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https://www.readbyqxmd.com/read/28319049/resisting-fatal-attraction-a-glioma-oncometabolite-prevents-cd8-t-cell-recruitment
#1
Liliana E Lucca, David A Hafler
Immunotherapy has emerged as a potent approach for treating aggressive cancers, such as non-small-cell lung tumors and metastatic melanoma. Clinical trials are now in progress for patients with malignant gliomas; however, a better understanding of how these tumors escape immune surveillance is required to enhance antitumor immune responses. With gliomas, the recruitment of CD8+ T cells to the tumor is impaired, in part preventing containment or elimination of the tumor. In this issue of the JCI, Kohanbash and colleagues present an elegant dissection of how gliomas exploit an enzymatic activity acquired through a common mutation to abrogate the migration of CD8+ T cells to the tumor...
March 20, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28319047/isocitrate-dehydrogenase-mutations-suppress-stat1-and-cd8-t-cell-accumulation-in-gliomas
#2
Gary Kohanbash, Diego A Carrera, Shruti Shrivastav, Brian J Ahn, Naznin Jahan, Tali Mazor, Zinal S Chheda, Kira M Downey, Payal B Watchmaker, Casey Beppler, Rolf Warta, Nduka A Amankulor, Christel Herold-Mende, Joseph F Costello, Hideho Okada
Mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 are among the first genetic alterations observed during the development of lower-grade glioma (LGG). LGG-associated IDH mutations confer gain-of-function activity by converting α-ketoglutarate to the oncometabolite R-2-hydroxyglutarate (2HG). Clinical samples and gene expression data from The Cancer Genome Atlas (TCGA) demonstrate reduced expression of cytotoxic T lymphocyte-associated genes and IFN-γ-inducible chemokines, including CXCL10, in IDH-mutated (IDH-MUT) tumors compared with IDH-WT tumors...
March 20, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28318643/cxcl10-alters-the-tumour-immune-microenvironment-and-disease-progression-in-a-syngeneic-murine-model-of-high-grade-serous-ovarian-cancer
#3
Katrina K Au, Nichole Peterson, Peter Truesdell, Gillian Reid-Schachter, Kasra Khalaj, Runhan Ren, Julie-Ann Francis, Charles H Graham, Andrew W Craig, Madhuri Koti
OBJECTIVE: We recently established that high STAT1 expression and associated T helper type I tumour immune microenvironment (TME) are prognostic and chemotherapy response predictive biomarkers in high-grade serous ovarian cancer (HGSC). STAT1 induced chemokine CXCL10 is key to the recruitment of lymphocytes in the TME and is significantly highly expressed in the tumours from patients with longer survival. In the current study we therefore aimed to elucidate the role CXCL10 in disease progression and tumour immune transcriptomic alterations using the ID8 syngeneic murine model of HGSC...
March 16, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28316372/dyslipidemia-rather-than-type-2-diabetes-mellitus-or-chronic-periodontitis-affects-the-systemic-expression-of-pro-and-anti-inflammatory-genes
#4
Rafael Nepomuceno, Bárbara Scoralick Villela, Sâmia Cruz Tfaile Corbi, Alliny De Souza Bastos, Raquel Alves Dos Santos, Catarina Satie Takahashi, Silvana Regina Perez Orrico, Raquel Mantuaneli Scarel-Caminaga
A high percentage of type 2 diabetes mellitus (T2D) patients are also affected by dyslipidemia and chronic periodontitis (CP), but no studies have determined the gene expression in patients that are simultaneously affected by all three diseases. We investigated the systemic expression of immune-related genes in T2D, dyslipidemia, and CP patients. One hundred and fifty patients were separated into five groups containing 30 individuals each: (G1) poorly controlled T2D with dyslipidemia and CP; (G2) well-controlled T2D with dyslipidemia and CP; (G3) normoglycemic individuals with dyslipidemia and CP; (G4) healthy individuals with CP; (G5) systemic and periodontally healthy individuals...
2017: Mediators of Inflammation
https://www.readbyqxmd.com/read/28304404/interactions-between-th1-cells-and-tregs-affect-regulation-of-hepatic-fibrosis-in-biliary-atresia-through-the-ifn-%C3%AE-stat1-pathway
#5
Jie Wen, Ying Zhou, Jun Wang, Jie Chen, Wenbo Yan, Jin Wu, Junkai Yan, Kejun Zhou, Yongtao Xiao, Yang Wang, Qiang Xia, Wei Cai
Regulatory T cells (Tregs) and CD4(+) T helper (Th) cells have important roles in bile duct injury of biliary atresia (BA). However, their impacts on liver fibrosis are undefined. Between 2013 and 2016, 146 patients with various stages of BA were enrolled in this study. Peripheral blood, liver biopsy and lymph node samples were collected. Flow cytometry, magnetic cell sorting and immunostaining were used to characterize lymphocytes from BA patients. Deficiency of Tregs was observed along with increased Th1, Th2 and Th17 frequencies in the peripheral blood and livers of BA patients...
March 17, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28303603/human-il-6-il-17-il-1%C3%AE-and-tnf-%C3%AE-differently-regulate-the-expression-of-pro-inflammatory-related-genes-tissue-factor-and-swine-leukocyte-antigen-class-i-in-porcine-aortic-endothelial-cells
#6
Hanchao Gao, Lu Liu, Yanli Zhao, Hidetaka Hara, Pengfei Chen, Jia Xu, Jia Tang, Ling Wei, Zesong Li, David K C Cooper, Zhiming Cai, Lisha Mou
BACKGROUND: Pro-inflammatory cytokines play important pathological effects in various diseases and allotransplantation; however, their pathological role in xenotransplantation remains elusive. In pig-to-human cell or organ transplantation, whether porcine cells or organs are activated by human cytokines or not as an important question needs to be investigated. METHODS: We investigated the effect of human IL-6, IFN-γ, IL-17, IL-1β, and TNF-α in xenotransplantation using several in vitro models and porcine aortic endothelial cells (PAECs) as target cells...
March 17, 2017: Xenotransplantation
https://www.readbyqxmd.com/read/28302507/design-and-synthesis-of-selective-cdk8-19-dual-inhibitors-discovery-of-4-5-dihydrothieno-3-4-3-4-benzo-1-2-d-isothiazole-derivatives
#7
Koji Ono, Hiroshi Banno, Masanori Okaniwa, Takaharu Hirayama, Naoki Iwamura, Yukiko Hikichi, Saomi Murai, Maki Hasegawa, Yuka Hasegawa, Kazuko Yonemori, Akito Hata, Kazunobu Aoyama, Douglas R Cary
To develop a novel series of CDK8/19 dual inhibitors, we employed structure-based drug design using docking models based on a library compound, 4,5-dihydroimidazolo[3',4':3,4]benzo[1,2-d]isothiazole 16 bound to CDK8. We designed various [5,6,5]-fused tricyclic scaffolds bearing a carboxamide group to maintain predicted interactions with the backbone CO and NH of Ala100 in the CDK8 kinase hinge region. We found that 4,5-dihydrothieno[3',4':3,4]benzo[1,2-d]isothiazole derivative 29a showed particularly potent enzymatic inhibitory activity in both CDK8/19 (CDK8 IC50: 0...
February 22, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28300845/digoxin-induced-retinal-degeneration-depends-on-rhodopsin
#8
Britta Landfried, Marijana Samardzija, Maya Barben, Christian Schori, Katrin Klee, Federica Storti, Christian Grimm
Na,K-ATPases are energy consuming ion pumps that are required for maintaining ion homeostasis in most cells. In the retina, Na,K-ATPases are especially important to sustain the dark current in photoreceptor cells needed for rapid hyperpolarization of rods and cones in light. Cardiac glycosides like digoxin inhibit the activity of Na,K-ATPases by targeting their catalytic alpha subunits. This leads to a disturbed ion balance, which can affect cellular function and survival. Here we show that the treatment of wild-type mice with digoxin leads to severe retinal degeneration and loss of vision...
March 16, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28295835/type-i-interferons-modulate-methotrexate-resistance-in-gestational-trophoblastic-neoplasia
#9
Kevin M Elias, Richard A Harvey, Kathleen T Hasselblatt, Michael J Seckl, Ross S Berkowitz
PROBLEM: Resistance to methotrexate is a leading clinical problem in gestational trophoblastic neoplasia (GTN), but there are limited laboratory models for this condition. METHOD OF STUDY: We created isogenic trophoblastic cell lines resistant to methotrexate and compared these to the parent cell lines using gene expression microarrays and qRT-PCR followed by mechanistic studies using recombinant cytokines, pathway inhibitors, and patient sera. RESULTS: Gene expression microarrays and focused analysis by qRT-PCR revealed methotrexate led to type I interferon upregulation, in particular interferon alpha 2 (IFNA2), and methotrexate resistance was associated with chronic low level increases in type I interferon expression...
March 14, 2017: American Journal of Reproductive Immunology: AJRI
https://www.readbyqxmd.com/read/28295457/hepatic-ifit3-predicts-interferon-%C3%AE-therapeutic-response-in-patients-of-hepatocellular-carcinoma
#10
Yingyun Yang, Ye Zhou, Jin Hou, Chunmei Bai, Zhenyang Li, Jia Fan, Irene O L Ng, Weiping Zhou, Huichuan Sun, Qiongzhu Dong, Joyce M F Lee, Chung-Mau Lo, Kwan Man, Yun Yang, Nan Li, Guoshan Ding, Yizhi Yu, Xuetao Cao
Adjuvant interferon-α (IFN-α) therapy is used to control certain types of cancer in clinics. For hepatocellular carcinoma (HCC), IFN-α therapy is effective in only a subgroup of HCC patients, therefore identifying biomarkers to predict the response to IFN-α therapy is of high significance and clinical utility. As the induced IFN-stimulated genes (ISGs) expression following IFN-α treatment plays pivotal roles in IFN-α effects, we screened ISGs expression in HCC tissues and found several ISGs were significantly decreased in HCC...
March 13, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28292965/repurposed-jak1-jak2-inhibitor-reverses-established-autoimmune-insulitis-in-non-obese-diabetic-mice
#11
Prerak M Trivedi, Kate L Graham, Nicholas A Scott, Misty R Jenkins, Suktilang Majaw, Robyn M Sutherland, Stacey Fynch, Andrew M Lew, Christopher J Burns, Balasubramanian Krishnamurthy, Thomas C Brodnicki, Stuart I Mannering, Thomas W Kay, Helen E Thomas
Recent advances in immunotherapeutics have not yet changed the routine management of autoimmune type 1 diabetes. There is an opportunity to repurpose therapeutics from other diseases to type 1 diabetes, especially when there is evidence for overlapping mechanisms. JAK1/JAK2 inhibitors are in development or clinical use for indications including rheumatoid arthritis. There is good evidence for activation of the JAK1/JAK2 and STAT1 pathway in human type 1 diabetes and in mouse models, especially in beta cells...
March 14, 2017: Diabetes
https://www.readbyqxmd.com/read/28289734/regulatory-mechanisms-of-hsp90
#12
Chrisostomos Prodromou
The ability of Hsp90 to activate a disparate clientele implicates this chaperone in diverse biological processes. To accommodate such varied roles, Hsp90 requires a variety of regulatory mechanisms that are coordinated in order to modulate its activity appropriately. Amongst these, the master-regulator heat shock factor 1 (HSF1) is critically important in upregulating Hsp90 during stress, but is also responsible, through interaction with specific transcription factors (such as STAT1 and Strap/p300) for the integration of a variety of biological signals that ultimately modulate Hsp90 expression...
January 30, 2017: Biochemistry & Molecular Biology Journal
https://www.readbyqxmd.com/read/28289093/a-hot-spot-on-interferon-alpha-beta-receptor-subunit-1-ifnar1-underpins-its-interaction-with-interferon-%C3%AE-and-dictates-signaling
#13
Nicole A de Weerd, Antony Y Matthews, Phillip R Pattie, Nollaig M Bourke, San S Lim, Julian P Vivian, Jamie Rossjohn, Paul J Hertzog
The interaction of IFN-β with its receptor IFNAR1 is vital for host-protective anti-viral and anti-proliferative responses, but signaling via this interaction can be detrimental if dysregulated. While it is established that IFNAR1 is an essential component of the IFNAR signaling complex, the key residues underpinning the IFN-β-IFNAR1 interaction are unknown. Guided by the crystal structure of the IFN-β-IFNAR1 complex, we used truncation variants and site directed mutagenesis to investigate domains and residues enabling complexation of IFN-β to IFNAR1...
March 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28288457/interferon-dependent-induction-of-clr-b-during-mouse-cytomegalovirus-infection-protects-bystander-cells-from-natural-killer-cells-via-nkr-p1b-mediated-inhibition
#14
Christina L Kirkham, Oscar A Aguilar, Tao Yu, Miho Tanaka, Aruz Mesci, Kuan-Lun Chu, Jason H Fine, Karen L Mossman, Rod Bremner, David S J Allan, James R Carlyle
Natural killer (NK) cells are innate lymphocytes that aid in self-nonself discrimination by recognizing cells undergoing pathological alterations. The NKR-P1B inhibitory receptor recognizes Clr-b, a self-encoded marker of cell health downregulated during viral infection. Here, we show that Clr-b loss during mouse cytomegalovirus (MCMV) infection is predicated by a loss of Clr-b (Clec2d) promoter activity and nascent transcripts, driven in part by MCMV ie3 (M122) activity. In contrast, uninfected bystander cells near MCMV-infected fibroblasts reciprocally upregulate Clr-b expression due to paracrine type-I interferon (IFN) signaling...
March 14, 2017: Journal of Innate Immunity
https://www.readbyqxmd.com/read/28288101/opposing-macrophage-polarization-programs-show-extensive-epigenomic-and-transcriptional-cross-talk
#15
Viviana Piccolo, Alessia Curina, Marco Genua, Serena Ghisletti, Marta Simonatto, Arianna Sabò, Bruno Amati, Renato Ostuni, Gioacchino Natoli
Stimulation of macrophages with interferon-γ (IFN-γ) and interleukin 4 (IL-4) triggers distinct and opposing activation programs. During mixed infections or cancer, macrophages are often exposed to both cytokines, but how these two programs influence each other remains unclear. We found that IFN-γ and IL-4 mutually inhibited the epigenomic and transcriptional changes induced by each cytokine alone. Computational and functional analyses revealed the genomic bases for gene-specific cross-repression. For instance, while binding motifs for the transcription factors STAT1 and IRF1 were associated with robust and IL-4-resistant responses to IFN-γ, their coexistence with binding sites for auxiliary transcription factors such as AP-1 generated vulnerability to IL-4-mediated inhibition...
March 13, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28286378/iron-reduces-m1-macrophage-polarization-in-raw264-7-macrophages-associated-with-inhibition-of-stat1
#16
Zhen-Shun Gan, Qian-Qian Wang, Jia-Hui Li, Xu-Liang Wang, Yi-Zhen Wang, Hua-Hua Du
Iron metabolism in inflammation has been mostly characterized in macrophages exposed to pathogens or inflammatory conditions. The aim of this study is to investigate the cross-regulatory interactions between M1 macrophage polarization and iron metabolism. Firstly, we characterized the transcription of genes related to iron homeostasis in M1 RAW264.7 macrophages stimulated by IFN-γ. The molecular signature of M1 macrophages showed high levels of iron storage (ferritin), a low level of iron export (ferroportin), and changes of iron regulators (hepcidin and transferrin receptors), which favour iron sequestration in the reticuloendothelial system and are benefit for inflammatory disorders...
2017: Mediators of Inflammation
https://www.readbyqxmd.com/read/28282916/blockage-of-glyoxalase-i-inhibits-colorectal-tumorigenesis-and-tumor-growth-via-upregulation-of-stat1-p53-and-bax-and-downregulation-of-c-myc-and-bcl-2
#17
Yuan Chen, Lei Fang, Jiali Zhang, Gefei Li, Mengni Ma, Changxi Li, Jianxin Lyu, Qing H Meng
GlyoxalaseI (GLOI) is an enzyme that catalyzes methylglyoxal metabolism. Overexpression of GLOI has been documented in numerous tumor tissues, including colorectal cancer (CRC). The antitumor effects of GLOI depletion have been demonstrated in some types of cancer, but its role in CRC and the mechanisms underlying this activity remain largely unknown. Our purpose was to investigate the antitumor effects of depleted GLOI on CRC in vitro and in vivo. RNA interference was used to deplete GLOI activity in four CRC cell lines...
March 9, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28282567/partial-dysfunction-of-stat1-profoundly-reduces-host-resistance-to-flaviviral-infection
#18
Maximilian Larena, Mario Lobigs
The genetic basis for a dramatically increased virus susceptibility phenotype of MHC-II knockout mice acquired during routine maintenance of the mouse strain was determined. Segregation of the susceptibility allele from the defective MHC-II locus combined with sequence capture and sequencing showed that a Y37L substitution in STAT1 accounted for high flavivirus susceptibility of a newly derived mouse strain, designated Tuara. Interestingly, the mutation in STAT1 gene gave only partial inactivation of the type I interferon antiviral pathway...
March 7, 2017: Virology
https://www.readbyqxmd.com/read/28276456/principal-components-analysis-based-unsupervised-feature-extraction-applied-to-gene-expression-analysis-of-blood-from-dengue-haemorrhagic-fever-patients
#19
Y-H Taguchi
Dengue haemorrhagic fever (DHF) sometimes occurs after recovery from the disease caused by Dengue virus (DENV), and is often fatal. However, the mechanism of DHF has not been determined, possibly because no suitable methodologies are available to analyse this disease. Therefore, more innovative methods are required to analyse the gene expression profiles of DENV-infected patients. Principal components analysis (PCA)-based unsupervised feature extraction (FE) was applied to the gene expression profiles of DENV-infected patients, and an integrated analysis of two independent data sets identified 46 genes as critical for DHF progression...
March 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28276425/the-shc1-adaptor-simultaneously-balances-stat1-and-stat3-activity-to-promote-breast-cancer-immune-suppression
#20
Ryuhjin Ahn, Valérie Sabourin, Alicia M Bolt, Steven Hébert, Stephanie Totten, Nicolas De Jay, Maria Carolina Festa, Yoon Kow Young, Young Kyuen Im, Tony Pawson, Antonis E Koromilas, William J Muller, Koren K Mann, Claudia L Kleinman, Josie Ursini-Siegel
Tyrosine kinase signalling within cancer cells is central to the establishment of an immunosuppressive microenvironment. Although tyrosine kinase inhibitors act, in part, to augment adaptive immunity, the increased heterogeneity and functional redundancy of the tyrosine kinome is a hurdle to achieving durable responses to immunotherapies. We previously identified the Shc1 (ShcA) scaffold, a central regulator of tyrosine kinase signalling, as essential for promoting breast cancer immune suppression. Herein we show that the ShcA pathway simultaneously activates STAT3 immunosuppressive signals and impairs STAT1-driven immune surveillance in breast cancer cells...
March 9, 2017: Nature Communications
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