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https://www.readbyqxmd.com/read/29140564/%C3%AE-catenin-and-il-1%C3%AE-dependent-cxcl10-production-drives-progression-of-disease-in-a-mouse-model-of-congenital-hepatic-fibrosis
#1
Eleanna Kaffe, Romina Fiorotto, Francesca Pellegrino, Valeria Mariotti, Mariangela Amenduni, Massimiliano Cadamuro, Luca Fabris, Mario Strazzabosco, Carlo Spirli
Congenital Hepatic Fibrosis (CHF), a genetic disease caused by mutations in the PKHD1 gene, encoding for the protein fibrocystin (FPC), is characterized by biliary dysgenesis, progressive portal fibrosis, and by a PKA-mediated activating phosphorylation of β-Catenin at Ser675. Biliary structures of Pkhd1(del4/del4) mice, a mouse model of CHF, secrete CXCL10 a chemokine able to recruit macrophages. The aim of this study is to clarify whether CXCL10 plays a pathogenetic role in disease progression in CHF/CD and to understand the mechanisms leading to increased CXCL10 secretion...
November 15, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29140428/hpv-negative-but-not-hpv-positive-oropharyngeal-carcinomas-induce-fibroblasts-to-support-tumour-invasion-through-micro-environmental-release-of-hgf-and-il-6
#2
Robert Bolt, Bernadette Foran, Craig Murdoch, Daniel W Lambert, Sally Thomas, Keith D Hunter
Human papillomavirus (HPV) infection is causally related to a subset of oropharyngeal carcinomas (OPC) and is linked to a more favourable prognosis compared to HPV-negative OPC. The mechanisms underlying this effect on prognosis are not fully understood, but interactions with the tumour microenvironment may be pivotal. Here, we investigated the role of the tumour microenvironment in HPV-positive compared to HPV-negative cancer using 2D and 3D modelling of OPC interactions with stromal fibroblasts. HPV-negative, but not HPV-positive, OPC-derived cell lines induced a rapid fibroblast secretory response that supported 2D cancer cell migration and invasion in vitro...
November 13, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/29139090/tofacitinib-a-review-in-rheumatoid-arthritis
#3
Sohita Dhillon
Tofacitinib (Xeljanz(®)) is a potent, selective JAK inhibitor that preferentially inhibits Janus kinase (JAK) 1 and JAK3. In the EU, oral tofacitinib 5 mg twice daily is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who have responded inadequately to, or who are intolerant of, one or more DMARDs. Several clinical studies of ≤ 24 months' duration showed that tofacitinib monotherapy (as first- or second-line treatment) and combination therapy with a conventional synthetic DMARD (csDMARD; as second- or third-line treatment) was effective in reducing signs and symptoms of disease and improving health-related quality of life (HR-QOL), with benefits sustained during long-term therapy (≤ 96 months)...
November 14, 2017: Drugs
https://www.readbyqxmd.com/read/29134817/the-bcr-abl1-negative-myeloproliferative-neoplasms-a-review-of-jak-inhibitors-in-the-therapeutic-armamentarium
#4
Martin Griesshammer, Parvis Sadjadian
The classical BCR-ABL1-negative myeloproliferative neoplasms (MPN) include primary myelofibrosis (PMF), polycythaemia vera (PV) and essential thrombocythaemia (ET). They are characterized by stem cell-derived clonal proliferation, harbour Janus kinase 2 (JAK2), or calreticulin (CALR), or myeloproliferative leukaemia virus oncogene (MPL) driver mutations and exert an over activated JAK-signal transducer and activator of transcription (STAT) pathway. Therefore JAK inhibiting strategies have been successfully investigated in MPN clinical trials...
November 14, 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/29134648/pharmacokinetics-pharmacodynamics-and-proposed-dosing-of-the-oral-jak1-and-jak2-inhibitor-baricitinib-in-pediatric-and-young-adult-candle-and-savi-patients
#5
Hanna Kim, Kristina M Brooks, Cheng Cai Tang, Paul Wakim, Mary Blake, Stephen R Brooks, Gina A Montealegre Sanchez, Adriana A de Jesus, Yan Huang, Wanxia Li Tsai, Massimo Gadina, Apurva Prakash, Jonathan Marcus Janes, Xin Zhang, William L Macias, Parag Kumar, Raphaela Goldbach-Mansky
Population pharmacokinetic (popPK) modeling was used to characterize the PK profile of the oral janus kinase (JAK)1/JAK2 inhibitor, baricitinib, in 18 patients with Mendelian interferonopathies who are enrolled in a compassionate use program. Patients received doses between 0.1 to 17 mg per day. Covariates of weight and renal function significantly influenced volume-of-distribution and clearance respectively. The half-life of baricitinib in patients less than 40kg was substantially shorter than in adult populations, requiring the need for dosing up to 4 times daily...
November 14, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29133913/nitric-oxide-mediated-inhibition-of-antigen-presentation-from-dcs-to-cd4-t-cells-in-cancer-and-measurement-of-stat1-nitration
#6
Joseph Markowitz, Jiang Wang, Zach Vangundy, Jia You, Vedat Yildiz, Lianbo Yu, Isaac P Foote, Owen E Branson, Andrew R Stiff, Taylor R Brooks, Brandon Biesiadecki, Thomas Olencki, Susheela Tridandapani, Michael A Freitas, Tracey Papenfuss, Mitch A Phelps, William E Carson
Myeloid derived suppressor cells (MDSC) produce nitric oxide (NO) and inhibit dendritic cell (DC) immune responses in cancer. DCs present cancer cell antigens to CD4(+) T cells through Jak-STAT signal transduction. In this study, NO donors (SNAP and DETA-NONOate) inhibited DC antigen presentation. As expected, MDSC isolated from peripheral blood mononuclear cells (PBMC) from cancer patients produced high NO levels. We hypothesized that NO producing MDSC in tumor-bearing hosts would inhibit DC antigen presentation...
November 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29132481/inhibitory-effect-of-ag490-on-stat3-signal-transduction-pathway-in-nasopharyngeal-carcinoma-cells
#7
Kai Li, Han Bao, Panying Zhang, Li Chen
OBJECTIVE: To determine the effect of JAK kinase inhibitor AG490 on proliferation and apoptosis of nasopharyngeal carcinoma cell line C666-1 and explore the inhibitory effect of AG490 on STAT3 signal transduction pathway. STUDY DESIGN: An experimental study. PLACE AND DURATION OF STUDY: Xi'an Ninth Hospital, Xi'an, China, from May 2015 to December 2016. METHODOLOGY: AG490 was applied to C666-1 cells. Cell proliferation was detected by MTTassay...
November 2017: Journal of the College of Physicians and Surgeons—Pakistan: JCPSP
https://www.readbyqxmd.com/read/29132131/il-6-promotes-fsh-induced-vegf-expression-through-jak-stat3-signaling-pathway-in-bovine-granulosa-cells
#8
Meng Yang, Lei Wang, Xurong Wang, Xuezhi Wang, Zhiqiang Yang, Jianxi Li
BACKGROUND/AIMS: Vascular endothelial growth factor (VEGF) has been demonstrated to play a pivotal role in the regulation of angiogenesis in ovarian follicular development, particularly during the preovulatory period. Although numerous studies have shown that interleukin-6 (IL-6) is one of the major inducing factors that regulate the expression of VEGF in non-ovarian cells, whether it involved in regulating the expression of VEGF in normal ovarian granulosa cells is still unknown. The aim of this study was to elucidate the mechanisms underlying the effect of IL-6 on FSH-induced VEGF expression in bovine granulosa cells derived from large follicles...
November 13, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29129493/overexpression-of-microrna-495-improves-the-intestinal-mucosal-barrier-function-by-targeting-stat3-via-inhibition-of-the-jak-stat3-signaling-pathway-in-a-mouse-model-of-ulcerative-colitis
#9
Xian-Qun Chu, Jing Wang, Guang-Xiang Chen, Guan-Qi Zhang, De-Yong Zhang, Yong-Yan Cai
We aim to investigate the role of microRNA-495 (miR-495) in the intestinal mucosal barrier by indirectly targeting signal transducer and activator of transcription 3 (STAT3) through the Janus kinase-signal transducer and activator of transcription (JAK)/STAT3 signaling pathway in a mouse model of ulcerative colitis (UC). BALB/c mice were selected for establishing mice model of UC, and intestinal tissues of normal and UC mice were collected. ELISA was conducted for detecting levels of TNF-α, IL-6, IFN-γ and IL-10...
October 12, 2017: Pathology, Research and Practice
https://www.readbyqxmd.com/read/29127481/expression-of-janus-kinase-1-in-vitiligo-psoriasis-before-and-after-narrow-band-uvb-a-case-control-study
#10
Hanan Rabea Nada, Dina Ahmed El Sharkawy, Maha Fathy Elmasry, Laila Ahmed Rashed, Sally Mamdouh
Janus kinases (JAKs) are non-receptor protein tyrosine kinases that are expressed in many tissues. Once the JAKs are activated, a cascade of further signaling events is triggered involving phosphorylation of selected receptor chain tyrosines, binding of signal transducer and activator of transcription (STAT) proteins and phosphorylation of these STATs. Due to their ability to selectively modulate immune function, targeted JAK inhibitors are promising candidates for some skin diseases such as psoriasis and atopic dermatitis...
November 10, 2017: Archives of Dermatological Research
https://www.readbyqxmd.com/read/29119628/stat3-expression-and-activity-are-up-regulated-in-diffuse-large-b-cell-lymphoma-of-dogs
#11
A L F V Assumpção, P C Jark, C C Hong, Z Lu, H M Ruetten, C M Heaton, M E Pinkerton, X Pan
BACKGROUND: The Janus Kinase (JAK) and Signal Transducer and Activator of Transcription (STAT) pathways play important roles in the pathogenesis of diffuse large B cell lymphoma (DLBCL) in humans, and up-regulated STAT3 expression and activity are associated with worse clinical outcome in humans. No studies have evaluated the JAK-STAT signaling pathway in DLBCL of dogs. HYPOTHESIS: STAT3 pathway is deregulated in DLBCL in dogs. We aim to assess the expression, activation, and cellular localization of STAT3 and mitogen-activated protein kinase ERK1/2 in DLBCL of dogs...
November 9, 2017: Journal of Veterinary Internal Medicine
https://www.readbyqxmd.com/read/29118906/rnai-mediated-silencing-of-nox4-inhibited-the-invasion-of-gastric-cancer-cells-through-jak2-stat3-signaling
#12
Xiang Gao, Jingping Sun, Chunyu Huang, Xiaohua Hu, Ning Jiang, Chenqi Lu
NADPH oxidase 4 (NOX4) is a member of the NADPH oxidase (NOX) family of enzymes and has been found abnormally expressed in human cancers. However, its role in gastric cancer (GC) is still unclear. In the current study, we reported that NOX4 expression levels were significantly up-regulated in GC tissues compared to normal tissues (P<0.0001). Higher NOX4 expression was significantly associated with poorer overall survival in GC patients. Silencing NOX4 in two NOX4 high expression GC cell lines, MGC-803 and BGC-823 cells, did not affect cell proliferation, while inhibited cell adhesion and cell invasion of GC cells...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/29115395/transforming-growth-factor-%C3%AE-1-promotes-migration-and-invasion-in-hepg2-cells-epithelial%C3%A2-to%C3%A2-mesenchymal-transition-via-jak-stat3-signaling
#13
Xiao-Long Lin, Mihua Liu, Yuanbo Liu, Huijun Hu, Yongquan Pan, Weiwen Zou, Xiaojuan Fan, Xuemei Hu
Transforming growth factor β1 (TGFβ1) is a cytokine with multiple functions. TGFβ1 significantly induces migration and invasion of liver cancer cells. However, the molecular mechanisms underlying this effect remain unclear. Epithelial‑to‑mesenchymal transition (EMT) is crucial for the development of invasion and metastasis in human cancers. The aim of the present study was to determine whether TGFβ1‑induced EMT promoted migration and invasion in HepG2 cells. The underlying mechanism and the effect of EMT on HepG2 cells were also investigated...
November 1, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29111217/ruxolitinib-partially-reverses-functional-nk-cell-deficiency-in-patients-with-stat1-gain-of-function-mutations
#14
Alexander Vargas-Hernandez, Emily M Mace, Ofer Zimmerman, Christa S Zerbe, Alexandra F Freeman, Sergio Rosenzweig, Jennifer W Leiding, Troy Torgerson, Matthew C Altman, Edith Schussler, Charlotte Cunningham-Rundles, Ivan K Chinn, Alexandre F Carisey, Imelda C Hanson, Nicholas L Rider, Steven M Holland, Jordan S Orange, Lisa R Forbes
BACKGROUND: Natural Killer (NK) cells are critical innate effector cells whose development is dependent on the JAK-STAT pathway. NK deficiency can result in severe or refractory viral infections. Patients with Signal Transducer and Activator of Transcription (STAT)1 gain of function (GOF) mutations have increased viral susceptibility. OBJECTIVE: We sought to investigate NK cell function in STAT1 GOF patients. METHODS: NK cell phenotype and function were determined in 16 STAT1 GOF patients...
October 27, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29108825/targeting-interferons-and-their-pathways-in-systemic-lupus-erythematosus
#15
REVIEW
François Chasset, Laurent Arnaud
Significant advances in the understanding of the molecular basis of innate immunity have led to the identification of interferons (IFNs), particularly IFN-α, as central mediators in the pathogenesis of Systemic Lupus Erythematosus. Therefore, targeting of IFNs and of their downstream pathways has emerged as important developments for novel drug research in SLE. Based on this, several specific interferon blocking strategies using anti-IFN-α antibodies, anti-type I interferon receptor antibodies, Interferon-α-kinoid, or anti-IFN-γ antibodies have all been assessed in recent clinical trials...
November 4, 2017: Autoimmunity Reviews
https://www.readbyqxmd.com/read/29107666/jak2-mutated-langerhans-cell-histiocytosis-associated-with-primary-myelofibrosis-treated-with-ruxolitinib
#16
Arturo Bonometti, Filippo Bagnoli, Daniele Fanoni, Luigia Venegoni, Laura Corti, Paola Bianchi, Elena Maria Elli, Giuseppe Isimbaldi, Vincenzo L'Imperio, Gianluca Nazzaro, Emanuela Passoni, Emilio Berti
The pathogenesis and cellular origin of Langerhans cell histiocytosis (LCH) are debated. Recently, mutations on MAPK and PI3K pathways have been linked to disrupted cell proliferation in LCH. Janus Kinase 2 (JAK2) mutations play the same role in Philadelphia-negative chronic myeloproliferative neoplasms. We describe the case of a patient affected by JAK2-positive Primary Myelofibrosis (PMF) who developed a clonally related LCH while in treatment with Ruxolitinib. JAK-inhibitors are well known to affect function and differentiation of different hematological lineages, including mononuclear phagocytes precursors...
October 28, 2017: Human Pathology
https://www.readbyqxmd.com/read/29106440/identification-of-pmn-released-mutagenic-factors-in-a-co-culture-model-for-colitis-associated-cancer
#17
Nicolas Granofszky, Michaela Lang, Vineeta Khare, Gerald Schmid, Theresa Scharl, Franziska Ferk, Kristine Jimenez, Siegfried Knasmüller, Christoph Campregher, Christoph Gasche
Microsatellite instability (MSI) is present in ulcerative colitis and colitis-associated colorectal cancers. Certain factors released by polymorphonuclear cells (PMN) may drive mucosal frameshift mutations resulting in MSI and cancer. Here, we applied a co-culture system with PMNs and colon epithelial cells to identify such culprit factors. Subjecting HCT116+chr3 and HCEC-1CT MSI-reporter cell lines harboring mono-, di- or tetranucleotide DNA repeats linked to EGFP to activated PMNs induced frameshift mutations within all repeats, as quantified by flow cytometry...
November 2, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/29104284/jak-inhibition-as-a-therapeutic-strategy-for-immune-and-inflammatory-diseases
#18
REVIEW
Daniella M Schwartz, Yuka Kanno, Alejandro Villarino, Michael Ward, Massimo Gadina, John J O'Shea
The discovery of cytokines as key drivers of immune-mediated diseases has spurred efforts to target their associated signalling pathways. Janus kinases (JAKs) are essential signalling mediators downstream of many pro-inflammatory cytokines, and small-molecule inhibitors of JAKs (jakinibs) have gained traction as safe and efficacious options for the treatment of inflammation-driven pathologies such as rheumatoid arthritis, psoriasis and inflammatory bowel disease. Building on the clinical success of first-generation jakinibs, second-generation compounds that claim to be more selective are currently undergoing development and proceeding to clinical trials...
November 6, 2017: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/29098608/novel-therapies-for-myelofibrosis
#19
REVIEW
Kristen Pettit, Olatoyosi Odenike
PURPOSE OF REVIEW: The purpose of the review was to provide a contemporary update of novel agents and targets under investigation in myelofibrosis in the Janus kinase (JAK) inhibitor era. RECENT FINDINGS: Myelofibrosis (MF) is a clonal stem cell disease characterized by marrow fibrosis and a heterogeneous disease phenotype with a variable degree of splenomegaly, cytopenias, and constitutional symptoms that significantly impact quality of life and survival. Overactive JAK/STAT signaling is a hallmark of MF...
November 2, 2017: Current Hematologic Malignancy Reports
https://www.readbyqxmd.com/read/29093269/b-cell-derived-il-4-acts-on-podocytes-to-induce-proteinuria-and-foot-process-effacement
#20
Alfred Hj Kim, Jun-Jae Chung, Shreeram Akilesh, Ania Koziell, Sanjay Jain, Jeffrey B Hodgin, Mark J Miller, Thaddeus S Stappenbeck, Jeffrey H Miner, Andrey S Shaw
The efficacy of B cell depletion therapies in diseases such as nephrotic syndrome and rheumatoid arthritis suggests a broader role in B cells in human disease than previously recognized. In some of these diseases, such as the minimal change disease subtype of nephrotic syndrome, pathogenic antibodies and immune complexes are not involved. We hypothesized that B cells, activated in the kidney, might produce cytokines capable of directly inducing cell injury and proteinuria. To directly test our hypothesis, we targeted a model antigen to the kidney glomerulus and showed that transfer of antigen-specific B cells could induce glomerular injury and proteinuria...
November 2, 2017: JCI Insight
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