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https://www.readbyqxmd.com/read/27875628/clinical-genomic-profiling-identifies-tyk2-mutation-and-overexpression-in-patients-with-neurofibromatosis-type-1-associated-malignant-peripheral-nerve-sheath-tumors
#1
Angela C Hirbe, Madhurima Kaushal, Mukesh Kumar Sharma, Sonika Dahiya, Melike Pekmezci, Arie Perry, David H Gutmann
BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that arise at an estimated frequency of 8% to 13% in individuals with neurofibromatosis type 1 (NF1). Compared with their sporadic counterparts, NF1-associated MPNSTs (NF1-MPNSTs) develop in young adults, frequently recur (approximately 50% of cases), and carry a dismal prognosis. As such, most individuals affected with NF1-MPNSTs die within 5 years of diagnosis, despite surgical resection combined with radiotherapy and chemotherapy...
November 22, 2016: Cancer
https://www.readbyqxmd.com/read/27815207/poly-i-c-facilitates-the-phosphorylation-of-ctenopharyngodon-idellus-type-i-ifn-receptor-subunits-and-jak-kinase
#2
Qunhao Hou, Ruiyue Gong, Xiancheng Liu, Huiling Mao, Xiaowen Xu, Dan Liu, Zao Dai, Haizhou Wang, Binhua Wang, Chengyu Hu
Members of the Janus kinase (JAK) family, JAK1 and TYK2 take part in JAK-STAT signaling pathway mediated by interferon in mammalian cells. Similar to the mammalian counterparts, fish JAK1 and TYK2 also perform their potential biological activities by phosphorylating cytokine receptors and STAT. In the present study, Ctenopharyngodon idellus JAK1 (CiJAK1) and TYK2 (CiTYK2) were cloned and identified. The full-length cDNA of CiJAK1 (KT724352.1) is 3829 bp, with an Open Reading Frame (ORF) of 3465 bp encoding a putative protein of 1154 amino acids...
November 1, 2016: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/27810495/psoriasis-risk-snps-and-their-association-with-hiv-1-control
#3
Joanne Nititham, Rashmi Gupta, Xue Zeng, Wendy Hartogensis, Douglas F Nixon, Steven G Deeks, Frederick M Hecht, Wilson Liao
Human evolution has resulted in selection for genetic polymorphisms beneficial in the defense against pathogens. However, such polymorphisms may have the potential to heighten the risk of autoimmune disease. Here, we investigated whether psoriasis-associated single nucleotide polymorphisms influence host control of HIV-1 infection. We studied psoriasis and viral immune response variants in three HIV-positive cohorts: (1) HIV-1 controllers and non-controllers in the Study of the Consequences of the Protease Inhibitor Era (SCOPE) cohort (n=366), (2) Individuals with primary HIV infection in the Options cohort (n=675), and (3) HIV-positive injection drug users from the Urban Health Study (UHS) (n=987)...
October 31, 2016: Human Immunology
https://www.readbyqxmd.com/read/27807284/resolving-tyk2-locus-genotype-to-phenotype-differences-in-autoimmunity
#4
Calliope A Dendrou, Adrian Cortes, Lydia Shipman, Hayley G Evans, Kathrine E Attfield, Luke Jostins, Thomas Barber, Gurman Kaur, Subita Balaram Kuttikkatte, Oliver A Leach, Christiane Desel, Soren L Faergeman, Jane Cheeseman, Matt J Neville, Stephen Sawcer, Alastair Compston, Adam R Johnson, Christine Everett, John I Bell, Fredrik Karpe, Mark Ultsch, Charles Eigenbrot, Gil McVean, Lars Fugger
Thousands of genetic variants have been identified, which contribute to the development of complex diseases, but determining how to elucidate their biological consequences for translation into clinical benefit is challenging. Conflicting evidence regarding the functional impact of genetic variants in the tyrosine kinase 2 (TYK2) gene, which is differentially associated with common autoimmune diseases, currently obscures the potential of TYK2 as a therapeutic target. We aimed to resolve this conflict by performing genetic meta-analysis across disorders; subsequent molecular, cellular, in vivo, and structural functional follow-up; and epidemiological studies...
November 2, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27802075/kinase-inactive-tyrosine-kinase-tyk2-supports-differentiation-of-brown-fat-cells
#5
Vidisha Raje, Marta Derecka, Marc Cantwell, Jeremy Meier, Karol Szczepanek, Jennifer D Sisler, Birgit Strobl, Ana Gamero, Thurl E Harris, Andrew C Larner
It has been known for decades that brown adipose tissue plays a central role in maintaining body temperature in hibernating animals, and human infants. Recently it has become evident that there are also depots of brown fat in adult humans, and the mass of brown fat is inversely correlated with body weight. There are a variety of transcription factors implicated in the differentiation of classical Myf5+ brown preadipocytes, one of the most important of which is PRDM16. We have recently identified that in addition to PRDM16, the tyrosine kinase Tyk2 and the STAT3 transcription factor are required for the differentiation of Myf5 positive brown preadipocytes both in cell culture and in mice...
November 1, 2016: Endocrinology
https://www.readbyqxmd.com/read/27788604/pirfenidone-exerts-a-suppressive-effect-on-ccl18-expression-in-u937-derived-macrophages-partly-by-inhibiting-stat6-phosphorylation
#6
Yoshinobu Saito, Arata Azuma, Kuniko Matsuda, Koichiro Kamio, Shinji Abe, Akihiko Gemma
CONTEXT: CC chemokine ligand 18 (CCL18) is suggested to play a role in the development of pulmonary fibrosis. Macrophages are thought to be the main source of CCL18, and the effect of pirfenidone, an anti-fibrotic agent for idiopathic pulmonary fibrosis, on the expression of CCL18 in macrophages warrants investigation. OBJECTIVE: The purpose of this study was to investigate the effect of pirfenidone on the expression of CCL18 in macrophages. MATERIALS AND METHODS: U937 cells were differentiated into macrophages by phorbol myristate acetate and then stimulated with recombinant IL-4 to induce the production of CCL18...
October 27, 2016: Immunopharmacology and Immunotoxicology
https://www.readbyqxmd.com/read/27774824/inhibitors-of-jak-family-kinases-an-update-on-the-patent-literature-2013-2015-part-1
#7
Jason G Kettle, Annika Åstrand, Matthew Catley, Neil P Grimster, Magnus Nilsson, Qibin Su, Richard Woessner
Introduction Janus kinases (JAKs) are a family of four enzymes; JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2) that are critical in cytokine signalling and are strongly linked to both cancer and inflammatory diseases. There are currently two launched JAK inhibitors for the treatment of human conditions: tofacitinib for Rheumatoid arthritis (RA) and ruxolitinib for myeloproliferative neoplasms including intermediate or high risk myelofibrosis and polycythemia vera. Areas covered This review covers patents claiming activity against one or more JAK family members in the period 2013-2015 inclusive, and covers 95 patents from 42 applicants, split over two parts...
October 24, 2016: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/27774822/inhibitors-of-jak-family-kinases-an-update-on-the-patent-literature-2013-2015-part-2
#8
Jason G Kettle, Annika Åstrand, Matthew Catley, Neil P Grimster, Magnus Nilsson, Qibin Su, Richard Woessner
Introduction Janus kinases (JAKs) are a family of four enzymes; JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2) that are critical in cytokine signalling and are strongly linked to both cancer and inflammatory diseases. There are currently two launched JAK inhibitors for the treatment of human conditions: tofacitinib for Rheumatoid arthritis (RA) and ruxolitinib for myeloproliferative neoplasms including intermediate or high risk myelofibrosis and polycythemia vera. Areas covered This review covers patents claiming activity against one or more JAK family members in the period 2013-2015 inclusive, and covers 95 patents from 42 applicants, split over two parts...
October 24, 2016: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/27774581/a-preliminary-study-of-new-single-polymorphisms-in-th17-pathway-for-psoriasis-in-the-korean-population
#9
Soo Young Kim, Min Seok Hur, Byung Gon Choi, Min Jung Kim, Yang Won Lee, Yong Beom Choe, Kyu Joong Ahn
Psoriasis is a polygenic and multifactorial disease showing ethnic differences in terms of its severity and frequency. Therapies targeting interleukin 17A (IL-17A), interleukin 17 receptor (IL-17R), and Janus kinases (JAKs) are in clinical development for the treatment of psoriasis, and their success suggests the essential role of these molecules in psoriasis. To investigate the genetic susceptibility in T helper 17 (Th17) cell signal transduction pathways for promoting psoriasis, we performed candidate gene and linkage disequilibrium analysis...
October 24, 2016: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/27733777/germline-activating-tyk2-mutations-in-pediatric-patients-with-two-primary-acute-lymphoblastic-leukemia-occurrences
#10
E Waanders, B Scheijen, M C J Jongmans, H Venselaar, S V van Reijmersdal, A H A van Dijk, A Pastorczak, R D A Weren, C E van der Schoot, M van de Vorst, E Sonneveld, N Hoogerbrugge, V H J van der Velden, B Gruhn, P M Hoogerbrugge, J J M van Dongen, A G van Kessel, F N van Leeuwen, R P Kuiper
The contribution of genetic predisposing factors to the development of pediatric acute lymphoblastic leukemia (ALL), the most frequently diagnosed cancer in childhood, has not been fully elucidated. Children presenting with multiple de novo leukemias are more likely to suffer from genetic predisposition. Here, we selected five of these patients and analyzed the mutational spectrum of normal and malignant tissues. In two patients, we identified germline mutations in TYK2, a member of the JAK tyrosine kinase family...
October 13, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27725180/crystal-structure-of-a-complex-of-the-intracellular-domain-of-interferon-%C3%AE-receptor-1-ifnlr1-and-the-ferm-sh2-domains-of-human-jak1
#11
Di Zhang, Alexander Wlodawer, Jacek Lubkowski
The crystal structure of a construct consisting of the FERM and SH2-like domains of the human Janus kinase 1 (JAK1) bound to a fragment of the intracellular domain of the interferon-λ receptor 1 (IFNLR1) has been determined at the nominal resolution of 2.1Å. In this structure, the receptor peptide forms an 85-Å-long extended chain, in which both the previously identified box1 and box2 regions bind simultaneously to the FERM and SH2-like domains of JAK1. Both domains of JAK1 are generally well ordered, with regions not seen in the crystal structure limited to loops located away from the receptor-binding regions...
October 7, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27711196/jak3-as-an-emerging-target-for-topical-treatment-of-inflammatory-skin-diseases
#12
Ana Karina Alves de Medeiros, Reinhart Speeckaert, Eline Desmet, Mireille Van Gele, Sofie De Schepper, Jo Lambert
The recent interest and elucidation of the JAK/STAT signaling pathway created new targets for the treatment of inflammatory skin diseases (ISDs). JAK inhibitors in oral and topical formulations have shown beneficial results in psoriasis and alopecia areata. Patients suffering from other ISDs might also benefit from JAK inhibition. Given the development of specific JAK inhibitors, the expression patterns of JAKs in different ISDs needs to be clarified. We aimed to analyze the expression of JAK/STAT family members in a set of prevalent ISDs: psoriasis, lichen planus (LP), cutaneous lupus erythematosus (CLE), atopic dermatitis (AD), pyoderma gangrenosum (PG) and alopecia areata (AA) versus healthy controls for (p)JAK1, (p)JAK2, (p)JAK3, (p)TYK2, pSTAT1, pSTAT2 and pSTAT3...
2016: PloS One
https://www.readbyqxmd.com/read/27693579/the-oxoglutarate-receptor-1-oxgr1-modulates-pressure-overload-induced-cardiac-hypertrophy-in-mice
#13
Ameh Omede, Min Zi, Sukhpal Prehar, Arfa Maqsood, Nicholas Stafford, Mamas Mamas, Elizabeth Cartwright, Delvac Oceandy
The G-protein-coupled receptors (GPCRs) family of proteins play essential roles in the heart, including in the regulation of cardiac hypertrophy. One member of this family, the oxoglutarate receptor 1 (OXGR1), may have a crucial role in the heart because it acts as a receptor for α-ketoglutarate, a metabolite that is elevated in heart failure patients. OXGR1 is expressed in the heart but its precise function during cardiac pathophysiological process is unknown. Here we used both in vivo and in vitro approaches to investigate the role of OXGR1 in cardiac hypertrophy...
October 28, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27615517/tyrosine-kinase-2-is-not-limiting-human-antiviral-type-iii-interferon-responses
#14
Sebastian Fuchs, Petra Kaiser-Labusch, Julia Bank, Sandra Ammann, Anja Kolb-Kokocinski, Christine Edelbusch, Heymut Omran, Stephan Ehl
Tyrosine kinase 2 (TYK2) associates with interferon (IFN) alpha receptor, IL-10 receptor (IL-10R) beta and other cytokine receptor subunits for signal transduction, in response to various cytokines, including type-I and type-III IFNs, IL-6, IL-10, IL-12 and IL-23. Data on TYK2 dependence on cytokine responses and in vivo consequences of TYK2 deficiency are inconsistent. We investigated a TYK2 deficient patient, presenting with eczema, skin abscesses, respiratory infections and IgE levels >1000 U/mL, without viral or mycobacterial infections and a corresponding cellular model to analyze the role of TYK2 in type-III IFN mediated responses and NK-cell function...
October 5, 2016: European Journal of Immunology
https://www.readbyqxmd.com/read/27511303/molecular-immunology-profiles-of-monkeys-following-xenografting-with-the-islets-and-heart-of-%C3%AE-1-3-galactosyltransferase-knockout-pigs
#15
Sun A Ock, Jungkyu Lee, Keon Bong Oh, Seongsoo Hwang, Ik Jin Yun, Curie Ahn, Hyun Keun Chee, Hwajung Kim, Jae Berm Park, Sung Joo Kim, Youngim Kim, Gi-Sun Im, EungWoo Park
Effective immunosuppression strategies and genetically modified animals have been used to prevent hyperacute and acute xenograft rejection; however, the underlying mechanisms remain unknown. In this study, we evaluated the expression of a comprehensive set of immune system-related genes (89 genes, including five housekeeping genes) in the blood of cynomolgus monkeys (~5 yr old) used as graft recipients, before and after the xenografting of the islets and heart from single and double α-1,3-galactosyltransferase (GalT) knockout (KO) pigs (<6 weeks old)...
September 2016: Xenotransplantation
https://www.readbyqxmd.com/read/27473820/janus-kinase-jak-inhibitors-in-the-treatment-of-inflammatory-and-neoplastic-diseases
#16
REVIEW
Robert Roskoski
The Janus kinase (JAK) family of non-receptor protein-tyrosine kinases consists of JAK1, JAK2, JAK3, and TYK2 (tyrosine kinase-2). Each of these proteins contains a JAK homology pseudokinase (JH2) domain that regulates the adjacent protein kinase domain (JH1). JAK1/2 and TYK2 are ubiquitously expressed whereas JAK3 is found predominantly in hematopoietic cells. The Janus kinase family is regulated by numerous cytokines including interleukins, interferons, and hormones such as erythropoietin, thrombopoietin, and growth hormone...
September 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/27472900/trisomy-21-consistently-activates-the-interferon-response
#17
Kelly D Sullivan, Hannah C Lewis, Amanda A Hill, Ahwan Pandey, Leisa P Jackson, Joseph M Cabral, Keith P Smith, L Alexander Liggett, Eliana B Gomez, Matthew D Galbraith, James DeGregori, Joaquín M Espinosa
Although it is clear that trisomy 21 causes Down syndrome, the molecular events acting downstream of the trisomy remain ill defined. Using complementary genomics analyses, we identified the interferon pathway as the major signaling cascade consistently activated by trisomy 21 in human cells. Transcriptome analysis revealed that trisomy 21 activates the interferon transcriptional response in fibroblast and lymphoblastoid cell lines, as well as circulating monocytes and T cells. Trisomy 21 cells show increased induction of interferon-stimulated genes and decreased expression of ribosomal proteins and translation factors...
2016: ELife
https://www.readbyqxmd.com/read/27462774/genomic-complexity-and-dynamics-of-clonal-evolution-in-childhood-acute-myeloid-leukemia-studied-with-whole-exome-sequencing
#18
Riccardo Masetti, Ilaria Castelli, Annalisa Astolfi, Salvatore Nicola Bertuccio, Valentina Indio, Marco Togni, Tamara Belotti, Salvatore Serravalle, Giuseppe Tarantino, Marco Zecca, Martina Pigazzi, Giuseppe Basso, Andrea Pession, Franco Locatelli
Despite significant improvement in treatment of childhood acute myeloid leukemia (AML), 30% of patients experience disease recurrence, which is still the major cause of treatment failure and death in these patients. To investigate molecular mechanisms underlying relapse, we performed whole-exome sequencing of diagnosis-relapse pairs and matched remission samples from 4 pediatric AML patients without recurrent cytogenetic alterations. Candidate driver mutations were selected for targeted deep sequencing at high coverage, suitable to detect small subclones (0...
July 22, 2016: Oncotarget
https://www.readbyqxmd.com/read/27440135/investigation-of-the-genetic-overlap-between-rheumatoid-arthritis-and-psoriatic-arthritis-in-a-greek-population
#19
E Myrthianou, M I Zervou, A Budu-Aggrey, E Eliopoulos, D Kardassis, D T Boumpas, N Kougkas, A Barton, P Sidiropoulos, G N Goulielmos
OBJECTIVES: Several rheumatoid arthritis (RA) susceptibility loci have also been found to be associated with psoriatic arthritis (PsA), demonstrating that there is a degree of genetic overlap between various autoimmune diseases. We sought to investigate whether single nucleotide polymorphisms (SNPs) mapping to previously reported RA and/or PsA susceptibility loci, including PLCL2, CCL21, REL, STAT4, CD226, PTPN22, and TYK2, are associated with risk for the two diseases in a genetically homogeneous Greek population...
July 20, 2016: Scandinavian Journal of Rheumatology
https://www.readbyqxmd.com/read/27401342/unique-and-shared-signaling-pathways-cooperate-to-regulate-the-differentiation-of-human-cd4-t-cells-into-distinct-effector-subsets
#20
Cindy S Ma, Natalie Wong, Geetha Rao, Akira Nguyen, Danielle T Avery, Kathryn Payne, James Torpy, Patrick O'Young, Elissa Deenick, Jacinta Bustamante, Anne Puel, Satoshi Okada, Masao Kobayashi, Ruben Martinez-Barricarte, Michael Elliott, Sara Sebnem Kilic, Jamila El Baghdadi, Yoshiyuki Minegishi, Aziz Bousfiha, Nic Robertson, Sophie Hambleton, Peter D Arkwright, Martyn French, Annaliesse K Blincoe, Peter Hsu, Dianne E Campbell, Michael O Stormon, Melanie Wong, Stephen Adelstein, David A Fulcher, Matthew C Cook, Polina Stepensky, Kaan Boztug, Rita Beier, Aydan Ikincioğullari, John B Ziegler, Paul Gray, Capucine Picard, Stéphanie Boisson-Dupuis, Tri Giang Phan, Bodo Grimbacher, Klaus Warnatz, Steven M Holland, Gulbu Uzel, Jean-Laurent Casanova, Stuart G Tangye
Naive CD4(+) T cells differentiate into specific effector subsets-Th1, Th2, Th17, and T follicular helper (Tfh)-that provide immunity against pathogen infection. The signaling pathways involved in generating these effector cells are partially known. However, the effects of mutations underlying human primary immunodeficiencies on these processes, and how they compromise specific immune responses, remain unresolved. By studying individuals with mutations in key signaling pathways, we identified nonredundant pathways regulating human CD4(+) T cell differentiation in vitro...
July 25, 2016: Journal of Experimental Medicine
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