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https://www.readbyqxmd.com/read/28934680/a-phase-1-study-of-the-janus-kinase-2-jak2-v617f-inhibitor-gandotinib-ly2784544-in-patients-with-primary-myelofibrosis-polycythemia-vera-and-essential-thrombocythemia
#1
Srdan Verstovsek, Ruben A Mesa, Mohamed E Salama, Li Li, Celine Pitou, Fabio P Nunes, Gregory L Price, Jennifer L Giles, Deborah N D'Souza, Richard A Walgren, Josef T Prchal
Mutations in Janus kinase 2 (JAK2) are implicated in the pathogenesis of Philadelphia-chromosome negative myeloproliferative neoplasms, including primary myelofibrosis, polycythemia vera, and essential thrombocythemia. Gandotinib (LY2784544), a potent inhibitor of JAK2 activity, shows increased potency for the JAK2(V617F) mutation. The study had a standard 3+3 dose-escalation design to define the maximum-tolerated dose. Primary objectives were to determine safety, tolerability, and recommended oral daily dose of gandotinib for patients with JAK2(V617F)-positive myelofibrosis, essential thrombocythemia, or polycythemia vera...
August 31, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28930494/simplify-1-a-phase-iii-randomized-trial-of-momelotinib-versus-ruxolitinib-in-janus-kinase-inhibitor-na%C3%A3-ve-patients-with-myelofibrosis
#2
Ruben A Mesa, Jean-Jacques Kiladjian, John V Catalano, Timothy Devos, Miklos Egyed, Andrzei Hellmann, Donal McLornan, Kazuya Shimoda, Elliott F Winton, Wei Deng, Ronald L Dubowy, Julia D Maltzman, Francisco Cervantes, Jason Gotlib
Purpose We evaluated the efficacy and safety of momelotinib, a potent and selective Janus kinase 1 and 2 inhibitor (JAKi), compared with ruxolitinib, in JAKi-naïve patients with myelofibrosis. Patients and Methods Patients (N = 432) with high risk or intermediate-2 risk or symptomatic intermediate-1 risk myelofibrosis were randomly assigned to receive 24 weeks of treatment with momelotinib 200 mg once daily or ruxolitinib 20 mg twice a day (or per label), after which all patients could receive open-label momelotinib...
September 20, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28929088/microbial-invasion-vs-tick-immune-regulation
#3
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/28927099/interleukin-6-identified-as-an-important-factor-in-hypoxia-and-aldehyde-dehydrogenase-based-gefitinib-adaptive-resistance-in-non-small-cell-lung-cancer-cells
#4
Shi-Min An, Hui-Min Lei, Xu-Ping Ding, Fan Sun, Chun Zhang, Ya-Bin Tang, Hong-Zhuan Chen, Ying Shen, Liang Zhu
Gefitinib resistance and relapse of the disease were the greatest challenges facing clinical therapy of non-small-cell lung cancer (NSCLC). Of note, regarding the hypoxia condition in solid tumor tissues in vivo, roles of hypoxia in gefitinib adaptive resistance and its association with lung cancer stem cells (LCSCs) have not been fully elucidated. In the present study, the role of hypoxia in gefitinib adaptive resistance and its association with aldehyde dehydrogenase (ALDH)-based LCSC gefitinib resistance were comparatively studied using RNA-sequencing (RNA-seq) technology...
September 2017: Oncology Letters
https://www.readbyqxmd.com/read/28925407/foxc2-coordinates-inflammation-and-browning-of-white-adipose-by-leptin-stat3-prdm16-signal-in-mice
#5
L Gan, Z Liu, F Feng, T Wu, D Luo, C Hu, C Sun
AIMS: The objective of this study is to characterize the relationship between forkhead box C2 protein (Foxc2) and leptin under adipose inflammatory response. METHODS: Lipopolysaccharide (LPS)-induced inflammatory model was conducted. Data from wild-type and ob/ob mice were used to compare the alternative role of leptin on Foxc2-mediated inflammation and browning. Transcriptional regulation and protein-protein interaction were analyzed by bioinformatics and proved by chromatin immunoprecipitation and co-immunoprecipitation experiment...
August 23, 2017: International Journal of Obesity: Journal of the International Association for the Study of Obesity
https://www.readbyqxmd.com/read/28922657/methods-employed-in-cytofluorometric-assessment-of-eryptosis-the-suicidal-erythrocyte-death
#6
Mohamed Jemaà, Myriam Fezai, Rosi Bissinger, Florian Lang
Suicidal erythrocyte death or eryptosis contributes to or even accounts for anemia in a wide variety of clinical conditions, such as iron deficiency, dehydration, hyperphosphatemia, vitamin D excess, chronic kidney disease (CKD), hemolytic-uremic syndrome, diabetes, hepatic failure, malignancy, arteriitis, sepsis, fever, malaria, sickle-cell disease, beta-thalassemia, Hb-C and G6PD-deficiency, Wilsons disease, as well as advanced age. Moreover, eryptosis is triggered by a myriad of xenobiotics and endogenous substances including cytotoxic drugs and uremic toxins...
September 1, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28914550/socs3-participates-in-cholinergic-pathway-regulation-of-synovitis-in-rheumatoid-arthritis
#7
Tong Li, Shiyao Wu, Sha Li, Xuelian Bai, Hui Luo, Xiaoxia Zuo
Stimulation of the cholinergic inflammatory pathway can promote collagen-induced arthritis (CIA) and inhibit synovitis by Janus kinase (JAK) 2 and signal transducer and activator of transcription (STAT) 3 signaling. Suppressor of cytokine signaling (SOCS) protein can also regulate inflammatory processes and activate JAK/STAT signal transduction, but its involvement in rheumatoid arthritis (RA) has not been demonstrated. This study investigated the effect of SOCS on cholinergic pathway regulation of synovitis in the fibroblast-like synoviocytes (FLSs) of RA and CIA mice...
September 15, 2017: Connective Tissue Research
https://www.readbyqxmd.com/read/28913408/hepatocyte-specific-deletion-of-mouse-lamin-a-c-leads-to-male-selective-steatohepatitis
#8
Raymond Kwan, Graham F Brady, Maria Brzozowski, Sujith V Weerasinghe, Hope Martin, Min-Jung Park, Makayla J Brunt, Ram K Menon, Xin Tong, Lei Yin, Colin L Stewart, M Bishr Omary
BACKGROUND & AIMS: Lamins are nuclear intermediate filament proteins that comprise the major components of the nuclear lamina. Mutations in LMNA, which encodes lamins A/C, cause laminopathies, including lipodystrophy, cardiomyopathy, and premature aging syndromes. However, the role of lamins in the liver is unknown, and it is unclear whether laminopathy-associated liver disease is caused by primary hepatocyte defects or systemic alterations. METHODS: To address these questions, we generated mice carrying a hepatocyte-specific deletion of Lmna (knockout [KO] mice) and characterized the KO liver and primary hepatocyte phenotypes by immunoblotting, immunohistochemistry, microarray analysis, quantitative real-time polymerase chain reaction, and Oil Red O and Picrosirius red staining...
November 2017: Cellular and Molecular Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/28911610/myrciaria-cauliflora-extract-improves-diabetic-nephropathy-via-suppression-of-oxidative-stress-and-inflammation-in-streptozotocin-nicotinamide-mice
#9
Jeng-Dong Hsu, Chia-Chun Wu, Chi-Nan Hung, Chau-Jong Wang, Hui-Pei Huang
Myrciaria cauliflora is a functional food rich in anthocyanins, possessing antioxidative and anti-inflammatory properties. Our previous results demonstrated M. cauliflora extract (MCE) had beneficial effects in diabetic nephropathy (DN) and via the inhibition of Ras/PI3K/Akt and kidney fibrosis-related proteins. The purpose of this study was to assess the benefit of MCE in diabetes associated with kidney inflammation and glycemic regulation in streptozotocin-nicotinamide (STZ/NA)-induced diabetic mice. Compared with the untreated diabetic group, MCE significantly improved blood glucose and serum biochemical characteristic levels...
October 2016: Journal of Food and Drug Analysis
https://www.readbyqxmd.com/read/28901902/simian-varicella-virus-inhibits-the-interferon-gamma-signalling-pathway
#10
Werner J D Ouwendijk, Suzanne van Veen, Ravi Mahalingam, Georges M G M Verjans
The alphaherpesvirus simian varicella virus (SVV) causes varicella and zoster in nonhuman primates. Herpesviruses evolved elaborate mechanisms to escape host immunity, but the immune evasion strategies employed by SVV remain ill-defined. We analysed whether SVV impairs the cellular response to key antiviral cytokine interferon-γ (IFNγ). SVV infection inhibited the expression of IFNγ-induced genes like C-X-C motif chemokine 10 and interferon regulatory factor 1. Phosphorylation and nuclear translocation of the signal transducer and activator of transcription 1 (STAT1) was blocked in SVV-infected cells, which did not involve cellular and viral phosphatases...
September 13, 2017: Journal of General Virology
https://www.readbyqxmd.com/read/28901399/downregulated-socs1-expression-activates-the-jak1-stat1-pathway-and-promotes-polarization-of-macrophages-into-m1-type
#11
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/28901387/triptolide-blocks-the-stat3-signaling-pathway-through-induction-of-protein-tyrosine-phosphatase-shp-1-in-multiple-myeloma-cells
#12
Ji-Hun Kim, Byoungduck Park
Triptolide, an active component extracted from the medicinal plant Tripterygium wilfordii Hook F., has been used to treat various diseases, including lupus, cancer, rheumatoid arthritis and nephritic syndrome. The present study investigated the effects of triptolide on multiple myeloma using western blotting and an electrophoretic mobility shift assay. Triptolide was found to suppress the inducible and constitutive activation of signal transducer and activator of transcription 3 (STAT3), which is closely associated with inflammation and tumorigenesis...
September 6, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28893190/canonical-and-non-canonical-jak-stat-transcriptional-targets-may-be-involved-in-distinct-and-overlapping-cellular-processes
#13
Amy Tsurumi, Connie Zhao, Willis X Li
BACKGROUND: The Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway has been well-characterized as a crucial signal transduction cascade that regulates vital biological responses including development, immunity and oncogenesis. Additionally to its canonical pathway that uses the phosphorylated form of the STAT transcription factor, recently the non-canonical pathway involving heterochromatin formation by unphosphorylated STAT was recently uncovered. Considering the significant role of the JAK/STAT pathway, we used the simple Drosophila system in which the non-canonical pathway was initially characterized, to compare putative canonical versus non-canonical transcriptional targets across the genome...
September 11, 2017: BMC Genomics
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
#14
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/28887947/therapeutic-pipeline-for-atopic-dermatitis-end-of-the-drought
#15
REVIEW
Amy S Paller, Kenji Kabashima, Thomas Bieber
Until the past year, our therapeutic armamentarium for treating atopic dermatitis (AD) was still primarily topical corticosteroids and, for more severe disease, systemic immunosuppressants. The pipeline of more targeted topical and systemic therapies is expanding based on our growing understanding of the mechanism for AD and is particularly focused on suppressing the skewed immune activation. Most agents are in phase 2 clinical trials. Crisaborole, a topical phosphodiesterase 4 (PDE4) inhibitor, became available in late 2016 in the United States for mild-to-moderate AD, with other PDE4 inhibitors, an agonist of the aryl hydrocarbon receptor, Janus kinase inhibitors, and commensal organisms also in trials for topical application...
September 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28884378/efficacy-of-topical-tofacitinib-in-promoting-hair-growth-in-non-scarring-alopecia-possible-mechanism-via-vegf-induction
#16
Jitlada Meephansan, J Thummakriengkrai, S Ponnikorn, W Yingmema, R Deenonpoe, P Suchonwanit
Tofacitinib is a Janus kinase 3 (JAK3) inhibitor that promotes hair growth; however, the efficacy and mechanism of this effect are not yet understood. This study aimed to evaluate the efficacy and mechanism of topical tofacitinib on hair growth in mice. Eight-week-old male C57BL/6 mice were divided equally into four groups and treated topically with tofacitinib, minoxidil, or vehicle once daily for 21 days. Weekly photographs were taken to determine the area and rate of hair growth, and tissue samples were collected for histopathological evaluation...
September 7, 2017: Archives of Dermatological Research
https://www.readbyqxmd.com/read/28884137/hepatitis-b-virus-activates-signal-transducer-and-activator-of-transcription-3-supporting-hepatocyte-survival-and-virus-replication
#17
Marianna Hösel, Maria Quasdorff, Marc Ringelhan, Hamid Kashkar, Svenja Debey-Pascher, Martin F Sprinzl, Jan-Hendrik Bockmann, Silke Arzberger, Dennis Webb, Gesa von Olshausen, Achim Weber, Joachim L Schultze, Hildegard Büning, Mathias Heikenwalder, Ulrike Protzer
BACKGROUND & AIMS: The human hepatitis B virus (HBV) is a major cause of chronic hepatitis and hepatocellular carcinoma, but molecular mechanisms driving liver disease and carcinogenesis are largely unknown. We therefore studied cellular pathways altered by HBV infection. METHODS: We performed gene expression profiling of primary human hepatocytes infected with HBV and proved the results in HBV-replicating cell lines and human liver tissue using real-time polymerase chain reaction and Western blotting...
November 2017: Cellular and Molecular Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/28881828/shp2-negatively-regulates-hla-abc-and-pd-l1-expression-via-stat1-phosphorylation-in-prostate-cancer-cells
#18
Zhuqing Liu, Yu Zhao, Juemin Fang, Ran Cui, Yuanyuan Xiao, Qing Xu
Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) is a ubiquitous protein tyrosine phosphatase that activates the signal transduction pathways of several growth factors and cytokines. In our study, SHP2 expression was very high in prostate cancer (PCa) cell lines, and the expression of phospho-signal transducer and activator of transcription 1 (p-STAT1) and STAT1 was very low. SHP2 knockdown upregulated the expression of p-STAT1 and downregulated phospho-extracellular signal regulated kinase (p-ERK)...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28879797/amorfrutin-a-inhibits-tnf-%C3%AE-induced-jak-stat-signaling-cell-survival-and-proliferation-of-human-cancer-cells
#19
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
#20
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
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