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https://www.readbyqxmd.com/read/29691471/baricitinib-induced-blockade-of-interferon-gamma-receptor-and-interleukin-6-receptor-for-the-prevention-and-treatment-of-graft-versus-host-disease
#1
Jaebok Choi, Matthew L Cooper, Karl Staser, Kidist Ashami, Kiran R Vij, Bing Wang, Lynne Marsala, Jessica Niswonger, Julie Ritchey, Bader Alahmari, Samuel Achilefu, Ikuo Tsunoda, Mark A Schroeder, John F DiPersio
The therapeutic benefits of allogeneic hematopoietic stem cell transplantation (allo-HSCT) are derived from the graft-versus-leukemia (GvL) effects of the procedure. There is a strong association between the GvL effects and graft-versus-host disease (GvHD), a major life-threatening complication of allo-HSCT. The limiting of GvHD while maintaining the GvL effect remains the goal of allo-HSCT. Therefore, identifying optimal therapeutic targets to selectively suppress GvHD while maintaining the GvL effects represents a significant unmet medical need...
April 2, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29687421/baricitinib-a-review-in-rheumatoid-arthritis
#2
Zaina T Al-Salama, Lesley J Scott
Baricitinib (Olumiant® ) is an oral, targeted synthetic DMARD that inhibits JAK1 and JAK2, which are implicated in the pathogenesis of rheumatoid arthritis (RA). This novel, small molecule is approved for use as monotherapy, or in combination with methotrexate, for the treatment of adults with moderate to severe active RA who responded inadequately to or were intolerant of ≥ 1 DMARD. In pivotal multinational trials, once-daily baricitinib 4 mg, with/without methotrexate (± another csDMARD), improved the signs and symptoms of RA, disease activity and physical function in DMARD-naive patients and in patients with an inadequate response to methotrexate, csDMARDs or TNF inhibitors; baricitinib treatment also slowed structural joint damage in DMARD-naive patients and in those with an inadequate response to methotrexate and csDMARDs...
April 23, 2018: Drugs
https://www.readbyqxmd.com/read/29685509/rankl-mediated-osteoclastogenic-differentiation-of-macrophages-in-the-abdominal-aorta-of-angiotensin-ii-infused-apolipoprotein-e-knockout-mice
#3
Teruyoshi Tanaka, Matthew Kelly, Yuichiro Takei, Dai Yamanouchi
OBJECTIVE: Osteoclastogenic activation of macrophages (OCG) occurs in human abdominal aortic aneurysms (AAAs) and in calcium chloride-induced degenerative AAAs in mice, which have increased matrix metalloproteinase activity. As the activity of OCG in dissecting aneurysms is not clear, we tested the hypothesis that OCG contributes to angiotensin II (Ang II)-induced dissecting aneurysm (Ang II-induced AAA) in apolipoprotein E knockout mice. METHODS: AAAs were produced in apolipoprotein E knockout mice via the administration of Ang II...
April 20, 2018: Journal of Vascular Surgery
https://www.readbyqxmd.com/read/29681434/a-placebo-controlled-phase-ii-study-of-ruxolitinib-in-combination-with-pemetrexed-and-cisplatin-for-first-line-treatment-of-patients-with-advanced-nonsquamous-non-small-cell-lung-cancer-and-systemic-inflammation
#4
Giuseppe Giaccone, Rachel E Sanborn, Saiama N Waqar, Alex Martinez-Marti, Santiago Ponce, Huiling Zhen, Gerard Kennealey, Susan Erickson-Viitanen, Eric Schaefer
BACKGROUND: Dysregulation of the Janus kinase (JAK)/signal transducers and activators of transcription pathway contributes to abnormal inflammatory responses and poor prognosis in non-small-cell lung cancer (NSCLC). We evaluated the JAK1/JAK2 inhibitor ruxolitinib plus pemetrexed/cisplatin first-line in patients with stage IIIB/IV or recurrent nonsquamous NSCLC with systemic inflammation (modified Glasgow prognostic score [mGPS] 1/2). PATIENTS AND METHODS: Part 1 was an open-label, safety run-in, in which we assessed ruxolitinib (15 mg twice daily [b...
March 23, 2018: Clinical Lung Cancer
https://www.readbyqxmd.com/read/29678906/rnai-screening-identifies-a-mechanosensitive-rock-jak2-stat3-network-central-to-myofibroblast-activation
#5
Raymond S Oh, Andrew J Haak, Karry M J Smith, Giovanni Ligresti, Kyoung Moo Choi, Tiao Xie, Shaohua Wang, Paula R Walters, Michael A Thompson, Michelle R Freeman, Logan J Manlove, Vivian M Chu, Carol Feghali-Bostwick, Anja C Roden, Jürgen Schymeinsky, Christina M Pabelick, Y S Prakash, Robert Vassallo, Daniel J Tschumperlin
Myofibroblasts play key roles in wound healing and pathologic fibrosis. Here we undertook an RNAi screen to characterize myofibroblast regulatory genes, using a high-content imaging approach to quantify alpha-smooth muscle actin stress fibers in cultured human fibroblasts. Screen hits were validated on physiological compliance hydrogels, and selected hits tested in primary fibroblasts from patients with idiopathic pulmonary fibrosis. Our RNAi screen led to the identification of STAT3 as an essential mediator of myofibroblast activation and function...
April 20, 2018: Journal of Cell Science
https://www.readbyqxmd.com/read/29675680/a-randomized-double-blind-phase-2-study-of-ruxolitinib-or-placebo-in-combination-with-capecitabine-in-patients-with-advanced-her2-negative-breast-cancer-and-elevated-c-reactive-protein-a-marker-of-systemic-inflammation
#6
Joyce O'Shaughnessy, Angela DeMichele, Cynthia X Ma, Paul Richards, Denise A Yardley, Gail Shaw Wright, Kevin Kalinsky, Ronald Steis, Sami Diab, Gerard Kennealey, Ryan Geschwindt, Wei Jiang, Hope S Rugo
PURPOSE: The Janus-associated kinase (JAK)/signal transducer and activator of transcription pathway is a key regulator of inflammatory signaling, associated with tumorigenesis, cell survival, and progression. This randomized phase 2 trial evaluated the efficacy and safety of the addition of ruxolitinib, a JAK1/JAK2 inhibitor, to capecitabine in patients with HER2-negative advanced breast cancer and high systemic inflammation (modified Glasgow Prognostic Score [mGPS] ≥ 1). METHODS: Patients with ≤ 2 prior chemotherapy regimens for advanced or metastatic disease or hormone receptor-positive patients with disease progression on prior hormonal therapies were randomized 1:1 to 21-day cycles of ruxolitinib (n = 76) or placebo (n = 73) plus capecitabine...
April 19, 2018: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29673861/il-6-knockout-mice-are-protected-from-cocaine-induced-kindling-behaviors-possible-involvement-of-jak2-stat3-and-pacap-signalings
#7
Huynh Nhu Mai, Yoon Hee Chung, Eun-Joo Shin, Naveen Sharma, Ji Hoon Jeong, Choon-Gon Jang, Kuniaki Saito, Toshitaka Nabeshima, Dora Reglodi, Hyoung-Chun Kim
IL-6 has been recognized as an anticonvulsant against certain neuroexcitotoxicities. We aimed to investigate on the interactive role between IL-6 and PACAP in cocaine-induced kindling behaviors. Although we found that cocaine (45 mg/kg, i.p./day x 5) significantly increased IL-6 and TNF-α expression, it resulted in a decrease in IFN-γ expression. We observed that the cocaine-induced increase in IL-6 expression was more pronounced than that in TNF-α expression. Genetic depletion of IL-6 significantly activated cocaine kindling behaviors...
April 16, 2018: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/29671256/effects-of-growth-hormone-on-pregnancy-rates-of-patients-with-thin-endometrium
#8
N Cui, A-M Li, Z-Y Luo, Z-M Zhao, Y-M Xu, J Zhang, A-M Yang, L-L Wang, G-M Hao, B-L Gao
PURPOSE: To investigate whether growth hormone (GH) could improve pregnancy rates of patients with thin endometrium by clinical study and laboratory experiments. MATERIALS AND METHODS: Ninety-three patients were randomized to either the GH-received group (40) or the routine exogenous administration of estrogens control group (53) for clinical study. The human endometrial carcinoma cell line RL95-2 was used for testing the role of GH with Western blot and real-time PCR by exposure to various concentrations of GH (0...
April 18, 2018: Journal of Endocrinological Investigation
https://www.readbyqxmd.com/read/29665657/recent-advances-in-the-diagnosis-and-management-of-primary-myelofibrosis
#9
Katsuto Takenaka, Kazuya Shimoda, Koichi Akashi
Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) in which dysregulation of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathways is the major pathogenic mechanism. Most patients with PMF carry a driver mutation in the JAK2, MPL (myeloproliferative leukemia), or CALR (calreticulin) genes. Mutations in epigenetic regulators and RNA splicing genes may also occur, and play critical roles in PMF disease progression. Based on revised World Health Organization diagnostic criteria for MPNs, both screening for driver mutations and bone marrow biopsy are required for a specific diagnosis...
April 20, 2018: Korean Journal of Internal Medicine
https://www.readbyqxmd.com/read/29665360/alpha7-nicotinic-acetylcholine-receptor-activation-protects-against-myocardial-reperfusion-injury-through-modulation-of-autophagy
#10
Zuoxu Hou, Yaguang Zhou, Hongyan Yang, Yan Liu, Xuechao Mao, Xinghua Qin, Xiaoliang Li, Xing Zhang, Yuanyuan Hu
Alpha7 nicotinic acetylcholine receptor (α7nAChR) activation alleviates myocardial ischemia/reperfusion (MI/R) injury. However, the underlying mechanisms remain unclear. Here, we investigated the role of autophagy in α7nAChR-mediated cardioprotection and the molecular mechanisms involved. Activating α7nAChR with PNU-282987 at the initiation of reperfusion reduced myocardial infarct size in MI/R rats. PNU-282987 treatment also significantly inhibited MI/R-induced myocardial autophagy dysfunction as evidenced by the reduction of LC3-II/LC3-I ratio, Beclin-1 and p62 abundance...
April 14, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29660364/silibinin-is-a-direct-inhibitor-of-stat3
#11
Sara Verdura, Elisabet Cuyàs, Laura Llorach-Parés, Almudena Pérez-Sánchez, Vicente Micol, Alfons Nonell-Canals, Jorge Joven, Manuel Valiente, Melchor Sánchez-Martínez, Joaquim Bosch-Barrera, Javier A Menendez
We herein combined experimental and computational efforts to delineate the mechanism of action through which the flavonolignan silibinin targets STAT3. Silibinin reduced IL-6 inducible, constitutive, and acquired feedback activation of STAT3 at tyrosine 705 (Y705). Silibinin attenuated the inducible phospho-activation of Y705 in GFP-STAT3 genetic fusions without drastically altering the kinase activity of the STAT3 upstream kinases JAK1 and JAK2. A comparative computational study based on docking and molecular dynamics simulation over 14 different STAT3 inhibitors (STAT3i) predicted that silibinin could directly bind with high affinity to both the Src homology-2 (SH2) domain and the DNA-binding domain (DBD) of STAT3...
April 14, 2018: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/29656438/renovascular-hypertension-associated-with-jak2-v617f-positive-myeloproliferative-neoplasms-treated-with-angioplasty-2-cases-and-literature-review
#12
Eikan Mishima, Takehiro Suzuki, Yoichi Takeuchi, Kazumasa Seiji, Noriko Fukuhara, Kei Takase, Hideo Harigae, Takaaki Abe, Sadayoshi Ito
Myeloproliferative neoplasms (MPNs) with Janus kinase 2 (JAK2) mutation are associated with a high risk for occlusive vascular diseases. We report 2 cases of renovascular hypertension associated with JAK2 V617F mutation-positive MPNs and provide a literature review. In Case 1, a 63-year-old woman had resistant hypertension, massive proteinuria, and erythrocytosis. Evaluations revealed right renal artery stenosis causing renovascular hypertension and polycythemia vera with JAK2 V617F mutation. Renin-angiotensin system inhibitors and subsequent angioplasty controlled the blood pressure and the proteinuria resolved...
April 14, 2018: Journal of Clinical Hypertension
https://www.readbyqxmd.com/read/29650801/the-role-of-jak2-inhibitors-in-mpn-seven-years-after-approval
#13
Francesco Passamonti, Margherita Maffioli
Myeloproliferative neoplasms (MPNs) include essential thrombocythemia, polycythemia vera (PV) and primary myelofibrosis (PMF). Phenotype-driver mutations of JAK2, CALR and MPL genes are present in MPNs and can be variably combined with additional mutations. Driver mutations entail a constitutive activation of the JAK2/STAT pathway, the key signaling cascade in MPNs. Among JAK2 inhibitors (JAKis), ruxolitinib (RUX) has been approved for the treatment of intermediate and high risk myelofibrosis (MF) and of PV inadequately controlled by or intolerant of hydroxyurea...
April 12, 2018: Blood
https://www.readbyqxmd.com/read/29650799/pervasive-mutations-of-jak-stat-pathway-genes-in-classical-hodgkin-lymphoma
#14
Enrico Tiacci, Erik Ladewig, Gianluca Schiavoni, Alex Penson, Elisabetta Fortini, Valentina Pettirossi, Yuchun Wang, Ariele Rosseto, Alessandra Venanzi, Sofija Vlasevska, Roberta Pacini, Simonetta Piattoni, Alessia Tabarrini, Alessandra Pucciarini, Barbara Bigerna, Alessia Santi, Alessandro M Gianni, Simonetta Viviani, Antonello Cabras, Stefano Ascani, Barbara Crescenzi, Cristina Mecucci, Laura Pasqualucci, Raul Rabadan, Brunangelo Falini
Dissecting the pathogenesis of classical Hodgkin lymphoma (cHL), a common cancer in young adults, remains challenging due to the rarity of tumor cells in involved tissues (usually <5%). Here, we analyzed the coding genome of cHL by microdissecting tumor and normal cells from 34 patient biopsies, for a total of ~50,000 singly isolated lymphoma cells. We uncovered several recurrently mutated genes, namely STAT6 (32% of cases), GNA13 (24%), XPO1 (18%) and ITPKB (16%), and document the functional role of mutant STAT6 in sustaining tumor cell viability...
April 12, 2018: Blood
https://www.readbyqxmd.com/read/29649626/novel-compounds-tad-1822-7-f2-and-f5-inhibited-hela-cells-growth-through-the-jak-stat-signaling-pathway
#15
Tianfeng Yang, Xianpeng Shi, Yuan Kang, Man Zhu, Mengying Fan, Dongdong Zhang, Yanmin Zhang
Cervical carcinoma remains the second most common malignancy with a high mortality rate among women worldwide. TAD-1822-7-F2 (F2) and TAD-1822-7-F5 (F5) are novel compounds synthesized on the chemical structure of taspine derivatives, and show an effective suppression for HeLa cells. Our study aims to confirm the potential targets of F2 and F5, and investigate the underlying mechanism of the inhibitory effect on HeLa cells. In this study, Real Time Cell Analysis and crystal violet staining assay were conducted to investigate the effect of F2 and F5 on HeLa cells proliferation...
April 9, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29645296/effects-of-jak1-2-inhibition-on-bone-marrow-stromal-cells-of-myeloproliferative-neoplasm-mpn-patients-and-healthy-individuals
#16
Dimitra Zacharaki, Roshanak Ghazanfari, Hongzhe Li, Hooi Ching Lim, Stefan Scheding
OBJECTIVE: Philadelphia-negative myeloproliferative neoplasms (MPNs) commonly share hyperactive JAK-STAT signaling affecting hematopoietic stem cells (HSC) and their progeny. The JAK1/2 inhibitor Ruxolitinib has remarkable clinical efficacy, including spleen reduction, improvement of constitutional symptoms, and bone marrow (BM) fibrosis reversal. Whether this is due to inhibition of JAK2-mutated HSC only, or whether Ruxolitinib also affects BM stroma is not known. METHODS: This study investigated potential effects of Ruxolitinib on BM mesenchymal stromal cells (MSC), which are not only major regulators of hematopoiesis but also contribute to fibrosis, from 10 healthy donors and 7 JAK2V617F -positive MPN patients...
April 12, 2018: European Journal of Haematology
https://www.readbyqxmd.com/read/29643232/increased-neutrophil-extracellular-trap-formation-promotes-thrombosis-in-myeloproliferative-neoplasms
#17
Ofir Wolach, Rob S Sellar, Kimberly Martinod, Deya Cherpokova, Marie McConkey, Ryan J Chappell, Alexander J Silver, Dylan Adams, Cecilia A Castellano, Rebekka K Schneider, Robert F Padera, Daniel J DeAngelo, Martha Wadleigh, David P Steensma, Ilene Galinsky, Richard M Stone, Giulio Genovese, Steven A McCarroll, Bozenna Iliadou, Christina Hultman, Donna Neuberg, Ann Mullally, Denisa D Wagner, Benjamin L Ebert
Thrombosis is a major cause of morbidity and mortality in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), clonal disorders of hematopoiesis characterized by activated Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. Neutrophil extracellular trap (NET) formation, a component of innate immunity, has been linked to thrombosis. We demonstrate that neutrophils from patients with MPNs are primed for NET formation, an effect blunted by pharmacological inhibition of JAK signaling...
April 11, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29627363/nesfatin-1-functions-as-a-switch-for-phenotype-transformation-and-proliferation-of-vsmcs-in-hypertensive-vascular-remodeling
#18
Qing-Bo Lu, Hui-Ping Wang, Zi-Han Tang, Han Cheng, Qiong Du, Yuan-Ben Wang, Wu-Bing Feng, Ke-Xue Li, Wei-Wei Cai, Li-Ying Qiu, Hai-Jian Sun
The phenotypic transformation from differentiated to dedifferentiated vascular smooth muscle cells (VSMCs) plays a crucial role in VSMC proliferation and vascular remodeling in many cardiovascular diseases including hypertension. Nesfatin-1, a multifunctional adipocytokine, is critically involved in the regulation of blood pressure. However, it is still largely unexplored whether nesfatin-1 is a potential candidate in VSMC phenotypic switch and proliferation in hypertension. Experiments were carried out in Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR), human VSMCs and primary rat aortic VSMCs...
April 5, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29627078/the-roles-of-jak2-in-dna-damage-and-repair-in-the-myeloproliferative-neoplasms-opportunities-for-targeted-therapy
#19
REVIEW
Theodoros Karantanos, Alison R Moliterno
The JAK2V617F-positive myeloproliferative neoplasms (MPN) serve as an excellent model for the study of genomic instability accumulation during cancer progression. Recent studies highlight the implication of JAK2 activating mutations in the development of DNA damage via reactive oxygen species (ROS) production, replication stress induction and the accumulation of genomic instability via the increased degradation of p53 and acquisition of a "mutagenic" phenotype. The accumulation of genomic instability and acquisition of mutations in critical DNA damage repair (DDR) mediators appears to be implicated in the progression of JAK2V617F-positive MPN...
March 30, 2018: Blood Reviews
https://www.readbyqxmd.com/read/29622655/repurposing-tofacitinib-as-an-anti-myeloma-therapeutic-to-reverse-growth-promoting-effects-of-the-bone-marrow-microenvironment
#20
Christine Lam, Ian D Ferguson, Margarette C Mariano, Yu-Hsiu T Lin, Megan Murnane, Hui Liu, Geoffrey A Smith, Sandy W Wong, Jack Taunton, Jun O Liu, Constantine S Mitsiades, Byron C Hann, Blake T Aftab, Arun P Wiita
The myeloma bone marrow microenvironment promotes proliferation of malignant plasma cells and resistance to therapy. Activation of JAK/STAT signaling is thought to be a central component of these microenvironment-induced phenotypes. In a prior drug repurposing screen, we identified tofacitinib, a pan-JAK inhibitor FDA-approved for rheumatoid arthritis, as an agent that may reverse the tumor-stimulating effects of bone marrow mesenchymal stromal cells. Here, we validated in vitro, in stromal-responsive human myeloma cell lines, and in vivo, in orthotopic disseminated xenograft models of myeloma, that tofacitinib showed efficacy in myeloma models...
April 5, 2018: Haematologica
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