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T cell inhibitory pathway

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https://www.readbyqxmd.com/read/29143824/pd-1-is-a-haploinsufficient-suppressor-of-t-cell-lymphomagenesis
#1
Tim Wartewig, Zsuzsanna Kurgyis, Selina Keppler, Konstanze Pechloff, Erik Hameister, Rupert Öllinger, Roman Maresch, Thorsten Buch, Katja Steiger, Christof Winter, Roland Rad, Jürgen Ruland
T cell non-Hodgkin lymphomas are a heterogeneous group of highly aggressive malignancies with poor clinical outcomes. T cell lymphomas originate from peripheral T cells and are frequently characterized by genetic gain-of-function variants in T cell receptor (TCR) signalling molecules. Although these oncogenic alterations are thought to drive TCR pathways to induce chronic proliferation and cell survival programmes, it remains unclear whether T cells contain tumour suppressors that can counteract these events...
November 15, 2017: Nature
https://www.readbyqxmd.com/read/29123965/ig-like-transcript-2-ilt2-suppresses-t-cell-function-in-chronic-lymphocytic-leukemia
#2
Mónica Villa-Álvarez, Seila Lorenzo-Herrero, Ana P Gonzalez-Rodriguez, Alejandro López-Soto, Angel R Payer, Esther Gonzalez-Garcia, Leticia Huergo-Zapico, Segundo Gonzalez
Chronic lymphocytic leukemia (CLL) is associated with a profound dysregulation of the immune system. Loss of T cell function is frequently caused in cancer by sustained signaling of inhibitory receptors. Here, we analyzed the role of the novel inhibitory receptor Ig-like transcript 2 (ILT2) in the pathogenesis of CLL. We observed that ILT2 expression was markedly reduced on leukemic cells, whereas it was increased on CD8 and CD4 T cells from CLL patients, particularly in those patients harboring chromosome 11q deletion, which includes the ATM gene...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/29118466/associations-of-functional-microrna-binding-site-polymorphisms-in-il23-th17-inflammatory-pathway-genes-with-gastric-cancer-risk
#3
Kaiyan Dong, Yajuan Xu, Qian Yang, Jiachen Shi, Jicheng Jiang, Yi Chen, Chunhua Song, Kaijuan Wang
IL23/Th17 axis acts as an inflammatory pathway in gastric carcinogenesis. MicroRNA- (miRNA-) binding site single-nucleotide polymorphisms (SNPs) of inflammatory genes may alter gastric cancer (GC) susceptibility. In this study, four miRNA binding site SNPs (rs3748067 of IL17A, rs887796, rs1468488 of IL17RA, and rs10889677 of IL23R) were genotyped from 500 patients and 500 controls. Unconditional logistic regression analyses and multifactor dimensionality reduction software were used to evaluate the relationships of SNPs with GC and gene-environment interactions, respectively...
2017: Mediators of Inflammation
https://www.readbyqxmd.com/read/29118090/complement-activation-via-a-c3a-receptor-pathway-alters-cd4-t-lymphocytes-and-mediates-lung-cancer-progression
#4
Jeff W Kwak, Jennifer Laskowski, Howard Y Li, Maria V McSharry, Trisha R Sippel, Bonnie L Bullock, Amber M Johnson, Joanna M Poczobutt, Alexander J Neuwelt, Stephen P Malkoski, Mary C Weiser-Evans, John Lambris, Eric T Clambey, Joshua M Thurman, Raphael A Nemenoff
The complement cascade is a part of the innate immune system which acts primarily to remove pathogens and injured cells. However, complement activation is also peculiarly associated with tumor progression. Here we report mechanistic insights into this association in multiple immunocompetent orthotopic models of lung cancer. After tumor engraftment, we observed systemic activation of the complement cascade as reflected by elevated levels of the key regulator C3a. Notably, growth of primary tumors and metastases was both strongly inhibited in C3-deficient mice (C3-/- mice), with tumors undetectable in many subjects...
November 8, 2017: Cancer Research
https://www.readbyqxmd.com/read/29118008/ctla-4-a-moving-target-in-immunotherapy
#5
Behzad Rowshanravan, Neil Halliday, David M Sansom
CD28 and CTLA-4 are members of a family of Immunoglobulin-related receptors that are responsible for various aspects of T cell immune regulation. The family includes CD28, CTLA-4 and ICOS as well as other proteins including PD-1, BTLA and TIGIT. These receptors have both stimulatory (CD28, ICOS) as well as inhibitory roles (CTLA-4, PD-1, BTLA and TIGIT) in T cell function. Increasingly these pathways are targeted as part of immune modulatory strategies to treat cancers, referred to generically as immune checkpoint blockade, and conversely to treat autoimmunity and CTLA-4 deficiency...
November 8, 2017: Blood
https://www.readbyqxmd.com/read/29117944/small-molecule-sigma1-modulator-induces-autophagic-degradation-of-pd-l1
#6
Christina M Maher, Jeffrey D Thomas, Derick A Haas, Charles G Longen, Halley M Oyer, Jane Y Tong, Felix J Kim
Emerging evidence suggests that Sigma1 (SIGMAR1, also known as sigma-1 receptor) is a unique ligand-regulated integral membrane scaffolding protein that contributes to cellular protein and lipid homeostasis. Previously, we demonstrated that some small molecule modulators of Sigma1 alter endoplasmic reticulum (ER) associated protein homeostasis pathways in cancer cells, including the unfolded protein response and autophagy. Programmed death-ligand 1 (PD-L1) is a type 1 integral membrane glycoprotein that is co-translationally inserted into the ER and is processed and transported through the secretory pathway...
November 8, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29106445/a-potent-hydroxamic-acid-based-small-molecule-inhibitor-a452-preferentially-inhibits-hdac6-activity-and-induces-cytotoxicity-toward-cancer-cells-irrespective-of-p53-status
#7
Hyun-Wook Ryu, Dong-Hee Shin, Dong Hoon Lee, Hye-Rim Won, So Hee Kwon
HDAC6-selective inhibitors are novel epigenetic anticancer agents. However, their precise mechanisms of action are incompletely understood. We investigated the anticancer mechanisms of the novel potent and selective HDAC6 inhibitor A452 compared with current clinically tested HDAC6 inhibitor ACY-1215. We demonstrate that A452 effectively inhibits the cell growth and viability of various cancer cell types, irrespective of p53 status. A452 induced apoptosis as evidenced by activated caspase 3 and PARP, increased Bak and Bax, and decreased Bcl-xL...
November 2, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/29096354/notch-signaling-pathway-dampens-tumor-infiltrating-cd8-t-cells-activity-in-patients-with-colorectal-carcinoma
#8
Weifeng Yu, Yanjun Wang, Peng Guo
CD8(+) T cells play critical role in controlling the metastasis and prognosis of cancer. Controversy remains as to the contribution of Notch signaling pathway in modulation of CD8(+) T cells activity and development of tumorigenesis. Thus, the aim of the current study was to investigate the immunoregulatory role of Notch signaling pathway to peripheral and tumor-infiltrating CD8(+) T cells in patients with colorectal carcinoma. A total of 46 patients with colorectal carcinoma and 20 health individuals were enrolled, and CD8(+) T cells were purified from both peripheral bloods and carcinoma specimens...
October 30, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29095944/mif-inhibition-interferes-with-the-inflammatory-and-t-cell-stimulatory-capacity-of-nod-macrophages-and-delays-autoimmune-diabetes-onset
#9
Hannelie Korf, Laura Breser, Jelter Van Hoeck, Janet Godoy, Dana P Cook, Benoit Stijlemans, Elien De Smidt, Carolien Moyson, João Paulo Monteiro Carvalho Mori Cunha, Virginia Rivero, Conny Gysemans, Chantal Mathieu
Macrophages contribute in the initiation and progression of insulitis during type 1 diabetes (T1D). However, the mechanisms governing their recruitment into the islets as well as the manner of retention and activation are incompletely understood. Here, we investigated a role for macrophage migration inhibitory factor (MIF) and its transmembrane receptor, CD74, in the progression of T1D. Our data indicated elevated MIF concentrations especially in long-standing T1D patients and mice. Additionally, NOD mice featured increased MIF gene expression and CD74+ leukocyte frequencies in the pancreas...
2017: PloS One
https://www.readbyqxmd.com/read/29095837/resveratrol-downregulates-inflammatory-pathway-activated-by-lymphotoxin-%C3%AE-tnf-%C3%AE-in-articular-chondrocytes-comparison-with-tnf-%C3%AE
#10
Constanze Buhrmann, Bastian Popper, Bharat B Aggarwal, Mehdi Shakibaei
While Lymphotoxin α (TNF-β), a product of lymphocytes, is known to play a pivotal role in inflammatory joint environment, resveratrol has been shown to possess anti-inflammatory and chondroprotective effects via activation of the histondeacetylase Sirt1. Whether TNF-β induction of inflammatory pathways in primary human chondrocytes (PCH) can be modulated by resveratrol, was investigated. Monolayer and alginate cultures of PCH were treated with TNF-β, anti-TNF-β, nicotinamide (NAM), antisense oligonucleotides against Sirt1 (Sirt1-ASO) and/or resveratrol and co-cultured with T-lymphocytes...
2017: PloS One
https://www.readbyqxmd.com/read/29083978/immunotherapy-regimens-for-metastatic-colorectal-carcinomas
#11
Babar Bashir, Adam E Snook
Metastatic colorectal cancer (mCRC) is a leading cause of cancer-related mortality with a 5-year overall survival rate of 13%. Despite recent advances in cancer immunotherapy, only the minority of CRC patients (<15%) with microsatellite instability can potentially benefit from immune checkpoint inhibitors, the only immunotherapy currently approved for mCRC. In that context, there is an unmet need to improve survival in mCRC. Our ever-increasing understanding of the immune system and its interactions with cancer has allowed development of multiple strategies to potentially improve outcomes in the majority of mCRC patients...
October 30, 2017: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/29075790/differential-contribution-of-tissue-factor-and-factor%C3%A2-xii-to-thrombin-generation-triggered-by-breast-and-pancreatic-cancer-cells
#12
Aurélie Rousseau, Annette K Larsen, Patrick Van Dreden, Michele Sabbah, Ismail Elalamy, Grigoris T Gerotziafas
Most cancer cells trigger thrombin generation (TG) to various extent. In the present study, we dissected the mechanisms responsible for the procoagulant activity of pancreatic adenocarcinoma cells (BXPC3), a highly thrombogenic cancer type, and breast cancer cells (MCF7), a less thombogenic tumor type. TG of normal plasma was assessed by the Thrombinoscope (CAT®) in the presence or absence of cancer cells. TG was also assessed in plasma depleted of clotting factors, in plasma spiked with tissue factor (TF) and/or procoagulant phospholipids, in plasma spiked with an anti-TF monoclonal antibody or with corn trypsin inhibitor (CTI)...
October 20, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/29061028/inhibitory-effects-of-panduratin-a-on-inflammation-and-osteoclastogenesis-induced-by-periodontitis-through-inhibition-of-mapk-pathways-in-vitro
#13
Haebom Kim, Mi-Bo Kim, Changhee Kim, Jae-Kwan Hwang
Periodontitis is an inflammatory disease caused by microbial lipopolysaccharide (LPS), destroying gingival tissues and alveolar bone in the periodontium. In the present study, we evaluated the anti-inflammatory and anti-osteoclastic effects of panduratin A, a chalcone compound isolated from Boesenbergia pandurata, in human gingival fibroblast-1 (HGF-1) and RAW 264.7 cells. Treatment of panduratin A to LPS-stimulated HGF-1 significantly reduced the expression of interleukin-1β, nuclear factor-kappa B (NF-κB), subsequently leading to inhibition of matrix metalloproteinase-2 (MMP-2), and MMP-8 compared with one in LPS control (**p < 0...
October 25, 2017: Journal of Microbiology and Biotechnology
https://www.readbyqxmd.com/read/29050819/relb-regulates-th17-differentiation-in-a-cell-intrinsic-manner
#14
Ievgen O Koliesnik, Nico Andreas, Vasily S Romanov, Sravya Sreekantapuram, Branislav Krljanac, Ronny Haenold, Falk Weih
The role of the alternative NF-κB pathway is mainly attributed to the lymphoid organ formation and blood cancer. However, its involvement in lymphocyte differentiation is not clearly defined. Recently, we have shown that uncontrolled activation of alternative NF-κB in mice lacking the NF-κB inhibitory protein p100 (p100(-/-) mice) hinders plasmablast proliferation and diminishes T cell independent responses. Here we show that hyperactivation of this pathway leads to a cell-intrinsic T cell defects. p100-deficient T helper cells displayed both an activation and a proliferation defect in vitro...
October 16, 2017: Immunobiology
https://www.readbyqxmd.com/read/29046346/t-cell-derived-cd70-delivers-an-immune-checkpoint-function-in-inflammatory-t-cell-responses
#15
Rachel E O'Neill, Wei Du, Hemn Mohammadpour, Emad Alqassim, Jingxin Qiu, George Chen, Philip L McCarthy, Kelvin P Lee, Xuefang Cao
The CD27-CD70 pathway is known to provide a costimulatory signal, with CD70 expressed on APCs and CD27 functions on T cells. Although CD70 is also expressed on activated T cells, it remains unclear how T cell-derived CD70 affects T cell function. Therefore, we have assessed the role of T cell-derived CD70 using adoptive-transfer models, including autoimmune inflammatory bowel disease and allogeneic graft-versus-host disease. Surprisingly, compared with wild-type T cells, CD70(-/-) T cells caused more severe inflammatory bowel disease and graft-versus-host disease and produced higher levels of inflammatory cytokines...
November 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29044189/tgf-%C3%AE-signalling-and-peg10-are-mutually-exclusive-and-inhibitory-in-chondrosarcoma-cells
#16
Naohiro Shinohara, Shingo Maeda, Yuhei Yahiro, Daisuke Sakuma, Kanehiro Matsuyama, Katsuyuki Imamura, Ichiro Kawamura, Takao Setoguchi, Yasuhiro Ishidou, Satoshi Nagano, Setsuro Komiya
Histological distinction between enchondroma and chondrosarcoma is difficult because of a lack of definitive biomarkers. Here, we found highly active transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signalling in human chondrosarcomas compared with enchondromas by immunohistochemistry of phosphorylated SMAD3 and SMAD1/5. In contrast, the chondrogenic master regulator SOX9 was dramatically down-regulated in grade 1 chondrosarcoma. Paternally expressed gene 10 (PEG10) was identified by microarray analysis as a gene overexpressed in chondrosarcoma SW1353 and Hs 819...
October 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29035366/cytoplasmic-p53-couples-oncogene-driven-glucose-metabolism-to-apoptosis-and-is-a-therapeutic-target-in-glioblastoma
#17
Wilson X Mai, Laura Gosa, Veerle W Daniels, Lisa Ta, Jonathan E Tsang, Brian Higgins, W Blake Gilmore, Nicholas A Bayley, Mitra Dehghan Harati, Jason T Lee, William H Yong, Harley I Kornblum, Steven J Bensinger, Paul S Mischel, P Nagesh Rao, Peter M Clark, Timothy F Cloughesy, Anthony Letai, David A Nathanson
Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for new therapeutic strategies in cancer. Here we show that although acute inhibition of EGFR-driven glucose metabolism induces only minimal cell death, it lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that after attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, targeting of EGFR-driven glucose metabolism in combination with pharmacological stabilization of p53 with the brain-penetrant small molecule idasanutlin resulted in synthetic lethality in orthotopic glioblastoma xenograft models...
November 2017: Nature Medicine
https://www.readbyqxmd.com/read/29027667/co-inhibitory-profile-and-cytotoxicity-of-cd57-pd-1-t-cells-in-end-stage-renal-disease-patients
#18
Rens Kraaijeveld, Gretchen N de Graav, Marjolein Dieterich, Nicolle H R Litjens, Dennis A Hesselink, Carla C Baan
Blockade of the CD80/86-CD28 pathway by belatacept after kidney transplantation is associated with an increased risk of rejection as compared with standard, calcineurin inhibitor (CNI)-based therapy. CD28(-) T-cells, which express CD57, are not susceptible to belatacept treatment. High number of CD4(+) CD57(+) PD-1(-) T-cells pre transplantation have been associated with a higher chance of rejection, although conflicting data have been reported. To investigate the working mechanism behind this possible higher chance of rejection, we studied the expression of co-inhibitory molecules (CD223, CD244 and PD-1), proliferative capacity and cytotoxic potential of FACS-sorted CD4(+) CD57(+) PD-1(-) and CD8(+) CD57(+) PD-1(-) T-cells, and their CD57(-) control populations, after allo antigen stimulation...
October 13, 2017: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/29021795/neuroendocrine-and-immune-responses-undertake-different-fates-following-tryptophan-or-methionine-dietary-treatment-tales-from-a-teleost-model
#19
Rita Azeredo, Marina Machado, António Afonso, Camino Fierro-Castro, Felipe E Reyes-López, Lluis Tort, Manuel Gesto, Marta Conde-Sieira, Jesús M Míguez, José L Soengas, Eva Kreuz, Sven Wuertz, Helena Peres, Aires Oliva-Teles, Benjamin Costas
Methionine and tryptophan appear to be fundamental in specific cellular pathways involved in the immune response mechanisms, including stimulation of T-regulatory cells by tryptophan metabolites or pro-inflammatory effects upon methionine supplementation. Thus, the aim of this study was to evaluate the immunomodulatory effect of these amino acids on the inflammatory and neuroendocrine responses in juveniles of European seabass, Dicentrarchus labrax. To achieve this, goal fish were fed for 14 days methionine and tryptophan-supplemented diets (MET and TRP, respectively, 2× dietary requirement level) or a control diet meeting the amino acids requirement levels (CTRL)...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28990585/the-diverse-functions-of-the-pd1-inhibitory-pathway
#20
REVIEW
Arlene H Sharpe, Kristen E Pauken
T cell activation is a highly regulated process involving peptide-MHC engagement of the T cell receptor and positive costimulatory signals. Upon activation, coinhibitory 'checkpoints', including programmed cell death protein 1 (PD1), become induced to regulate T cells. PD1 has an essential role in balancing protective immunity and immunopathology, homeostasis and tolerance. However, during responses to chronic pathogens and tumours, PD1 expression can limit protective immunity. Recently developed PD1 pathway inhibitors have revolutionized cancer treatment for some patients, but the majority of patients do not show complete responses, and adverse events have been noted...
October 9, 2017: Nature Reviews. Immunology
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