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https://www.readbyqxmd.com/read/29322424/expression-and-purification-of-jak1-and-socs1-for-structural-and-biochemical-studies
#1
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/29316837/ruxolitinib-for-the-treatment-of-patients-with-steroid-refractory-gvhd-an-introduction-to-the-reach-trials
#2
Madan Jagasia, Robert Zeiser, Michael Arbushites, Patricia Delaite, Brian Gadbaw, Nikolas von Bubnoff
For patients with hematologic malignancies and disorders, allogeneic hematopoietic stem cell transplantation offers a potentially curative treatment option. Many patients develop graft-versus-host disease (GVHD), a serious complication and leading cause of nonrelapse mortality. Corticosteroids are the standard first-line treatment for GVHD; however, patients often become steroid-refractory or remain corticosteroid-dependent. New second-line treatment options are needed to improve patient outcomes. Here we review the role of JAK1 and JAK2 in acute and chronic GVHD...
January 10, 2018: Immunotherapy
https://www.readbyqxmd.com/read/29316631/psoriasis-a-stat3-centric-view
#3
REVIEW
Enzo Calautti, Lidia Avalle, Valeria Poli
Signal Transducer and Activator of Transcription (STAT)3 has recently emerged as a key player in the development and pathogenesis of psoriasis and psoriatic-like inflammatory conditions. Indeed, STAT3 hyperactivation has been reported in virtually every cell type involved in disease initiation and maintenance, and this factor mediates the signal of most cytokines that are involved in disease pathogenesis, including the central Interleukin (IL)-23/IL-17/IL-22 axis. Despite the recent availability of effective biological agents (monoclonal antibodies) against IL-17 and IL-23, which have radically changed the current standard of disease management, the possibility of targeting either STAT3 itself or, even better, the family of upstream activators Janus kinases (JAK1, 2, 3, and TYK2) offers additional therapeutic options...
January 6, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29311136/pharmacokinetics-and-disposition-of-momelotinib-revealed-a-disproportionate-human-metabolite-%C3%A2-resolution-for-clinical-development
#4
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/29301607/force-mediated-proinvasive-matrix-remodeling-driven-by-tumor-associated-mesenchymal-stem-like-cells-in-glioblastoma
#5
Eun-Jung Lim, Yongjoon Suh, Seungmo Kim, Seok-Gu Kang, Su-Jae Lee
In carcinoma, cancer-associated fibroblasts participate in force-mediated extracellular matrix (ECM) remodeling, consequently leading to invasion of cancer cells. Likewise, the ECM remodeling actively occurs in glioblastoma (GBM) and the consequent microenvironmental stiffness is strongly linked to migration behavior of GBM cells. However, in GBM the stromal cells responsible for force-mediated ECM remodeling remain unidentified. We show that tumor-associated mesenchymal stem-like cells (tMSLCs) provide a proinvasive matrix condition in GBM by force-mediated ECM remodeling...
January 5, 2018: BMB Reports
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
#6
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/29296821/progenitor-b-1-b-cell-acute-lymphoblastic-leukemia-is-associated-with-collaborative-mutations-in-3-critical-pathways
#7
Sheryl M Gough, Liat Goldberg, Marbin Pineda, Robert L Walker, Yuelin J Zhu, Sven Bilke, Yang Jo Chung, Joseph Dufraine, Subhadip Kundu, Elad Jacoby, Terry J Fry, Susanna Fischer, Renate Panzer-Grümayer, Paul S Meltzer, Peter D Aplan
B-1 and B-2 lymphocytes are derived from distinct developmental pathways and represent layered arms of the innate and adaptive immune systems, respectively. In contrast to a majority of murine B-cell malignancies, which stain positive with the B220 antibody, we discovered a novel form of B-cell leukemia in NUP98-PHF23 (NP23) transgenic mice. The immunophenotype (Lin- B220- CD19+ AA4.1+) was identical to that of progenitor (pro) B-1 cells, and VH gene usage was skewed toward 3' V regions, similar to murine fetal liver B cells...
September 12, 2017: Blood Advances
https://www.readbyqxmd.com/read/29296819/impact-of-genomic-alterations-on-outcomes-in-myelofibrosis-patients-undergoing-jak1-2-inhibitor-therapy
#8
Jay Y Spiegel, Caroline McNamara, James A Kennedy, Tony Panzarella, Andrea Arruda, Tracy Stockley, Mahadeo Sukhai, Mariam Thomas, Justyna Bartoszko, Jenny Ho, Nancy Siddiq, Dawn Maze, Aaron Schimmer, Andre Schuh, Hassan Sibai, Karen Yee, Jamie Claudio, Rebecca Devlin, Mark D Minden, Suzanne Kamel-Reid, Vikas Gupta
In myelofibrosis (MF), driver mutations in JAK2, MPL, or CALR impact survival and progression to blast phase, with the greatest risk conferred by triple-negative status. Subclonal mutations, including mutations in high-molecular risk (HMR) genes, such as ASXL1, EZH2, IDH1/2, and SRSF2 have also been associated with inferior prognosis. However, data evaluating the impact of next-generation sequencing in MF patients treated with JAK1/2 inhibitors are lacking. Using a 54-gene myeloid panel, we performed targeted sequencing on 100 MF patients treated with ruxolitinib (n = 77) or momelotinib (n = 23) and correlated mutational profiles with treatment outcomes...
September 12, 2017: Blood Advances
https://www.readbyqxmd.com/read/29296813/oncogenic-role-and-therapeutic-targeting-of-abl-class-and-jak-stat-activating-kinase-alterations-in-ph-like-all
#9
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/29295936/gene-regulation-and-suppression-of-type-i-interferon-signaling-by-stat3-in-diffuse-large-b-cell-lymphoma
#10
Li Lu, Fen Zhu, Meili Zhang, Yangguang Li, Amanda C Drennan, Shuichi Kimpara, Ian Rumball, Christopher Selzer, Hunter Cameron, Ashley Kellicut, Amanda Kelm, Fangyu Wang, Thomas A Waldmann, Lixin Rui
STAT3 is constitutively activated in many cancers and regulates gene expression to promote cancer cell survival, proliferation, invasion, and migration. In diffuse large B cell lymphoma (DLBCL), activation of STAT3 and its kinase JAK1 is caused by autocrine production of IL-6 and IL-10 in the activated B cell-like subtype (ABC). However, the gene regulatory mechanisms underlying the pathogenesis of this aggressive lymphoma by STAT3 are not well characterized. Here we performed genome-wide analysis and identified 2,251 STAT3 direct target genes, which involve B cell activation, survival, proliferation, differentiation, and migration...
January 2, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29285104/carboxymethyl-chitosan-attenuates-inducible-nitric-oxide-synthase-and-promotes-interleukin-10-production-in-rat-chondrocytes
#11
Ying Kong, Yuanmin Zhang, Xiaowei Zhao, Guodong Wang, Qingkuan Liu
Osteoarthritis (OA) is a common age-related degenerative joint disease, which is caused by the breakdown of joint cartilage and the underlying bone. Carboxymethyl (CM)-chitosan is a soluble derivative of chitosan that has similar physicochemical properties to the extracellular proteoglycans identified in hyaline cartilage. Previous studies have demonstrated that CM-chitosan serves a protective role in a rabbit OA model. The aim of the present study was to investigate the effect of CM-chitosan on NO production and inflammation through its upregulation of interleukin (IL)-10, and the activation of the janus kinase (JAK)/signal transducer and activator of transcription (STAT)/suppressor of cytokine signaling (SOCS) signaling pathway...
December 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29278700/pafr-deficiency-alleviates-myocardial-ischemia-reperfusion-injury-in-mice-via-suppressing-inflammation-oxidative-stress-and-apoptosis
#12
En-Wei Wang, Yang-Yang Han, Xu-Sheng Jia
Myocardial ischemia/reperfusion (I/R) still have high morbidity and mortality worldwide. Platelet activating factor (PAF) is a potent phospholipid regulator of inflammation. PAF acts on a single receptor (PAFR), which is expressed on cellular and nuclear membranes of various cell types. The study is aimed to explore if PAFR could modulate myocardial I/R injury in mice. PAFR expressions began to up-regulate at 1 h, and reached peak at 24 h. PAFR deletion markedly attenuated myocardial I/R injury, evidenced by the reduced infarct size and the improved cardiac function...
December 23, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29277359/soho-state-of-the-art-update-and-next-questions-mpn
#13
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/29248622/partial-enteral-nutrition-increases-intestinal-siga-levels-in-mice-undergoing-parenteral-nutrition-in-a-dose-dependent-manner
#14
Haifeng Sun, Jingcheng Bi, Qiucheng Lei, Xiao Wan, Tingting Jiang, Chao Wu, Xinying Wang
BACKGROUND AND AIMS: Partial enteral nutrition (PEN) protects parenteral nutrition (PN) induced gut mucosal immunity impairment. However, the gastrointestinal function of most patients with PN is too poor to tolerate full dosage of PEN and no guidelines recommend PEN dose. We aimed to identify an optimal PEN dose and to understand the protective mechanism. METHODS: Mice were assigned to groups with total parenteral nutrition (TPN), total enteral nutrition (TEN), or various degrees of PEN with PN...
December 14, 2017: International Journal of Surgery
https://www.readbyqxmd.com/read/29235894/pacritinib-and-its-use-in-the-treatment-of-patients-with-myelofibrosis-who-have-thrombocytopenia
#15
Adolfo Enrique Diaz, Ruben A Mesa
The treatment landscape for myelofibrosis (MF) has reached the molecular era by targeting different pathways that are implied in this myeloproliferative neoplasm. A few years ago, the first-in-class JAK1/JAK2 inhibitor ruxolitinib, demonstrated reductions in both constitutional symptoms and splenomegaly, leading to the US FDA approval. The development or worsening of cytopenias in patients receiving ruxolitinib uncovered an unmet need that has been addressed by alternative approaches. Pacritinib, a dual JAK2 and FLT3 inhibitor which also inhibits IRAK1, has demonstrated the ability to favorably impact MF-associated splenomegaly and symptom burden, while having limited myelosuppression with manageable gastrointestinal toxicity...
December 13, 2017: Future Oncology
https://www.readbyqxmd.com/read/29228628/drug-sensitivity-profiling-identifies-potential-therapies-for-lymphoproliferative-disorders-with-overactive-jak-stat3-signaling
#16
Heikki Kuusanmäki, Olli Dufva, Elina Parri, Arjan J van Adrichem, Hanna Rajala, Muntasir M Majumder, Bhagwan Yadav, Alun Parsons, Wing C Chan, Krister Wennerberg, Satu Mustjoki, Caroline A Heckman
Constitutive JAK/STAT3 signaling contributes to disease progression in many lymphoproliferative disorders. Recent genetic analyses have revealed gain-of-function STAT3 mutations in lymphoid cancers leading to hyperactivation of STAT3, which may represent a potential therapeutic target. Using a functional reporter assay, we screened 306 compounds with selective activity against various target molecules to identify drugs capable of inhibiting the cellular activity of STAT3. Top hits were further validated with additional models including STAT3-mutated natural killer (NK)-cell leukemia/lymphoma cell lines and primary large granular lymphocytic (LGL) leukemia cells to assess their ability to inhibit STAT3 phosphorylation and STAT3 dependent cell viability...
November 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/29228564/inhibitors-of-the-pi3k-mtor-pathway-prevent-stat5-phosphorylation-in-jak2v617f-mutated-cells-through-pp2a-cip2a-axis
#17
Niccolò Bartalucci, Laura Calabresi, Manjola Balliu, Serena Martinelli, Maria Caterina Rossi, Jean Luc Villeval, Francesco Annunziato, Paola Guglielmelli, Alessandro M Vannucchi
Inhibition of the constitutively activated JAK/STAT pathway in JAK2V617F mutated cells by the JAK1/JAK2 inhibitor ruxolitinib resulted in clinical benefits in patients with myeloproliferative neoplasms. However, evidence of disease-modifying effects remains scanty; furthermore, some patients do not respond adequately to ruxolitinib, or have transient responses, thus novel treatment strategies are needed. Here we demonstrate that ruxolitinib causes incomplete inhibition of STAT5 in JAK2V617F mutated cells due to persistence of phosphorylated serine residues of STAT5b, that conversely are targeted by PI3K and mTORC1 inhibitors...
November 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/29228427/mir-155-regulates-lymphoma-cell-proliferation-and-apoptosis-through-targeting-socs3-jak-stat3-signaling-pathway
#18
X-D Li, X-M Li, J-W Gu, X-C Sun
OBJECTIVE: Janus kinase (JAK)- signal transducer and activator of transcription (STAT) signaling pathway participates in regulating cell proliferation, differentiation, and apoptosis, and related to lymphoma. Suppressors of cytokine signaling 3 (SOCS3) is a negative regulator of the JAK-STAT signaling pathway. SOCS3 reduction and miR-155 up-regulation are associated with lymphoma pathogenesis. Bioinformatics analysis showed the complementary binding site between miR-155 and SOCS3. This study aimed to investigate the role of miR-155 in regulating SOCS3/JAK-STAT signaling pathway and affecting diffuse large B cell lymphoma (DLBCL) cell proliferation and apoptosis...
November 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/29228301/targeted-inhibition-of-janus-kinases-abates-interfon-gamma-induced-invasive-behaviour-of-fibroblast-like-synoviocytes
#19
Thomas Karonitsch, Denise Beckmann, Karolina Dalwigk, Birgit Niederreiter, Paul Studenic, Ruth A Byrne, Johannes Holinka, Florian Sevelda, Adelheid Korb-Pap, Günter Steiner, Josef S Smolen, Thomas Pap, Hans P Kiener
Objectives: The aim was to explore the function of the T-cell cytokine IFNγ for mesenchymal tissue remodelling in RA and to determine whether IFNγ signalling controls the invasive potential of fibroblast-like synoviocytes (FLS). Methods: To assess architectural responses, FLS were cultured in three-dimensional micromasses. FLS motility was analysed in migration and invasion assays. Signalling events relevant to cellular motility were defined by western blots. Baricitinib and small interfering RNA pools were used to suppress Janus kinase (JAK) functions...
December 7, 2017: Rheumatology
https://www.readbyqxmd.com/read/29224367/effect-of-ruxolitinib-therapy-on-the-quality-of-life-of-japanese-patients-with-myelofibrosis
#20
Kenji Oritani, Kohshi Ohishi, Shinichiro Okamoto, Keita Kirito, Norio Komatsu, Tetsuzo Tauchi, Hiroshi Handa, Shigeki Saito, Katsuto Takenaka, Kazuya Shimoda, Hikaru Okada, Taro Amagasaki, Shiho Wakase, Kojiro Shimozuma, Koichi Akashi
OBJECTIVES: Myelofibrosis (MF) is associated with a significant symptom burden that severely impacts patient quality of life (QOL). Ruxolitinib, a potent Janus kinase 1 (JAK1)/JAK2 inhibitor, led to substantial improvements in splenomegaly, MF-associated symptoms, and QOL in the phase 3 COMFORT studies, proving superior to placebo and best available therapy. We evaluated the effect of ruxolitinib on symptoms and QOL in Japanese patients with MF. METHODS: We conducted a pooled analysis of studies A2202 (NCT01392443) and AJP01 (NCT02087059) of ruxolitinib in Japanese patients with MF (N = 81)...
December 9, 2017: Current Medical Research and Opinion
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