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JAK inhibitor

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https://www.readbyqxmd.com/read/28938529/defining-a-therapeutic-window-for-kinase-inhibitors-in-leukemia-to-avoid-neutropenia
#1
Kate McArthur, Akshay A D'Cruz, David Segal, Kurt Lackovic, Andrew F Wilks, Joanne A O'Donnell, Cameron J Nowell, Motti Gerlic, David C S Huang, Christopher J Burns, Ben A Croker
Neutropenia represents one of the major dose-limiting toxicities of many current cancer therapies. To circumvent the off-target effects of cytotoxic chemotherapeutics, kinase inhibitors are increasingly being used as an adjunct therapy to target leukemia. In this study, we conducted a screen of leukemic cell lines in parallel with primary neutrophils to identify kinase inhibitors with the capacity to induce apoptosis of myeloid and lymphoid cell lines whilst sparing primary mouse and human neutrophils. We have utilized a high-throughput live cell imaging platform to demonstrate that cytotoxic drugs have limited effects on neutrophil viability but are toxic to hematopoietic progenitor cells, with the exception of the topoisomerase I inhibitor SN-38...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28929088/microbial-invasion-vs-tick-immune-regulation
#2
REVIEW
Daniel E Sonenshine, Kevin R Macaluso
Ticks transmit a greater variety of pathogenic agents that cause disease in humans and animals than any other haematophagous arthropod, including Lyme disease, Rocky Mountain spotted fever, human granulocytic anaplasmosis, babesiosis, tick-borne encephalitis, Crimean Congo haemorhagic fever, and many others (Gulia-Nuss et al., 2016). Although diverse explanations have been proposed to explain their remarkable vectorial capacity, among the most important are their blood feeding habit, their long term off-host survival, the diverse array of bioactive molecules that disrupt the host's natural hemostatic mechanisms, facilitate blood flow, pain inhibitors, and minimize inflammation to prevent immune rejection (Hajdušek et al...
2017: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/28919782/inhibitory-effects-of-a-selective-jak2-inhibitor-on-adrenocorticotropic-hormone-production-and-proliferation-of-corticotroph-tumor-att20-cells
#3
Yuko Asari, Kazunori Kageyama, Yuki Nakada, Mizuki Tasso, Shinobu Takayasu, Kanako Niioka, Noriko Ishigame, Makoto Daimon
PURPOSE: The primary cause of Cushing's disease is adrenocorticotropic hormone (ACTH)-producing pituitary adenomas. EGFR signaling induces POMC mRNA-transcript levels and ACTH secretion from corticotroph tumors. The Jak-STAT pathway is located downstream of EGFR signaling; therefore, a Jak2 inhibitor could be an effective therapy for EGFR-related tumors. In this study, we determined the effect of a potent and selective Jak2 inhibitor, SD1029, on ACTH production and proliferation in mouse AtT20 corticotroph tumor cells...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28901399/downregulated-socs1-expression-activates-the-jak1-stat1-pathway-and-promotes-polarization-of-macrophages-into-m1-type
#4
Yan-Bing Liang, Hao Tang, Zhi-Bin Chen, Li-Jin Zeng, Jing-Guo Wu, Wen Yang, Zhen-Yu Li, Zhong-Fu Ma
Macrophage polarization is flexible, and involves in different signaling pathways and various transcription factors. Suppressor of cytokine signaling (SOCS) is an important inhibitor of cytokine signaling pathways and also a key physiological regulator for natural and acquired immunity systems. Following transfection of SOCS1 short hairpin (sh)RNA into mouse macrophage cells, reverse transcription‑quantitative polymerase chain reaction demonstrated that the mRNA levels of Janus kinase (JAK)1 and signal transducer and activator of transcription (STAT)1 increased significantly...
August 29, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28891341/small-molecule-therapy-for-managing-moderate-to-severe-psoriatic-arthritis
#5
Luisa Costa, Antonio Del Puente, Rosario Peluso, Marco Tasso, Paolo Caso, Maria Sole Chimenti, Vincenzo Sabbatino, Nicolò Girolimetto, Carolina Benigno, Nicoletta Bertolini, Aurora Del Puente, Roberto Perricone, Raffaele Scarpa, Francesco Caso
The majority of psoriatic arthritis (PsA) patients experience a good clinical response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biologic therapies (bDMARDs). However, treatment failure with these drugs can represent a relevant clinical problem. Moreover, in daily clinical practice, the appropriate identification of patients eligible for these agents can be conditioned by numerous aspects, mainly represented by comorbidities, such as history of malignancies, chronic and recurrent infectious diseases...
September 11, 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28891251/dose-exposure-response-modeling-to-support-dosing-recommendation-for-phase-3-development-of-baricitinib-in-patients-with-rheumatoid-arthritis
#6
X Zhang, L Chua, C Ernest, W Macias, T Rooney, L S Tham
Baricitinib is an oral inhibitor of Janus kinases (JAK), selective for JAK1 and 2. It demonstrated dose-dependent efficacy in patients with moderate-to-severe rheumatoid arthritis in a Phase 2b study up to 24 weeks. Population pharmacokinetic/pharmacodynamic models were developed to characterize concentration-time profiles and dose/exposure-response relationships for the key efficacy (proportion of patients achieving American College of Rheumatology 20%, 50%, or 70% response rate) and safety endpoints (incidence of anemia) for the Phase 2b study...
September 11, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28890086/sensory-neurons-co-opt-classical-immune-signaling-pathways-to-mediate-chronic-itch
#7
Landon K Oetjen, Madison R Mack, Jing Feng, Timothy M Whelan, Haixia Niu, Changxiong J Guo, Sisi Chen, Anna M Trier, Amy Z Xu, Shivani V Tripathi, Jialie Luo, Xiaofei Gao, Lihua Yang, Samantha L Hamilton, Peter L Wang, Jonathan R Brestoff, M Laurin Council, Richard Brasington, András Schaffer, Frank Brombacher, Chyi-Song Hsieh, Robert W Gereau, Mark J Miller, Zhou-Feng Chen, Hongzhen Hu, Steve Davidson, Qin Liu, Brian S Kim
Mammals have evolved neurophysiologic reflexes, such as coughing and scratching, to expel invading pathogens and noxious environmental stimuli. It is well established that these responses are also associated with chronic inflammatory diseases, including asthma and atopic dermatitis. However, the mechanisms by which inflammatory pathways promote sensations such as itch remain poorly understood. Here, we show that type 2 cytokines directly activate sensory neurons in both mice and humans. Further, we demonstrate that chronic itch is dependent on neuronal IL-4Rα and JAK1 signaling...
September 21, 2017: Cell
https://www.readbyqxmd.com/read/28889969/andrographolide-inhibits-influenza-a-virus-induced-inflammation-in-a-murine-model-through-nf-%C3%AE%C2%BAb-and-jak-stat-signaling-pathway
#8
Yi Ding, Lizhu Chen, Wenjiao Wu, Jie Yang, Zifeng Yang, Shuwen Liu
Influenza viruses, the main cause of respiratory tract diseases, cause high morbidity and mortality in humans. Excessive inflammation in the lungs is proposed to be a hallmark for the severe influenza virus infection, especially influenza A virus infection. Strategies against inflammation induced by influenza A virus infection could be a potential anti-influenza therapy. Here, lethal dose of mouse-adapted H1N1 strain PR8A/PR/8/34 was inoculated C57BL/6 mice to detect the anti-influenza activity of andrographolide, the active component of traditional Chinese medicinal herb Andrographis paniculata, with or without influenza virus entry inhibitor CL-385319...
September 7, 2017: Microbes and Infection
https://www.readbyqxmd.com/read/28887107/efficacy-of-systemic-treatments-of-psoriasis-on-pruritus-a-systemic-literature-review-and-meta-analysis
#9
Chloé Théréné, Emilie Brenaut, Thomas Barnetche, Laurent Misery
In the course of the last 30 years, several studies have clearly documented that pruritus is a very frequent symptom of psoriasis and its impact on the patients' quality of life. The variety of available systemic treatments for psoriasis is increasing rapidly. Our objective was to assess their efficacy on pruritus based on a systematic literature review. A systematic literature search was performed using PubMed and Trip Database (from January 1990 to September 2016) to find published clinical trials for the treatments of psoriasis, then a meta-analysis was performed...
September 5, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28879797/amorfrutin-a-inhibits-tnf-%C3%AE-induced-jak-stat-signaling-cell-survival-and-proliferation-of-human-cancer-cells
#10
Chunliu Mi, Juan Ma, Ke Si Wang, Zhe Wang, Ming Yue Li, Jun Bo Li, Xuezheng Li, Lian Xun Piao, Guang Hua Xu, Xuejun Jin
CONTEXT: Amorfrutin A is a natural product isolated from the fruits of Amorpha fruticosa L. and has been shown to exhibit multiple bioeffector functions. In the present study, we investigated whether amorfrutin A exerts anticancer effects by inhibiting STAT3 activation in cervical cancer cells. OBJECTIVE: To investigate the effectiveness of amorfrutin A as a treatment of cancer, and determine the underlying pharmacological mechanism of action. MATERIALS AND METHODS: HeLa, SK-Hep1, MDA-MB-231 and HCT116 cells were used in this study...
September 7, 2017: Immunopharmacology and Immunotoxicology
https://www.readbyqxmd.com/read/28879441/egfr-and-kras-mutations-do-not-enrich-for-the-activation-of-il-6-jak1-or-phosphorylated-stat3-in-resected-lung-adenocarcinoma
#11
Timothy D Clay, Prudence A Russell, Hongdo Do, Vijaya Sundararajan, Matthew Conron, Gavin M Wright, Benjamin Solomon, Alexander Dobrovic, Sue-Anne McLachlan, Melissa M Moore
Resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) against EGFR mutant lung adenocarcinoma develops after a median of nine to thirteen months. Upregulation of the interleukin-6 (IL-6)/Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway may be a potential source of resistance to EGFR TKIs. We undertook a detailed assessment of the IL-6/JAK1/phosphorylated STAT3 (pSTAT3) pathway in resected lung adenocarcinoma specimens, with special interest in whether the presence of an EGFR mutation enriched for pSTAT3 positivity...
September 6, 2017: Medical Oncology
https://www.readbyqxmd.com/read/28874440/blocking-gp130-signaling-suppresses-autotaxin-expression-in-adipocytes-and-improves-insulin-sensitivity-in-diet-induced-obesity
#12
Shuhong Sun, Ran Wang, Jianwen Song, Ming Guan, Na Li, Xiaotian Zhang, Zhenwen Zhao, Junjie Zhang
Autotaxin (ATX), which is highly expressed and secreted by adipocytes, functions as the key enzyme to generate lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC). Adipose tissue is the main source of circulating ATX that modulates plasma LPA levels. Up-regulation of ATX expression in obese patients and mice is closely related with insulin resistance and impaired glucose tolerance. However, the mechanism of ATX expression in adipocytes remains largely unknown. In this study, we found that gp130-mediated JAK-STAT3 activation was required for abundant ATX expression in adipocytes...
September 5, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28865178/inhibition-of-il-6-jak-stat3-signaling-in-castration-resistant-prostate-cancer-cells-enhances-the-nk-cell-mediated-cytotoxicity-via-alteration-of-pd-l1-nkg2d-ligand-levels
#13
LiJun Xu, XiaoDong Chen, MingJing Shen, Dong-Rong Yang, Laifu Fang, Guobin Weng, Ying Tsai, Peter C Keng, Yuhchyau Chen, Soo Ok Lee
To investigate whether IL-6 signaling affects the susceptibility of castration resistant prostate cancer (CRPC) cells to cytotoxic action of natural killer (NK) cells, CRPC cell lines (having different IL-6 level) were developed by lentiviral transduction. While observing no secreted IL-6 level in parental C4-2 and CWR22Rv1 cells, we found the IL-6 expression/secretion in these cells was induced after the transduction process and the IL-6 level difference in C4-2siIL-6/sc and CWR22siIL-6/sc cell CRPC cell sets could be detected...
September 2, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28864870/20-s-25-methoxyl-dammarane-3%C3%AE-12%C3%AE-20-triol-negatively-regulates-activation-of-stat3-and-erk-pathways-and-exhibits-anti-cancer-effects-in-hepg2-cells
#14
Hui-Han Ai, Zi-Long Zhou, Lu-Guo Sun, Mei-Ting Yang, Wei Li, Chun-Lei Yu, Zhen-Bo Song, Yan-Xin Huang, Yin Wu, Lei Liu, Xiao-Guang Yang, Yu-Qing Zhao, Yong-Li Bao, Yu-Xin Li
The pro-inflammatory cytokine interleukin 6 (IL-6), via activating its downstream JAK/STAT3 and Ras/ERK signaling pathways, is involved in cell growth, proliferation and anti-apoptotic activities in various malignancies. To screen inhibitors of IL-6 signaling, we constructed a STAT3 and ERK dual-pathway responsive luciferase reporter vector (Co.RE). Among several candidates, the natural compound 20(S)-25-methoxyl-dammarane-3β, 12β, 20-triol (25-OCH3-PPD, GS25) was identified to clearly inhibit the luciferase activity of Co...
September 1, 2017: Apoptosis: An International Journal on Programmed Cell Death
https://www.readbyqxmd.com/read/28864784/sh003-reverses-drug-resistance-by-blocking-signal-transducer-and-activator-of-transcription-3-stat3-signaling-in-breast-cancer-cells
#15
Hye-Sook Seo, Jin Mo Ku, Hee-Jae Lee, Jong-Kyu Woo, Chunhoo Cheon, Mia Kim, Bo-Hyoung Jang, Yong Cheol Shin, Seong-Gyu Ko
Overcoming drug resistance is an important task for investigators and clinician to achieve successful chemotherapy in cancer patients. Drug resistance is caused by various factors, including the overexpression of P-glycoprotein (P-gp, MDR1). The development of new, useful compounds that overcome drug resistance is urgent. SH003 is extracted from the mixture of three different herbs, and its anti-cancer effect has been revealed in different cancer cell types. In the present study, we investigated whether SH003 is able to reverse drug resistance using paclitaxel-resistant breast cancer cells (MCF-7/PAC)...
September 1, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/28859967/a-jak2-selective-inhibitor-potently-reverses-the-immune-suppression-by-modulating-the-tumor-microenvironment-for-cancer-immunotherapy
#16
Wei He, Yi Zhu, Ruoyu Mu, Jinzhi Xu, Xiaoyi Zhang, Chunming Wang, Qiu Li, Zhen Huang, Junfeng Zhang, Yi Pan, Jianlin Han, Lei Dong
Small molecule therapeutics can be potent tools for cancer immunotherapy. They may be devised to target the tumor associated macrophages (TAMs) and regulatory T cells (Treg), which are major immunosuppressive cells in the tumor microenvironment. The infiltration and functionalization of these cells, which essentially promote tumor development, are mediated by the hyper-activation of the Jak-STAT3 signaling pathway. Here, we demonstrated that compound 9#, a novel inhibitor of Jak2, could suppress Jak2-STAT3 signaling in macrophages (peritoneal macrophages and THP-1 cells) and direct the macrophages towards the pro-inflammatory (M1-like) phenotype...
August 28, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28854975/ruxolitinib-nilotinib-cotreatment-inhibits-leukemia-propagating-cells-in-philadelphia-chromosome-positive-all
#17
Yuan Kong, Yi-Lin Wu, Yang Song, Min-Min Shi, Xie-Na Cao, Hong-Yan Zhao, Ya-Zhen Qin, Yue-Yun Lai, Hao Jiang, Qian Jiang, Xiao-Jun Huang
BACKGROUND: As one of the major treatment obstacles in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL), relapse of Ph(+)ALL may result from the persistence of leukemia-propagating cells (LPCs). Research using a xenograft mouse assay recently determined that LPCs were enriched in the CD34(+)CD38(-)CD58(-) fraction in human Ph(+)ALL. Additionally, a cohort study demonstrated that Ph(+)ALL patients with a LPCs phenotype at diagnosis exhibited a significantly higher cumulative incidence of relapse than those with the other cell phenotypes even with uniform front-line imatinib-based therapy pre- and post-allotransplant, thus highlighting the need for novel LPCs-based therapeutic strategies...
August 30, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28853089/role-of-jak1-jak2-and-jak3-in-functional-stimulation-of-mesenchymal-precursor-cells-by-alkaloid-songorine
#18
G N Zyuz'kov, E V Udut, L A Miroshnichenko, E V Simanina, T Yu Polyakova, L A Stavrova, V V Udut, M Yu Minakova, A M Dygai, A V Chaikovskii, V I Agafonov, V V Zhdanov
We studied the role of some JAK in the effect of diterpene alkaloid songorine on realization of the growth potential of mesenchymal precursor cells. The participation of JAK1, JAK2, and JAK3 in stimulation of proliferation of the precursor cells was demonstrated. Specific inhibitors of these JAK reduced the yield of fibroblast CFU and the rate of their division. Inhibition of JAK2 against the background of songorine treatment increased the rate of precursor differentiation.
August 29, 2017: Bulletin of Experimental Biology and Medicine
https://www.readbyqxmd.com/read/28852199/mutant-jak3-phosphoproteomic-profiling-predicts-synergism-between-jak3-inhibitors-and-mek-bcl2-inhibitors-for-the-treatment-of-t-cell-acute-lymphoblastic-leukemia
#19
S Degryse, C E de Bock, S Demeyer, I Govaerts, S Bornschein, D Verbeke, K Jacobs, S Binos, D A Skerrett-Byrne, H C Murray, N M Verrills, P Van Vlierberghe, J Cools, M D Dun
Mutations in the interleukin-7 receptor (IL7R) or the JAK3 kinase occur frequently in T-cell acute lymphoblastic leukemia (T-ALL) and both are able to drive cellular transformation and the development of T-ALL in mouse models. However, the signal transduction pathways downstream of JAK3 mutations remain poorly characterized. Here, we describe the phosphoproteome downstream of the JAK3(L857Q)/(M511I) activating mutations in transformed Ba/F3 lymphocyte cells. Signaling pathways regulated by JAK3 mutants were assessed following acute inhibition of JAK1/JAK3 using the JAK kinase inhibitors ruxolitinib or tofacitinib...
August 30, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28845577/the-safety-and-immunogenicity-of-live-zoster-vaccination-in-patients-with-rheumatoid-arthritis-before-starting-tofacitinib-a-randomized-phase-ii-trial
#20
Kevin L Winthrop, Ann G Wouters, Ernest H Choy, Koshika Soma, Jennifer A Hodge, Chudy I Nduaka, Pinaki Biswas, Elie Needle, Sherry Passador, Christopher F Mojcik, William F Rigby
OBJECTIVE: Patients with rheumatoid arthritis (RA) are at increased risk of herpes zoster, and vaccination is recommended for patients ages 50 years and older, prior to starting treatment with biologic agents or tofacitinib. Tofacitinib is an oral JAK inhibitor for the treatment of RA. We evaluated its effect on the immune response and safety of live zoster vaccine (LZV). METHODS: In this phase II, 14-week, placebo-controlled trial, patients ages 50 years and older who had active RA and were receiving background methotrexate were given LZV and randomized to receive tofacitinib 5 mg twice daily or placebo 2-3 weeks postvaccination...
August 28, 2017: Arthritis & Rheumatology
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