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https://www.readbyqxmd.com/read/28523588/advances-in-the-development-of-janus-kinase-inhibitors-in-inflammatory-bowel-disease-future-prospects
#1
Mathurin Flamant, Josselin Rigaill, Stephane Paul, Xavier Roblin
Inflammatory bowel disease (IBD) is caused by a dysregulation of the immune system, inducing the production of proinflammatory cytokines and adhesion molecules. A better understanding of the mucosal immune response in IBD has led to the development of new drugs directed at inflammatory cytokines and leukocyte-trafficking molecules. Beyond tumor necrosis factor antagonists and anti-integrin molecules, which act by blocking the interaction between gut-specific lymphocytes and their receptor on vascular endothelium, the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway represents a new target in IBD...
May 18, 2017: Drugs
https://www.readbyqxmd.com/read/28521411/reduced-rkip-expression-levels-are-associated-with-frequent-non-small-cell-lung-cancer-metastasis-and-stat3-phosphorylation-and-activation
#2
Ansheng Wang, Guixin Duan, Chengling Zhao, Yuan Gao, Xuegang Liu, Zuyi Wang, Wei Li, Kangwu Wang, Wei Wang
The current study examined the role of Raf kinase inhibitor protein (RKIP) in non-small cell lung cancer (NSCLC) metastasis. A total of 100 patients with NSCLC were recruited following pathological diagnosis in the First Affiliated Hospital of Bengbu Medical College. The patients were classified and statistically analyzed according to their clinicopathological characteristics and tumor-node-metastasis stage. Paired tumor tissue and adjacent non-tumor tissue samples were subject to pathological diagnosis and western blot analysis...
May 2017: Oncology Letters
https://www.readbyqxmd.com/read/28513593/jak3-deficiency-blocks-innate-lymphoid-cell-development
#3
M L Robinette, M Cella, J B Telliez, T K Ulland, A D Barrow, K Capuder, S Gilfillan, L-L Lin, L D Notarangelo, M Colonna
Loss-of-function mutations in the tyrosine kinase JAK3 cause autosomal recessive severe combined immunodeficiency (SCID). Defects in this form of SCID are restricted to the immune system, which led to the development of immunosuppressive JAK inhibitors. We find that the B6.Cg-Nr1d1(tm1Ven)/LazJ mouse line purchased from Jackson Laboratories harbors a spontaneous mutation in Jak3, generating a SCID phenotype and an inability to generate antigen-independent professional cytokine-producing innate lymphoid cells (ILCs)...
May 17, 2017: Mucosal Immunology
https://www.readbyqxmd.com/read/28508871/non-cell-autonomous-activation-of-il-6-stat3-signaling-mediates-fgf19-driven-hepatocarcinogenesis
#4
Mei Zhou, Hong Yang, R Marc Learned, Hui Tian, Lei Ling
Hepatocellular carcinoma (HCC), a primary malignancy of the liver, is the second leading cause of cancer mortality worldwide. Fibroblast Growth Factor 19 (FGF19) is one of the most frequently amplified genes in HCC patients. Moreover, mice expressing an FGF19 transgene have been shown to develop HCC. However, the downstream signalling pathways that mediate FGF19-dependent tumorigenesis remain to be deciphered. Here we show that FGF19 triggers a previously unsuspected, non-cell-autonomous program to activate STAT3 signalling in hepatocytes through IL-6 produced in the liver microenvironment...
May 16, 2017: Nature Communications
https://www.readbyqxmd.com/read/28501913/chronic-myeloid-leukemia-immunobiology-and-novel-immunotherapeutic-approaches
#5
Emilie Cayssials, Francois Guilhot
Imatinib has revolutionized the treatment and prognosis of chronic myeloid leukemia (CML) with survival rates now approaching those of the age-matched healthy population. To be able to discontinue tyrosine kinase inhibitor (TKI) treatment, it is necessary to develop complementary therapies to target minimal residual disease. Recent findings by a number of investigators in both CML mouse models and CML patients offer evidence that many factors in the leukemic microenvironment can collectively contribute to immune escape, including expansion of myeloid-derived suppressor cells, programmed death-1/programmed death-1 ligand interactions resulting in T-cell impairment, expression of soluble suppressive factors such as soluble CD25, and down-regulation of MHC molecules by CML cells...
May 13, 2017: BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy
https://www.readbyqxmd.com/read/28500170/jak2-inhibitors-for-myeloproliferative-neoplasms-what-is-next
#6
Prithviraj Bose, Srdan Verstovsek
Since its approval in 2011, the Janus kinase (JAK) 1/2 inhibitor ruxolitinib has evolved to become the centerpiece of therapy for myelofibrosis (MF), and its use in patients with hydroxyurea resistant/intolerant polycythemia vera (PV) is steadily increasing. A number of other JAK2 inhibitors have entered clinical testing, but none has been approved yet, and many discontinued. Importantly, the activity of these agents is not restricted to patients with JAK2 V617F or exon 12 mutations. Although JAK2 inhibitors provide substantial clinical benefit, their disease-modifying activity is limited, and rational combinations with other targeted agents are needed, particularly in MF, where survival is short...
May 12, 2017: Blood
https://www.readbyqxmd.com/read/28496202/inhibition-of-jak-stat-signaling-reduces-the-activation-of-pancreatic-stellate-cells-in-vitro-and-limits-caerulein-induced-chronic-pancreatitis-in-vivo
#7
Hannah M Komar, Gregory Serpa, Claire Kerscher, Erin Schwoegl, Thomas A Mace, Ming Jin, Ming-Chen Yang, Ching-Shih Chen, Mark Bloomston, Michael C Ostrowski, Phil A Hart, Darwin L Conwell, Gregory B Lesinski
Chronic pancreatitis (CP) is a fibro-inflammatory disease leading to pain, maldigestion, and pancreatic insufficiency. No therapeutic options exist due to a limited understanding of the biology of CP pathology. Recent findings implicate pancreatic stellate cells (PSC) as prominent mediators of inflammatory and fibrotic processes during CP. Here, we utilized primary and immortalized PSC obtained from mice and patients with CP or pancreatic cancer to examine the effect of Jak/STAT and MAPK pathway inhibition in vitro...
May 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28492557/cryptotanshinone-inhibits-human-glioma-cell-proliferation-in-vitro-and-in-vivo-through-shp-2-dependent-inhibition-of-stat3-activation
#8
Liang Lu, Sulin Zhang, Cuixian Li, Chun Zhou, Dong Li, Peiqing Liu, Min Huang, Xiaoyan Shen
Malignant gliomas (MGs) are one of the most common primary brain cancers in adults with a high mortality rate and relapse rate. Thus, finding better effective approaches to treat MGs has become very urgent. Here, we studied the effects of cryptotanshinone (CTS) on MGs in vitro and in vivo, and explored the underlying mechanisms. Effects of CTS in vitro on cell proliferation, cycle, migration and invasion were evaluated. The activation of JAK/STATs signaling was detected by western blot and immunofluorescenc staining...
May 11, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28490530/il-6-promotes-epithelial-to-mesenchymal-transition-of-human-peritoneal-mesothelial-cells-possibly-through-jak2-stat3-signaling-pathway
#9
Jing Xiao, Yanan Gong, Ying Chen, Dahai Yu, Xiaoyang Wang, Xiaoxue Zhang, Yanna Dou, Dong Liu, Genyang Cheng, Shan Lu, Wenming Yuan, Yansheng Li, Zhanzheng Zhao
Long-term peritoneal dialysis (PD) therapy results in functional and structural alteration of the peritoneal membrane, including epithelial-to-mesenchymal transition (EMT). Interleukin 6 (IL-6) is a local pleiotropic cytokine, hypothesized to play an important role in EMT. This study was designed to investigate the role of IL-6 in EMT and peritoneal membrane dysfunction in long-term PD patients by assessing the level of IL-6 in dialysate and exploring the relationship between IL-6, the related signaling pathway JAK2/STAT3, and EMT, using in vitro cellular and molecular techniques...
May 10, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28484265/jak-stat-pathway-inhibition-overcomes-il7-induced-glucocorticoid-resistance-in-a-subset-of-human-t-cell-acute-lymphoblastic-leukemias
#10
C Delgado-Martin, L K Meyer, B J Huang, K A Shimano, M S Zinter, J V Nguyen, G A Smith, J Taunton, S S Winter, J R Roderick, M A Kelliher, T M Horton, B L Wood, D Teachey, M L Hermiston
While outcomes for children with T-cell acute lymphoblastic leukemia (T-ALL) have improved dramatically, survival rates for patients with relapsed/refractory disease remain dismal. Prior studies indicate that glucocorticoid (GC) resistance is more common than resistance to other chemotherapies at relapse. Additionally, failure to clear peripheral blasts during a prednisone prophase correlates with an elevated risk of relapse in newly diagnosed patients. Here we show that intrinsic GC resistance is present at diagnosis in early thymic precursor (ETP) T-ALLs as well as in a subset of non-ETP T-ALLs...
May 9, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28482851/checkpoint-inhibitors-in-hematological-malignancies
#11
REVIEW
Chi Young Ok, Ken H Young
Inhibitory molecules such as PD-1, CTLA-4, LAG-3, or TIM-3 play a role to keep a balance in immune function. However, many cancers exploit such molecules to escape immune surveillance. Accumulating data support that their functions are dysregulated in lymphoid neoplasms, including plasma cell myeloma, myelodysplastic syndrome, and acute myeloid leukemia. In lymphoid neoplasms, aberrations in 9p24.1 (PD-L1, PD-L2, and JAK2 locus), latent Epstein-Barr virus infection, PD-L1 3'-untranslated region disruption, and constitutive JAK-STAT pathway are known mechanisms to induce PD-L1 expression in lymphoma cells...
May 8, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28476935/a-schistosoma-japonicum-infection-promotes-the-expansion-of-myeloid-derived-suppressor-cells-by-activating-the-jak-stat3-pathway
#12
Quan Yang, Huaina Qiu, Hongyan Xie, Yanwei Qi, Hefei Cha, Jiale Qu, Mei Wang, Yuanfa Feng, Xin Ye, Jianbing Mu, Jun Huang
Myeloid-derived suppressor cells (MDSCs), a heterogeneous group of immune cells from the myeloid lineage, play an important part in suppression of host immune responses during many pathologic conditions, including cancer and infectious diseases. Thus, understanding the functional diversity of these cells as well as the underlying mechanisms is crucial for the development of disease control strategies. The role of MDSCs during Schistosoma japonicum infection, however, is not clear, and there is a lack of systematic study so far...
May 5, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28476581/tumour-associated-macrophages-activate-migration-and-stat3-in-pancreatic-ductal-adenocarcinoma-cells-in-co-cultures
#13
Aino Salmiheimo, Harri Mustonen, Sanna Vainionpää, Zhanlong Shen, Esko Kemppainen, Pauli Puolakkainen, Hanna Seppänen
OBJECTIVES: Tumour-associated macrophages participate in tumour development and progression. The aim of this study was to assess the interactions of pancreatic cancer cells and pro-inflammatory M1 and anti-inflammatory M2 macrophages, specifically their effect on pancreatic cancer cell migration and the changes in STAT-signalling. METHODS: Monocytes were isolated from healthy subjects and differentiated into macrophages with M-CSF. The macrophages were polarized towards M1 by IL-12 and towards M2 by IL-10...
April 24, 2017: Pancreatology: Official Journal of the International Association of Pancreatology (IAP) ... [et Al.]
https://www.readbyqxmd.com/read/28474336/comparative-genomic-expression-signatures-of-signal-transduction-pathways-and-targets-in-paediatric-burkitt-lymphoma-a-children-s-oncology-group-report
#14
Sanghoon Lee, Nancy S Day, Rodney R Miles, Sherrie L Perkins, Megan S Lim, Janet Ayello, Carmella van de Ven, Lauren Harrison, Nader K El-Mallawany, Stanton Goldman, Mitchell S Cairo
Burkitt lymphoma (BL) is the most common histological subtype of non-Hodgkin lymphoma (NHL) in children and adolescents. Through the introduction of short intensive multi-agent chemoimmunotherapy, survival has improved significantly over the past 30 years. However, this successful approach is limited by significant chemotherapy-induced acute toxicity and risk of developing resistant disease, demonstrating the need to identify less toxic and targeted therapies. We analysed the comparative genomic signature and targetable signalling pathways in paediatric BL (PEBL) samples from the Children's Oncology Group study (ANHL01P1) by genomic profiling and selected genes were confirmed by quantitative real time polymerase chain reaction...
May 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28473813/asunaprevir-evokes-hepatocytes-innate-immunity-to-restrict-the-replication-of-hepatitis-c-and-dengue-virus
#15
Wei-Lun Tsai, Jin-Shiung Cheng, Chih-Wen Shu, Kwok-Hung Lai, Hoi-Hung Chan, Chun-Ching Wu, Jing-Mei Wu, Ping-I Hsu, Raymond T Chung, Tsung-Hsien Chang
Type I Interferon-mediated innate immunity against Flaviviridae, such as Hepatitis C virus (HCV) and Dengue virus (DENV), involves TLR3, RIG-I-like receptor (RLR) and JAK-STAT signal pathways. Asunaprevir is a newly developed HCV protease inhibitor for HCV treatment. Whether, asunaprevir activates innate immunity to restrict viral infection is unclear. Thus, this study investigates the effect of asunaprevir on innate immunity and its influence on HCV and DENV infection. Huh 7.5.1, Hep-G2 cells, JFH-1 infection model, and DENV-2 infection were used for the analysis...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28472186/stat2-is-involved-in-the-pathogenesis-of-psoriasis-by-promoting-cxcl11-and-ccl5-production-by-keratinocytes
#16
Claus Johansen, Anne Hald Rittig, Maike Mose, Trine Bertelsen, Isabella Weimar, Jakob Nielsen, Thomas Andersen, Tue Kruse Rasmussen, Bent Deleuran, Lars Iversen
The JAK/STAT signaling pathway is suggested to play an important role in the pathogenesis of psoriasis, and recently JAK/STAT inhibitors have shown promising results in psoriasis treatment. The present study aimed to characterize the role of STAT2 in psoriasis. We demonstrated an increased expression of STAT2 and an increased level of phosphorylated/activated STAT2 in lesional compared with nonlesional psoriatic skin. Gene silencing of STAT2 by siRNA in human keratinocytes revealed that upon IFNα stimulation CXCL11 and CCL5 were the only two cytokines, among 102 analyzed, found to be regulated through a STAT2-dependent mechanism...
2017: PloS One
https://www.readbyqxmd.com/read/28472150/both-mapk-and-stat3-signal-transduction-pathways-are-necessary-for-il-6-dependent-hepatic-stellate-cells-activation
#17
Polina Kagan, Maya Sultan, Irina Tachlytski, Michal Safran, Ziv Ben-Ari
BACKGROUND: During liver injury, hepatic stellate cells (HSCs) can undergo activation and transform into alpha-smooth muscle actin (αSMA)-expressing contractile myofibroblast-like cells, leading to deposition of excessive scar matrix. We have recently demonstrated that depletion of adenosine deaminase acting on double-stranded RNA (ADAR1) from mouse hepatocytes leads to HSC activation and induction of inflammation and hepatic fibrosis that is mediated by interleukin 6 (IL-6). Our aim was to identify and characterize the molecular pathways involved in the direct, inflammation-independent activation of HSCs by IL-6...
2017: PloS One
https://www.readbyqxmd.com/read/28470343/pbmc-activation-via-the-erk-and-stat-signaling-pathways-enhances-the-anti-tumor-activity-of-staphylococcal-enterotoxin-a
#18
Xueting Liu, Liping Zeng, Zhongqiu Zhao, Jianxing He, Yang Xie, Lanyan Xiao, Shan Wang, Junyan Zhang, Zehong Zou, Ying He, Ailin Tao, Jianguo Zhang
Staphylococcal enterotoxin A (SEA) is well known as a superantigen and is highly potent in activating T lymphocytes. And it has been used clinically as an immunomodifier in the treatment of a number of tumors for years. However, the mechanism of its action remains largely unclear. In this study, SEA was found to significantly inhibit the proliferation and induce the death of human lung carcinoma A549 cells when co-cultured with human peripheral blood mononuclear cells (PBMCs). SEA could also induce the proliferation of human PBMCs and stimulate human PBMCs to release a wide range of cytokines that have broad anti-tumor activities such as IFN-γ, TNF-α, IL-2...
May 3, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28468969/protein-kinase-ck2-controls-the-fate-between-th17-cell-and-regulatory-t-cell-differentiation
#19
Sara A Gibson, Wei Yang, Zhaoqi Yan, Yudong Liu, Amber L Rowse, Amy S Weinmann, Hongwei Qin, Etty N Benveniste
CK2 is a highly conserved and pleiotropic serine/threonine kinase that promotes many prosurvival and proinflammatory signaling pathways, including PI3K/Akt/mTOR and JAK/STAT. These pathways are essential for CD4(+) T cell activation and polarization, but little is known about how CK2 functions in T cells. In this article, we demonstrate that CK2 expression and kinase activity are induced upon CD4(+) T cell activation. Targeting the catalytic activity of CK2 using the next-generation small molecule inhibitor CX-4945 in vitro significantly and specifically inhibited mouse and human Th17 cell differentiation while promoting the generation of Foxp3(+) regulatory T cells (Tregs)...
May 3, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28468777/the-multi-kinase-inhibitor-debio-0617b-reduces-maintenance-and-self-renewal-of-primary-human-aml-cd34-stem-progenitor-cells
#20
Maximilien Murone, Ramin Radpour, Antoine Attinger, Anne Vaslin Chessex, Anne-Laure Huguenin, Christian M Schürch, Yara Banz, Saumitra Sengupta, Michel Aguet, Stefania Rigotti, Yogeshwar Bachhav, Frederic Massiere, Murali Ramachandra, Andres McAllister, Carsten Riether
Acute myelogenous leukemia (AML) is initiated and maintained by leukemia stem cells (LSCs). LSCs are therapy-resistant, cause relapse and represent a major obstacle for the cure of AML. Resistance to therapy is often mediated by aberrant tyrosine kinase (TK) activation. These TKs primarily activate downstream signaling via STAT3/STAT5. In this study, we analyzed the potential to therapeutically target aberrant TK signaling and to eliminate LSCs via the multi-TK inhibitor Debio 0617B. Debio 0617B has a unique profile targeting key kinases upstream of STAT3/STAT5 signaling such as JAK, SRC, ABL and class III/V receptor TKs...
May 3, 2017: Molecular Cancer Therapeutics
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