity are not well understood, as some granulomas are able to control bacteria growth and others fail to do so, permitting bacterial spread. In this issue of the European Journal of Immunology, Venkatasubramanian et al. [Eur. J. Immunol. 2016. 46: 464-479] show that mice lacking the tissue factor gene in myeloid cells have augmented M. tuberculosis growth and increased inflammation in the lungs. This suggests that tissue factor, an initiator of coagulation, is important for the generation of fibrin, which supports granuloma formation. This article demonstrates for the first time the involvement of tissue factor in inducing effective immunity against M. tuberculosis, and sheds new lights on the complex interplay between host inflammatory response, the coagulation system, and the control of M. tuberculosis infection
One-carbon metabolism in cancer
Cells require one-carbon units for nucleotide synthesis, methylation and reductive metabolism, and these pathways support the high proliferative rate of cancer cells. As such, anti-folates, drugs that target one-carbon metabolism, have long been used in the treatment of cancer. Amino acids, such as serine are a major one-carbon source, and cancer cells are particularly susceptible to deprivation of one-carbon units by serine restriction or inhibition of de novo serine synthesis. Recent work has also begun to decipher the specific pathways and sub-cellular compartments that are important for one-carbon metabolism in cancer cells. In this review we summarise the historical understanding of one-carbon metabolism in cancer, describe the recent findings regarding the generation and usage of one-carbon units and explore possible future therapeutics that could exploit the dependency of cancer cells on one-carbon metabolism
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Glutamine supports pancreatic cancer growth through a Kras-regulated metabolic pathway
Cancer cells exhibit metabolic dependencies that distinguish them from their normal counterparts1. Among these addictions is an increased utilization of the amino acid glutamine (Gln) to fuel anabolic processes2. Indeed, the spectrum of Gln-dependent tumors and the mechanisms whereby Gln supports cancer metabolism remain areas of active investigation. Here we report the identification of a non-canonical pathway of Gln utilization in human pancreatic ductal adenocarcinoma (PDAC) cells that is required for tumor growth. While most cells utilize glutamate dehydrogenase (GLUD1) to convert Gln-derived glutamate (Glu) into α-ketoglutarate in the mitochondria to fuel the tricarboxylic acid (TCA) cycle, PDAC relies on a distinct pathway to fuel the TCA cycle such that Gln-derived aspartate is transported into the cytoplasm where it can be converted into oxaloacetate (OAA) by aspartate transaminase (GOT1). Subsequently, this OAA is converted into malate and then pyruvate, ostensibly increasing the NADPH/NADP+ ratio which can potentially maintain the cellular redox state. Importantly, PDAC cells are strongly dependent on this series of reactions, as Gln deprivation or genetic inhibition of any enzyme in this pathway leads to an increase in reactive oxygen species and a reduction in reduced glutathione. Moreover, knockdown of any component enzyme in this series of reactions also results in a pronounced suppression of PDAC growth in vitro and in vivo. Furthermore, we establish that the reprogramming of Gln metabolism is mediated by oncogenic Kras, the signature genetic alteration in PDAC, via the transcriptional upregulation and repression of key metabolic enzymes in this pathway. The essentiality of this pathway in PDAC and the fact that it is dispensable in normal cells may provide novel therapeutic approaches to treat these refractory tumors
Simultaneous Activation of Complement and Coagulation by MBL-Associated Serine Protease 2
The complement system is an important immune mechanism mediating both recognition and elimination of foreign bodies. The lectin pathway is one pathway of three by which the complement system is activated. The characteristic protease of this pathway is Mannan-binding lectin (MBL)-associated serine protease 2 (MASP2), which cleaves complement proteins C2 and C4. We present a novel and alternative role of MASP2 in the innate immune system. We have shown that MASP2 is capable of promoting fibrinogen turnover by cleavage of prothrombin, generating thrombin. By using a truncated active form of MASP2 as well as full-length MASP2 in complex with MBL, we have shown that the thrombin generated is active and can cleave both factor XIII and fibrinogen, forming cross-linked fibrin. To explore the biological significance of these findings we showed that fibrin was covalently bound on a bacterial surface to which MBL/MASP2 complexes were bound. These findings suggest that, as has been proposed for invertebrates, limited clotting may contribute to the innate immune response
Fibrin Facilitates Both Innate and T Cell-Mediated Defense against Yersinia pestis
The gram-negative bacterium Yersinia pestis causes plague, a rapidly progressing and often fatal disease. The formation of fibrin at sites of Y. pestis infection supports innate host defense against plague, perhaps by providing a non-diffusible spatial cue that promotes the accumulation of inflammatory cells expressing fibrin-binding integrins. This report demonstrates that fibrin is an essential component of T cell-mediated defense against plague but can be dispensable for antibody-mediated defense. Genetic or pharmacologic depletion of fibrin abrogated innate and T cell-mediated defense in mice challenged intranasally with Y. pestis. The fibrin-deficient mice displayed reduced survival, increased bacterial burden, and exacerbated hemorrhagic pathology. They also showed fewer neutrophils within infected lung tissue and reduced neutrophil viability at sites of liver infection. Depletion of neutrophils from wild type mice weakened T cell-mediated defense against plague. The data suggest that T cells combat plague in conjunction with neutrophils, which require help from fibrin in order to withstand Y. pestis encounters and effectively clear bacteria
TAp73 promotes anti-senescence-anabolism not proliferation
Medical Research Council, United Kingdom, by MIUR, MinSan/IDI-IRCCS (RF73, RF57), by the Italian Association for Cancer Research (AIRC) investigator grants awarded to G.M
Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis
Most tumors exhibit increased glucose metabolism to lactate, however, the extent to which glucose-derived metabolic fluxes are used for alternative processes is poorly understood [1, 2]. Using a metabolomics approach with isotope labeling, we found that in some cancer cells a relatively large amount of glycolytic carbon is diverted into serine and glycine metabolism through phosphoglycerate dehydrogenase (PHGDH). An analysis of human cancers showed that PHGDH is recurrently amplified in a genomic region of focal copy number gain most commonly found in melanoma. Decreasing PHGDH expression impaired proliferation in amplified cell lines. Increased expression was also associated with breast cancer subtypes, and ectopic expression of PHGDH in mammary epithelial cells disrupted acinar morphogenesis and induced other phenotypic alterations that may predispose cells to transformation. Our findings show that the diversion of glycolytic flux into a specific alternate pathway can be selected during tumor development and may contribute to the pathogenesis of human cancer.National Institutes of Health (U.S.)National Cancer Institute (U.S.)Smith Family FoundationDamon Runyon Cancer Research FoundationBurroughs Wellcome Fun
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