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https://www.readbyqxmd.com/read/29340620/delivery-of-tapasin-modified-ctl-epitope-peptide-via-cytoplasmic-transduction-peptide-induces-ctls-by-jak-stat-signaling-pathway-in-vivo
#1
Shanshan Wu, Xiaohua Chen, Yuyan Tang, Yi Zhang, Dan Li, Jie Chen, Jieling Wang, Zhenghao Tang, Guoqing Zang, Yongsheng Yu
Hepatitis B virus (HBV)-specific cytotoxic T lymphocytes (CTLs) play a vital role in viral control and clearance. Recent studies have elucidated that Tapasin, an endoplasmic reticulum chaperone, is a well-known molecule that appears to be essential in peptide-loading process. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway plays an important role in immune response regulation and cytokines secretion. We have previously verified that fusion protein CTP-HBcAg18-27-Tapasin could facilitate the maturation of bone marrow derived dendritic cells and enhance specific CTLs responses in vitro, which might be associated with the activation of JAK/STAT signaling pathway...
January 11, 2018: Acta Biochimica et Biophysica Sinica
https://www.readbyqxmd.com/read/29340061/analysis-of-the-mutational-landscape-of-classic-hodgkin-lymphoma-identifies-disease-heterogeneity-and-potential-therapeutic-targets
#2
Elena Mata, Antonio Díaz-López, Ana M Martín-Moreno, Margarita Sánchez-Beato, Ignacio Varela, María J Mestre, Carlos Santonja, Fernando Burgos, Javier Menárguez, Mónica Estévez, Mariano Provencio, Beatriz Sánchez-Espiridión, Eva Díaz, Carlos Montalbán, Miguel A Piris, Juan F García
Defining the mutational landscape of classic Hodgkin lymphoma is still a major research goal. New targeted next-generation sequencing (NGS) techniques may identify pathogenic mechanisms and new therapeutic opportunities related to this disease. We describe the mutational profile of a series of 57 cHL cases, enriched in Hodgkin and Reed-Sternberg (HRS) cells. Overall, the results confirm the presence of strong genomic heterogeneity. However, several variants were consistently detected in genes related to relevant signaling pathways, such as GM-CSF/IL-3, CBP/EP300, JAK/STAT, NF-kappaB, and numerous variants of genes affecting the B-cell receptor (BCR) pathway, such as BTK, CARD11, BCL10, among others...
December 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29330929/adipocytes-affect-castration-resistant-prostate-cancer-cells-to-develop-the-resistance-to-cytotoxic-action-of-nk-cells-with-alterations-of-pd-l1-nkg2d-ligand-levels-in-tumor-cells
#3
Lijun Xu, Mingjing Shen, Xiaodong Chen, Rongying Zhu, Dong-Rong Yang, Ying Tsai, Peter C Keng, Yuhchyau Chen, Soo Ok Lee
BACKGROUND: Obesity affects prostate cancer (PCa) progression, and the periprostatic adipose tissue adjacent to the prostate is considered a driving force of disease progression. Adipocytes are the main cell population in adipose tissues and their paracrine role contributes to PCa progression, however its implication in modulating immune reactions remains largely unknown. We investigated the adipocyte role in controlling the susceptibility of castration-resistant PCa (CRPC) cells to the cytotoxic action of natural killer (NK) cells...
January 12, 2018: Prostate
https://www.readbyqxmd.com/read/29330478/interaction-of-suppressor-of-cytokine-signalling-3-with-cavin-1-links-socs3-function-and-cavin-1-stability
#4
Jamie J L Williams, Nasser Alotaiq, William Mullen, Richard Burchmore, Libin Liu, George S Baillie, Fred Schaper, Paul F Pilch, Timothy M Palmer
Effective suppression of JAK-STAT signalling by the inducible inhibitor "suppressor of cytokine signalling 3" (SOCS3) is essential for limiting signalling from cytokine receptors. Here we show that cavin-1, a component of caveolae, is a functionally significant SOCS3-interacting protein. Biochemical and confocal imaging demonstrate that SOCS3 localisation to the plasma membrane requires cavin-1. SOCS3 is also critical for cavin-1 stabilisation, such that deletion of SOCS3 reduces the expression of cavin-1 and caveolin-1 proteins, thereby reducing caveola abundance in endothelial cells...
January 12, 2018: Nature Communications
https://www.readbyqxmd.com/read/29322424/expression-and-purification-of-jak1-and-socs1-for-structural-and-biochemical-studies
#5
Nicholas P D Liau, Jeffrey J Babon
Interferon gamma (IFNγ) is a potent inflammatory and immune cytokine. IFNγ signals via the interferon gamma receptor (IFNGR), which is constitutively bound to Janus Kinase (JAK) 1 and JAK2 via its intracellular domain. These two JAK proteins then initiate the inflammatory signaling cascade. The most potent inhibitor of IFNγ signaling is Suppressor of Cytokine Signaling 1 (SOCS1). SOCS1 negatively regulates IFNγ signaling pathway (and other pathways) by directly inhibiting JAKs. Here, we describe a protocol for the recombinant production and purification of the JAK1 kinase domain and its inhibitor SOCS1, for structural and biochemical studies...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29317823/european-perspective-on-the-management-of-rheumatoid-arthritis-clinical-utility-of-tofacitinib
#6
REVIEW
Paweł Kawalec, Katarzyna Śladowska, Iwona Malinowska-Lipień, Tomasz Brzostek, Maria Kózka
Xeljanz® (tofacitinib) is an oral small-molecule inhibitor that reversibly inhibits Janus-activated kinase (JAK)-dependent cytokine signaling, thus reducing inflammation. As a result of these mechanisms, effects on the immune system such as a moderate decrease in the total lymphocyte count, a dose-dependent decrease in natural killer (NK) cell count, and an increase in B-cell count have been observed. Therefore, tofacitinib provides an innovative approach to modulating the immune and inflammatory responses in patients with rheumatoid arthritis (RA), which is especially important in individuals who do not respond to tumor necrosis factor inhibitors or show a loss of response over time...
2018: Therapeutics and Clinical Risk Management
https://www.readbyqxmd.com/read/29311136/pharmacokinetics-and-disposition-of-momelotinib-revealed-a-disproportionate-human-metabolite-%C3%A2-resolution-for-clinical-development
#7
Jim Zheng, Yan Xin, Jingyu Zhang, Raju Subramanian, Bernard P Murray, J Andrew Whitney, Matthew R Warr, John Ling, Lisa Moorehead, Ellen Kwan, Jeffrey Hemenway, Bill J Smith, Jeffrey A Silverman
Momelotinib (MMB) is a small molecule inhibitor of Janus kinase (JAK)1/2 and of activin A receptor type 1 (ACVR1), in clinical development for the treatment of myeloproliferative neoplasms. The pharmacokinetics and disposition of [14C]MMB were characterized in a single-dose, human mass balance study. Metabolism and the pharmacologic activity of key metabolites were elucidated in multiple in vitro and in vivo experiments. MMB was rapidly absorbed following oral dosing with approximately 97% of the radioactivity recovered, primarily in feces with urine as a secondary route...
January 8, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29305625/ifn-%C3%AE-induces-a-preferential-long-lasting-expression-of-mhc-class-i-in-human-pancreatic-beta-cells
#8
Alexandra Coomans de Brachène, Reinaldo S Dos Santos, Laura Marroqui, Maikel L Colli, Lorella Marselli, Raghavendra G Mirmira, Piero Marchetti, Decio L Eizirik
AIMS/HYPOTHESIS: IFN-α, a cytokine expressed in human islets from individuals affected by type 1 diabetes, plays a key role in the pathogenesis of diabetes by upregulating inflammation, endoplasmic reticulum (ER) stress and MHC class I overexpression, three hallmarks of islet histology in early type 1 diabetes. We tested whether expression of these mediators of beta cell loss is reversible upon IFN-α withdrawal or IFN-α pathway inhibition. METHODS: IFN-α-induced MHC class I overexpression, ER stress and inflammation were evaluated by flow cytometry, immunofluorescence and real-time PCR in human EndoC-βH1 cells or human islets exposed to IFN-α with or without the presence of Janus kinase (JAK) inhibitors...
January 5, 2018: Diabetologia
https://www.readbyqxmd.com/read/29301960/genomic-correlates-of-response-to-immune-checkpoint-therapies-in-clear-cell-renal-cell-carcinoma
#9
Diana Miao, Claire A Margolis, Wenhua Gao, Martin H Voss, Wei Li, Dylan J Martini, Craig Norton, Dominick Bossé, Stephanie M Wankowicz, Dana Cullen, Christine Horak, Megan Wind-Rotolo, Adam Tracy, Marios Giannakis, Frank Stephen Hodi, Charles G Drake, Mark W Ball, Mohamad E Allaf, Alexandra Snyder, Matthew D Hellmann, Thai Ho, Robert J Motzer, Sabina Signoretti, William G Kaelin, Toni K Choueiri, Eliezer M Van Allen
Immune checkpoint inhibitors targeting the programmed cell death-1 receptor (PD-1) improve survival in a subset of patients with clear cell renal cell carcinoma (ccRCC). To identify genomic alterations in ccRCC that correlate with response to anti-PD-1 monotherapy, we performed whole exome sequencing of metastatic ccRCC from 35 patients. We found that clinical benefit was associated with loss-of-function mutations in the PBRM1 gene (p=0.012), which encodes a subunit of a SWI/SNF chromatin remodeling complex (the PBAF subtype)...
January 4, 2018: Science
https://www.readbyqxmd.com/read/29300535/hematopoietic-cell-transplantation-in-primary-immunodeficiency-conventional-and-emerging-indications
#10
Mary A Slatter, Andrew R Gennery
Haematopoietic stem cell transplantation (HSCT) is an established curative treatment for many primary immunodeficiencies. Advances in donor selection, graft manipulation, conditioning and treatment of complications, mean that survival for many conditions is now around 90%. Next generation sequencing is identifying new immunodeficiencies, many of which are treatable with HSCT. Challenges remain however with short and long-term sequalae. This article reviews latest developments in HSCT for conventional primary immunodeficiencies and presents data on outcome for emerging diseases, Areas covered: This article reviews recently published literature detailing advances, particularly in conditioning regimens and new methods of T-lymphocyte depletion, as well as new information regarding approach and out come of transplanting patients with conventional primary immunodeficiencies...
January 4, 2018: Expert Review of Clinical Immunology
https://www.readbyqxmd.com/read/29298069/identification-of-n-cis-3-methyl-7h-pyrrolo-2-3-d-pyrimidin-4-yl-amino-cyclobutyl-propane-1-sulfonamide-pf-04965842-a-selective-jak1-clinical-candidate-for-the-treatment-of-autoimmune-diseases
#11
Michael L Vazquez, Neelu Kaila, Joseph W Strohbach, John D Trzupek, Matthew F Brown, Mark E Flanagan, Mark J MItton-Fry, Timothy A Johnson, Ruth E TenBrink, Eric P Arnold, Arindrajit Basak, Steven E Heasley, Soojin Kwon, Jonathan Langille, Mihir D Parikh, Sarah H Griffin, Jeffrey M Casavant, Brian A Duclos, Ashley E Fenwick, Thomas M Harris, Seungil Han, Nicole L Caspers, Martin E Dowty, Xin Yang, Mary Ellen Banker, Martin Hegen, Peter T Symanowicz, Li Li, Lu Wang, Tsung H Lin, Jason Jussif, James D Clark, Jean-Baptiste Telliez, Ralph P Robinson, Ray Unwalla
Janus kinases (JAKs) are intracellular tyrosine kinases that mediate the signaling of numerous cytokines and growth factors involved in the regulation of immunity, inflammation and hematopoiesis. As JAK1 pairs with JAK2, JAK3 and TYK2, a JAK1-selective inhibitor would be expected to inhibit many cytokines involved in inflammation and immune function, while avoiding inhibition of the JAK2 homodimer regulating EPO and TPO signaling. Our efforts began with tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid arthritis (RA)...
January 3, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29296813/oncogenic-role-and-therapeutic-targeting-of-abl-class-and-jak-stat-activating-kinase-alterations-in-ph-like-all
#12
Kathryn G Roberts, Yung-Li Yang, Debbie Payne-Turner, Wenwei Lin, Jacob K Files, Kirsten Dickerson, Zhaohui Gu, Jack Taunton, Laura J Janke, Taosheng Chen, Mignon L Loh, Stephen P Hunger, Charles G Mullighan
New therapies for Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) patients are urgently needed. The genetic landscape of Ph-like ALL is characterized by a diverse array of kinase-activating alterations (including rearrangements, sequence mutations, and copy number alterations), suggesting that patients with Ph-like ALL are candidates for targeted therapy, similar to BCR-ABL1 ALL. We sought to investigate the functional role and targetability of the spectrum of kinase-activating alterations identified in Ph-like ALL...
September 12, 2017: Blood Advances
https://www.readbyqxmd.com/read/29295721/down-regulation-of-microrna-135-promotes-sensitivity-of-non-small-cell-lung-cancer-to-gefitinib-by-targeting-trim16
#13
Ning Wang, Tingting Zhang
Personalized treatment targeting epidermal growth factor receptor (EGFR) becomes a promising way for treatment of non-small cell lung cancer (NSCLC). Gefitinib, a tyrosine kinases inhibitor, is the first drug for NSCLC, which easily leads to drug resistance. Our study was aimed to explore the functional role of microRNA (miR)-135 in the sensitivity to gefitinib of NSCLC cells. Expression of miR-135 in normal cells and NSCLC cells was assessed. Then, the effects of abnormally expressed miR-135 on cell viability, migration, invasion, apoptosis, sensitivity to gefitinib, and the expression levels of adhesion molecules and programmed death ligand 1 (PD-L1) were all analyzed in H1650 and H1975 cells...
January 2, 2018: Oncology Research
https://www.readbyqxmd.com/read/29290986/the-effect-of-the-jak2-inhibitor-tg101209-against-t-cell-acute-lymphoblastic-leukemia-t-all-is-mediated-by-inhibition-of-jak-stat-signaling-and-activation-of-the-crosstalk-between-apoptosis-and-autophagy-signaling
#14
Zhao Cheng, Yifang Yi, Sisi Xie, Haizhi Yu, Hongling Peng, Guangsen Zhang
Previous reports have shown that active JAK2 contributes to T cell acute lymphoblastic leukaemia (T-ALL) development and that JAK inhibitors may be a potential treatment for T-ALL. In the current study, the JAK2 inhibitor TG101209 was used to treat T-ALL cell lines and primary T-ALL cells. The effects of TG101209 on T-ALL cells were determined, and the signaling proteins related to cell growth, apoptosis and autophagy were analysed. The results indicated that TG101209 significantly inhibited T-ALL cell proliferation and induced cell apoptosis in a dose-dependent manner...
December 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/29289756/the-role-of-janus-kinase-signaling-in-graft-versus-host-disease-and-graft-versus-leukemia
#15
REVIEW
Mark A Schroeder, Jaebok Choi, Karl Staser, John F DiPersio
For patients with hematologic malignancies, allogeneic hematopoietic cell transplantation (alloHCT) offers a potential curative treatment option, primarily due to an allogeneic immune response against recipient tumor cells (ie, graft-versus-leukemia [GVL] activity). However, many recipients of alloHCT develop graft-versus-host disease (GVHD), in which allogeneic immune responses lead to the damage of healthy tissue. GVHD is a leading cause of nonrelapse mortality and a key contributor to morbidity among patients undergoing alloHCT...
December 28, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/29280197/fulminant-cryptococcus-neoformans-infection-with-fatal-pericardial-tamponade-in-a-patient-with-chronic-myelomonocytic-leukemia-who-was-treated-with-ruxolitinib-case-report-and-review-of-fungal-pericarditis
#16
Jing Liu, Elie Mouhayar, Jeffrey J Tarrand, Dimitrios P Kontoyiannis
Cryptococcus neoformans is a saprophytic fungal pathogen that can cause serious illness in immune-compromised hosts and it presents with a wide variety of clinical symptoms. We present a fatal case of fulminant C. neoformans infection presenting as pericardial tamponade in a 71-year-old male with chronic myelomonocytic leukemia undergoing chemotherapy with the JAK-STAT inhibitor ruxolitinib. We also review the published cases of fungal pericarditis/tamponade. In addition to illustrating an atypical presentation of C...
December 27, 2017: Mycoses
https://www.readbyqxmd.com/read/29278854/overexpression-of-alk4-inhibits-cell-proliferation-and-migration-through-the-inactivation-of-jak-stat3-signaling-pathway-in-glioma
#17
Chaojun Song, Bo Fan, Zhengzheng Xiao
Aristaless-like homeobox 4 (ALK4) is a member of ALK proteins family and plays an important role in tumorigenesis. However, the expression and function of ALK4 in glioma remain largely unknown. The aim of our study was to elucidate its expression pattern in human glioma tissues and cell lines, as well as its functions in glioma cells. Our results demonstrated that ALK4 was lowly expressed in human glioma tissues and cell lines. Additionally, overexpression of ALK4 significantly suppressed the proliferation, migration and invasion of glioma cells, as well as inhibited the epithelial-mesenchymal transition (EMT) phenotype in glioma cells...
December 23, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29277359/soho-state-of-the-art-update-and-next-questions-mpn
#18
REVIEW
Prithviraj Bose, Jason Gotlib, Claire N Harrison, Srdan Verstovsek
The discovery of the activating Janus kinase (JAK)2V617F mutation in 2005 in most patients with the classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) spurred intense interest in research into these disorders, culminating in the identification of activating mutations in MPL in 2006 and indels in the gene encoding calreticulin (CALR) in 2013, thus providing additional mechanistic explanations for the universal activation of JAK-signal transducer and activator of transcription (JAK-STAT) observed in these conditions, and the success of the JAK1/2 inhibitor ruxolitinib, which first received regulatory approval in 2011...
January 2018: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/29276236/janus-kinase-inhibitors-for-the-treatment-of-rheumatoid-arthritis
#19
Senir Turan, Scot Walker
Rheumatoid arthritis (RA) is a disease where the immune system attacks the linings of the joints, resulting in joint pain, stiffness, swelling, and destruction. Although many products are available for the treatment of RA, limitations such as adverse reactions and tolerance greatly affect adherence. Many of the current biologic disease-modifying antirheumatic drugs on the market are injectables, leaving a void to be filled for a product that can be taken orally. The most advanced of these approaches, the Janus kinase (JAK) inhibitors, are oral drugs that have not only made a breakthrough in RA, but also other skin conditions...
November 2017: Hospital Pharmacy
https://www.readbyqxmd.com/read/29276155/jak-stat-1-signaling-is-required-for-reserve-intestinal-stem-cell-activation-during-intestinal-regeneration-following-acute-inflammation
#20
Camilla A Richmond, Hannah Rickner, Manasvi S Shah, Tracy Ediger, Luke Deary, Fanny Zhou, Alessio Tovaglieri, Diana L Carlone, David T Breault
The intestinal epithelium serves as an essential barrier to the outside world and is maintained by functionally distinct populations of rapidly cycling intestinal stem cells (CBC ISCs) and slowly cycling, reserve ISCs (r-ISCs). Because disruptions in the epithelial barrier can result from pathological activation of the immune system, we sought to investigate the impact of inflammation on ISC behavior during the regenerative response. In a murine model of αCD3 antibody-induced small-intestinal inflammation, r-ISCs proved highly resistant to injury, while CBC ISCs underwent apoptosis...
December 18, 2017: Stem Cell Reports
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