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https://www.readbyqxmd.com/read/27910962/baricitinib-jak-inhibition-for-rheumatoid-arthritis
#1
J Gras
Rheumatoid arthritis (RA), a chronic autoimmune inflammatory disease characterized by inflammation and joint destruction, is associated with pain, progressive disability, systemic comorbidities and early death. Conventional disease-modifying antirheumatic drugs (DMARDs) and biological DMARDs (bDMARDs) have been able to achieve remission or a very low disease activity status for RA. Nevertheless, since many patients do not reach a sufficient response with DMARDs or present with unacceptable side effects, new therapies are needed...
October 2016: Drugs of Today
https://www.readbyqxmd.com/read/27908414/licl-regulates-mitochondrial-biogenesis-during-megakaryocyte-development
#2
Ram Babu Undi, Usha Gutti, Ravi Kumar Gutti
JAK-STAT, PI3K-AKT and MAPK signaling pathways are involved in platelet production process. Although wnt signaling has been reported in the biogenesis of platelets, but its role in megakaryocyte development is not well studied. We used an inducible canonical wnt signaling system that utilizes LiCl (GSK-3β inhibitor). LiCl could activate wnt signaling pathway along with maturation of megakaryocytes. Mitochondrial staining showed an increase in mitochondrial mass upon induction with LiCl. Also, mitochondrial markers PGC-1α and TFAM were up regulated with increase in mitochondrial DNA content...
January 2017: Journal of Trace Elements in Medicine and Biology
https://www.readbyqxmd.com/read/27907166/vaccinia-virus-protein-c6-inhibits-type-i-ifn-signalling-in-the-nucleus-and-binds-to-the-transactivation-domain-of-stat2
#3
Jennifer H Stuart, Rebecca P Sumner, Yongxu Lu, Joseph S Snowden, Geoffrey L Smith
The type I interferon (IFN) response is a crucial innate immune signalling pathway required for defense against viral infection. Accordingly, the great majority of mammalian viruses possess means to inhibit this important host immune response. Here we show that vaccinia virus (VACV) strain Western Reserve protein C6, is a dual function protein that inhibits the cellular response to type I IFNs in addition to its published function as an inhibitor of IRF-3 activation, thereby restricting type I IFN production from infected cells...
December 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27906090/muscle-specific-deletion-of-socs3-increases-the-early-inflammatory-response-but-does-not-affect-regeneration-after-myotoxic-injury
#4
Kristy Swiderski, Savant S Thakur, Timur Naim, Jennifer Trieu, Annabel Chee, David I Stapleton, René Koopman, Gordon S Lynch
BACKGROUND: Muscles of old animals are injured more easily and regenerate poorly, attributed in part to increased levels of circulating pro-inflammatory cytokines. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling cascade is a key mediator of inflammatory cytokine action, and signaling via this pathway is increased in muscles with aging. As a negative regulator of JAK/STAT signaling, a key mediator of myogenic proliferation and differentiation, altered expression of suppressor of cytokine signaling (SOCS3) is likely to have important consequences for muscle regeneration...
October 24, 2016: Skeletal Muscle
https://www.readbyqxmd.com/read/27905994/the-role-of-il-10-in-mycobacterium-avium-subsp-paratuberculosis-infection
#5
REVIEW
Tariq Hussain, Syed Zahid Ali Shah, Deming Zhao, Srinand Sreevatsan, Xiangmei Zhou
Mycobacterium avium subsp. paratuberculosis (MAP) is an intracellular pathogen and is the causative agent of Johne's disease of domestic and wild ruminants. Johne's disease is characterized by chronic granulomatous enteritis leading to substantial economic losses to the livestock sector across the world. MAP persistently survives in phagocytic cells, most commonly in macrophages by disrupting its early antibacterial activity. MAP triggers several signaling pathways after attachment to pathogen recognition receptors (PRRs) of phagocytic cells...
December 1, 2016: Cell Communication and Signaling: CCS
https://www.readbyqxmd.com/read/27905037/involvement-of-jak1-jak2-and-jak3-in-stimulation-of-functional-activity-of-mesenchymal-progenitor-cells-by-fibroblast-growth-factor
#6
G N Zyuz'kov, V V Zhdanov, E V Udut, L A Miroshnichenko, E V Simanina, T Yu Polyakova, L A Stavrova, V V Udut, M Yu Minakova, A M Dygai
We studied the involvement of individual JAK kinases in the realization of the growth potential of mesenchymal precursors under the effect of fibroblast growth factor. The important role of JAK2 and JAK3 in determining the initial level of mitotic activity of progenitor cells and participation of JAK1 in this process under conditions of cytokine stimulation of progenitor cells were demonstrated. Specific inhibitors of these kinases reduced the yield of fibroblast CFU and the rate of their division. Moreover, blockade of JAK1, JAK2, and JAK3 under the effect of fibroblast growth factor was accompanied by an increase in the intensity of progenitor cell differentiation...
December 1, 2016: Bulletin of Experimental Biology and Medicine
https://www.readbyqxmd.com/read/27903968/novel-src-abl-tyrosine-kinase-inhibitor-bosutinib-suppresses-neuroblastoma-growth-via-inhibiting-src-abl-signaling
#7
Shayahati Bieerkehazhi, Zhenghu Chen, Yanling Zhao, Yang Yu, Huiyuan Zhang, Sanjeev A Vasudevan, Sarah E Woodfield, Ling Tao, Joanna S Yi, Jodi A Muscal, Jonathan C Pang, Shan Guan, Hong Zhang, Jed G Nuchtern, Hui Li, Huiwu Li, Jianhua Yang
Neuroblastoma (NB) is the most common extracranial solid tumor in children. Aberrant activation of the non-receptor tyrosine kinases Src and c-Abl contributes to the progression of NB. Thus, targeting these kinases could be a promising strategy for NB therapy. In this paper, we report that the potent dual Src/Abl inhibitor bosutinib exerts anti-tumor effects on NB. Bosutinib inhibited NB cell proliferation in a dose-dependent manner and suppressed colony formation ability of NB cells. Mechanistically, bosutinib effectively decreased the activity of Src/Abl and PI3K/AKT/mTOR, MAPK/ERK, and JAK/STAT3 signaling pathways...
November 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/27903500/primary-resistance-to-pd-1-blockade-mediated-by-jak%C3%A2-mutations
#8
Daniel Sanghoon Shin, Jesse M Zaretsky, Helena Escuin-Ordinas, Angel Garcia-Diaz, Siwen Hu-Lieskovan, Anusha Kalbasi, Catherine S Grasso, Willy Hugo, Salemiz Sandoval, Davis Y Torrejon, Nicolaos Palaskas, Gabriel Abril Rodriguez, Giulia Parisi, Ariel Azhdam, Bartosz Chmielowski, Grace Cherry, Elizabeth Seja, Beata Berent-Maoz, I Peter Shintaku, Dung Thi Le, Drew M Pardoll, Luis A Diaz, Paul C Tumeh, Thomas G Graeber, Roger S Lo, Begoña Comin-Anduix, Antoni Ribas
Loss of function mutations in JAK½ can lead to acquired resistance to anti-programmed death protein 1 (PD-1) therapy. We reasoned they may also be involved in primary resistance to anti-PD-1 therapy. JAK½ inactivating mutations were noted in tumor biopsies of 1 of 23 patients with melanoma and in 1 of 16 patients with mismatch repair deficient colon cancer treated with PD-1 blockade. Both cases had a high mutational load but did not respond to anti-PD-1 therapy. Two out of 48 human melanoma cell lines had JAK½ mutations, which led to lack of PD-L1 expression upon interferon gamma exposure mediated by inability to signal through the interferon gamma receptor pathway...
November 30, 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27901106/the-role-of-pim1-pim2-kinases-in-tumors-of-the-male-reproductive-system
#9
Manuel Pedro Jiménez-García, Antonio Lucena-Cacace, María José Robles-Frías, Maja Narlik-Grassow, Carmen Blanco-Aparicio, Amancio Carnero
The PIM family of serine/threonine kinases has three highly conserved isoforms (PIM1, PIM2 and PIM3). PIM proteins are regulated through transcription and stability by JAK/STAT pathways and are overexpressed in hematological malignancies and solid tumors. The PIM kinases possess weak oncogenic abilities, but enhance other genes or chemical carcinogens to induce tumors. We generated conditional transgenic mice that overexpress PIM1 or PIM2 in male reproductive organs and analyzed their contribution to tumorigenesis...
November 30, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27899802/genomic-and-transcriptional-landscape-of-p2ry8-crlf2-positive-childhood-acute-lymphoblastic-leukemia
#10
C Vesely, C Frech, C Eckert, G Cario, A Mecklenbräuker, U Zur Stadt, K Nebral, F Kraler, S Fischer, A Attarbaschi, M Schuster, C Bock, H Cavé, A von Stackelberg, M Schrappe, M A Horstmann, G Mann, O A Haas, R Panzer-Grümayer
Children with P2RY8-CRLF2-positive ALL have an increased relapse risk. Their mutational and transcriptional landscape as well as the respective patterns at relapse remains largely elusive. We therefore performed an integrated analysis of whole-exome and RNA-sequencing in 41 major clone fusion-positive cases including 19 matched diagnosis/relapse pairs. We detected a variety of frequently subclonal and highly instable JAK/STAT but also RTK/Ras pathway activating mutations in 76% of cases at diagnosis and virtually all relapses...
November 30, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27898153/postconcussive-symptom-overreporting-in-iraq-afghanistan-veterans-with-mild-traumatic-brain-injury
#11
Sarah M Jurick, Elizabeth W Twamley, Laura D Crocker, Chelsea C Hays, Henry J Orff, Shahrokh Golshan, Amy J Jak
A comprehensive evaluation, including the assessment of neurobehavioral symptoms, has been instituted at the Department of Veterans Affairs (VA) healthcare system to address the large number of Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) Veterans returning with mild traumatic brain injuries (mTBIs). The Validity-10 is measure of symptom overreporting embedded within the Neurobehavioral Symptom Inventory, a component of the comprehensive evaluation that assesses postconcussive symptom severity...
2016: Journal of Rehabilitation Research and Development
https://www.readbyqxmd.com/read/27895317/il-4-a-direct-target-of-mir-340-429-is-involved-in-radiation-induced-aggressive-tumor-behavior-in-human-carcinoma-cells
#12
Eun Sook Kim, Young Eun Choi, Su Jin Hwang, Young-Hoon Han, Myung-Jin Park, In Hwa Bae
Radiotherapy induces the production of cytokines, thereby increasing aggressive tumor behavior. This radiation effect results in the failure of radiotherapy and increases the mortality rate in patients. We found that interleukin-4 (IL-4) and IL-4Rα (IL-4 receptor) are highly expressed in various human cancer cells subsequent to radiation treatment. In addition, IL-4 is highly overexpressed in metastatic carcinoma tissues compared with infiltrating carcinoma tissues. High expression of IL-4 in patients with cancer is strongly correlated with poor survival...
November 24, 2016: Oncotarget
https://www.readbyqxmd.com/read/27894402/hsp90-inhibitor-enhances-anti-proliferative-and-apoptotic-effects-of-celecoxib-on-ht-29-colorectal-cancer-cells-via-increasing-bax-bcl-2-ratio
#13
A Mohammadi, M M Yaghoobi, A GholamhoseynianNajar, B Kalantari-Khandani, H Sharifi, M Saravani
Due to the high prevalence and mortality rate of colorectal cancer (CRC), new treatment approaches like combination therapy seem to be necessary. The relationship between chronic inflammation and colorectal cancer development and progression has been shown to be important. Celecoxib, a selective COX-2 inhibitor, is the only non-steroidal anti-inflammatory drug (NSAID) that has been approved for cancer therapy and prevention. Because of cardiovascular side effects of COX-2 inhibitors, combination therapy may improve the therapeutic profile...
October 31, 2016: Cellular and Molecular Biology
https://www.readbyqxmd.com/read/27894215/the-molecular-pathogenesis-of-mantle-cell-lymphoma
#14
Niklas Vogt, Beiying Dai, Tabea Erdmann, Wolfgang E Berdel, Georg Lenz
Mantle cell lymphoma (MCL) is characterized by the translocation t(11;14) leading to constitutive cyclin D1 overexpression. However, overexpression of cyclin D1 alone is insufficient to cause malignant transformation. Secondary genetic alterations and deregulated signaling pathways involved in DNA damage response, cell proliferation, and apoptosis are indispensable for MCL lymphomagenesis. Recent studies investigating the biology of MCL have revealed crucial importance of B-cell receptor (BCR), nuclear factor-kappa B (NF-κB), phosphoinositide 3-kinase (PI3K), and BCL2 signaling for the molecular pathogenesis of MCL...
November 28, 2016: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/27892610/beside-to-bench-jak-inhibitor-ruxolitinib-inhibits-the-expression-of-cytokines-characteristic-of-cutaneous-lupus-erythematosus
#15
Anna Sophie Klaeschen, Dominik Wolf, Peter Brossart, Thomas Bieber, Joerg Wenzel
This study was stimulated by the clinical observation of a rapid response of a chilblain lupus patient to treatment with JAK1/2-kinase inhibitor ruxolitinib. We investigated the in-vivo expression of phospho-JAK2 in CLE skin samples as well as the immunomodulatory in-vitro effect of ruxolitinib in cultured immortalized keratinocytes and in a 3D human epidermis model (epiCS). Our results demonstrate that ruxolitinib significantly decreases the production of CLE-typical cytokines (CXCL10, CXCL9, MxA) and might be a promising drug for future clinical studies in patients with CLE and related autoimmune skin diseases...
November 28, 2016: Experimental Dermatology
https://www.readbyqxmd.com/read/27889106/expression-of-the-jak-stat-signaling-pathway-in-the-ligamentum-flavum-of-patients-with-lumbar-spinal-canal-stenosis
#16
Hitoshi Yamahata, Koji Osuka, Tatsuro Aoyama, Muneyoshi Yasuda, Hiroshi Tokimura, Kazunori Arita, Masakazu Takayasu
BACKGROUND: Ligamentum flavum (LF) hypertrophy is an important cause of lumbar spinal canal stenosis (LSS), one of the most common spinal disorders in the elderly. Although many cytokines are reported to be associated with LF hypertrophy, the intracellular signaling system is rarely discussed. The purpose of this study was to identify the JAK/STAT signaling pathway and to examine the role of the JAK/STAT systems in the hypertrophied LF. METHODS: The LF of 10 LSS patients was analyzed and the expression of JAK1, STAT3, phosphorylated (p)-STAT3, and actin was examined by Western blot analysis...
November 23, 2016: Journal of Orthopaedic Science: Official Journal of the Japanese Orthopaedic Association
https://www.readbyqxmd.com/read/27888751/remote-ischemic-preconditioning-attenuates-egr-1-expression-following-myocardial-ischemia-reperfusion-injury-through-activation-of-the-jak-stat-pathway
#17
H Mudaliar, B Rayner, M Billah, N Kapoor, W Lay, A Dona, R Bhindi
BACKGROUND/OBJECTIVES: Remote ischemic preconditioning (RIPC) protects the myocardium from ischemia/reperfusion (I/R) injury however the molecular pathways involved in cardioprotection are yet to be fully delineated. Transcription factor Early growth response-1 (Egr-1) is a key upstream activator in a variety of cardiovascular diseases. In this study, we elucidated the role of RIPC in modulating the regulation of Egr-1. METHODS: This study subjected rats to transient blockade of the left anterior descending (LAD) coronary artery with or without prior RIPC of the hind-limb muscle and thereafter excised the heart 24h following surgical intervention...
November 10, 2016: International Journal of Cardiology
https://www.readbyqxmd.com/read/27888216/drosophila-sulf1-is-required-for-the-termination-of-intestinal-stem-cell-division-during-regeneration
#18
Masahiko Takemura, Hiroshi Nakato
Stem cell division is activated to trigger regeneration in response to tissue damage. The molecular mechanisms by which this stem cell mitotic activity is properly repressed at the end of regeneration are poorly understood. Here we show that a specific modification of heparan sulfate (HS) is critical in regulating Drosophila intestinal stem cell (ISC) division during normal midgut homeostasis and regeneration. Loss of the extracellular HS endosulfatase Sulf1 results in increased ISC division during normal homeostasis, which is caused by upregulation of mitogenic signaling including the JAK/STAT, EGFR, and Hedgehog pathways...
November 25, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/27887955/treatment-of-hypereosinophilic-syndrome-with-cutaneous-involvement-with-the-jak-inhibitors-tofacitinib-and-ruxolitinib
#19
Brett King, Alfred Ian Lee, Jaehyuk Choi
No abstract text is available yet for this article.
November 22, 2016: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/27884974/from-leeches-to-personalized-medicine-evolving-concepts-in-the-management-of-polycythemia-vera
#20
Alessandro Maria Vannucchi
Polycythemia vera (PV), a clonal disorders of hematopoietic stem/progenitor cells that manifests with prevalent expansion of red cell mass, is the most frequent among chronic myeloproliferative neoplasms (MPN). It is characterized by a V617F point mutation in JAK2 exon 14 , or less common mutations in exon 12, in virtually all cases. The landmark discovery of autonomously activated JAK/STAT signaling pathway paved the way for the clinical development of the first target drug, the JAK1 and JAK2 inhibitor ruxolitinib, that is now approved for patients with resistance or intolerance to hydroxyurea...
November 24, 2016: Haematologica
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