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https://www.readbyqxmd.com/read/28448787/relationship-between-her2-and-jak-stat-socs3-signaling-pathway-and-clinicopathological-features-and-prognosis-of-ovarian-cancer
#1
An-Quan Shang, Jian Wu, Feng Bi, Yu-Jie Zhang, Lei-Rong Xu, Ling-Ling Li, Fei-Fei Chen, Wei-Wei Wang, Jian-Jun Zhu, You-Yi Liu
OBJECTIVE: The study aims to explore the relationship between expressions of HER2 and JAK/STAT3-SOCS3 signaling pathway and clinicopathological features and prognosis of ovarian cancer (OC). METHODS: A total of 136 OC patients were collected. Immunohistochemistry was applied to measure the expressions of STAT3, p-STAT3, SOCS3, HER2 and p-HER2 in the tumor tissues and adjacent normal tissues. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the mRNA expressions of HER2, SOCS3 and STAT3 and western blotting was applied for protein expressions of HER2, p-HER2, SOCS3, STAT3 and p-STAT3 in the tumor tissues and adjacent normal tissues...
April 27, 2017: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/28441920/investigational-janus-kinase-inhibitors-in-development-for-myelofibrosis
#2
Prithviraj Bose, Abdallah Abou Zahr, Srdan Verstovsek
INTRODUCTION: Since the discovery of the activating V617F mutation in Janus kinase 2 (JAK2), a number of pharmacologic inhibitors of JAK2 have entered clinical trials for patients with myelofibrosis. However, ruxolitinib, approved in 2011, remains the only one currently available for treatment of myelofibrosis, with many others having been discontinued for toxicity, and considerable uncertainty surrounding the future of those still in development. AREAS COVERED: The available clinical data on pacritinib and momelotinib, the two agents in the most advanced phases of clinical testing in myelofibrosis, are examined in detail...
April 25, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28436280/persistent-foot-ulcer-due-to-ruxolitinib-therapy-for-primary-myelofibrosis
#3
Michael Del Rosario, Henry Tsai, Constantin A Dasanu
Primary myelofibrosis is characterized by bone marrow fibrosis, splenomegaly and presence of JAK-2 V617F mutation in more than 90% of patients. Ruxolitinib is a Janus kinase inhibitor used for the treatment of primary myelofibrosis. We describe herein a persistent foot ulcer development attributed to ruxolitinib therapy. We are unaware of any previous reports of this phenomenon in the scientific literature. A thorough examination of the lower extremities is perhaps necessary before initiating this oral agent...
January 1, 2017: Journal of Oncology Pharmacy Practice
https://www.readbyqxmd.com/read/28419187/kaposi-sarcoma-in-a-patient-treated-with-ruxolitinib
#4
G G Loscocco, M Vannucchi, C Paoli, A Franci, L Pieri, F Annunziato, D Massi, A M Vannucchi
No abstract text is available yet for this article.
April 13, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28410228/identification-of-a-novel-functional-jak1-s646p-mutation-in-acute-lymphoblastic-leukemia
#5
Qian Li, Botao Li, Liangding Hu, Hongmei Ning, Min Jiang, Danhong Wang, Tingting Liu, Bin Zhang, Hu Chen
The survival rate of childhood acute lymphoblastic leukemia (ALL) is approaching 90%, while the prognosis of adults remains poor due to the limited therapeutic approaches. In order to identify new targets for ALL, we performed whole-exome sequencing on four adults with B-ALL and discovered a somatic JAK1 S646P mutation. Sanger sequencing of JAK1 was conducted on 53 ALL patients, and two cases exhibited A639G and P960S mutations separately. Functional studies demonstrated that only JAK1 S646P mutation could activate multiple signaling pathways, drive cytokine-independent cell growth, and promote proliferation of malignant cells in nude mice...
March 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28405527/jak-stat-mediated-chronic-inflammation-impairs-cytotoxic-t-lymphocyte-activation-to-decrease-anti-pd-1-immunotherapy-efficacy-in-pancreatic-cancer
#6
Chunwan Lu, Asif Talukder, Natasha M Savage, Nagendra Singh, Kebin Liu
Human pancreatic cancer does not respond to immune check point blockade immunotherapy. One key feature of pancreatic cancer is the association between its progression and chronic inflammation. Emerging evidence supports a key role for the JAK-STAT pathway in pancreatic cancer inflammation. We aimed at testing the hypothesis that sustained JAK-STAT signaling suppresses cytotoxic T lymphocyte (CTL) activation to counteract anti-PD-1 immunotherapy-induced CTL activity in pancreatic cancer. We show that human pancreatic carcinomas express high level of PD-L1 and exhibit low level of CTL infiltration...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28402197/minimal-residual-disease-or-cure-in-mpns-rationales-and-perspectives-on-combination-therapy-with-interferon-alpha2-and-ruxolitinib
#7
Mads Emil Bjørn, Hans Carl Hasselbalch
The therapeutic landscape of the Philadelphia-negative myeloproliferative neoplasms (MPNs) is markedly changing consequent to the development of JAK-inhibitors and the use of ruxolitinib (RUX) in patients with myelofibrosis (MF) and patients with polycythemia vera (PV) who develop refractoriness or intolerance to hydroxyurea. The use of Interferon-alpha2 (IFN) is rapidly expanding in several countries, based upon favourable safety and efficacy profiles in several single-arm studies during the last 30 years, displaying complete hematological remissions in a large proportion of patients, a reduction in the JAK2V617 F and CALR mutational burden and in a subset of patients with PV with normalisation of the bone marrow after long-term treatment - even being sustained for several years after discontinuation of IFN...
April 12, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28397975/the-jak2-stat5-signaling-pathway-as-a-potential-therapeutic-target-in-canine-mastocytoma
#8
Alexandra Keller, Bettina Wingelhofer, Barbara Peter, Karin Bauer, Daniela Berger, Susanne Gamperl, Martin Reifinger, Sabine Cerny-Reiterer, Richard Moriggl, Michael Willmann, Peter Valent, Emir Hadzijusufovic
BACKGROUND: Mastocytoma are frequently diagnosed cutaneous neoplasms in dogs. In non-resectable mastocytoma patients, novel targeted drugs are often applied. The transcription factor STAT5 has been implicated in the survival of human neoplastic mast cells (MC). Our study evaluated the JAK2/STAT5 pathway as a novel target in canine mastocytoma. MATERIALS AND METHODS: We employed inhibitors of JAK2 (R763, TG101348, AZD1480, ruxolitinib) and STAT5 (pimozide, piceatannol) and evaluated their effects on 2 mastocytoma cell lines, C2 and NI-1...
April 11, 2017: Veterinary and Comparative Oncology
https://www.readbyqxmd.com/read/28395559/management-of-myelofibrosis-jak-inhibition-and-beyond
#9
Maximilian Stahl, Amer M Zeidan
Myelofibrosis (MF) is characterized by bone marrow fibrosis with subsequent extramedullary hematopoiesis and abnormal cytokine expression leading to splenomegaly, constitutional symptoms and cytopenias. The discovery of the JAK2 V617F mutation in the majority of MF patients has been followed by significant progress in drug development for MF. Areas covered: In this article, we review advances in the understanding of the underlying disease biology, prognostic assessment and therapeutic modalities for MF. We provide clinical trial evidence behind using the JAK2 inhibitor ruxolitinib, erythropoiesis stimulating agents, androgens, immunomodulatory drugs, interferon, cytoreductive drugs and hypomethylating agents in MF...
April 26, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28390737/treatment-of-vitiligo-with-the-topical-janus-kinase-inhibitor-ruxolitinib
#10
Brooke Rothstein, Deep Joshipura, Ami Saraiya, Rana Abdat, Huda Ashkar, Yana Turkowski, Vaneeta Sheth, Victor Huang, Shiu Chung Au, Courtney Kachuk, Nicole Dumont, Alice B Gottlieb, David Rosmarin
BACKGROUND: Existing therapies for vitiligo are limited in efficacy and can be associated with undesirable side effects. Topical Janus kinase inhibitors may offer a new therapeutic option for vitiligo. OBJECTIVE: We sought to assess the role of topical ruxolitinib 1.5% cream, a Janus kinase inhibitor, in vitiligo treatment. METHODS: This 20-week, open-label, proof-of-concept trial of twice-daily topical ruxolitinib 1.5% cream was conducted in 12 patients with a minimum of 1% affected body surface area of vitiligo...
April 5, 2017: Journal of the American Academy of Dermatology
https://www.readbyqxmd.com/read/28386106/mpl-activation-directly-induces-fibrocyte-differentiation-to-cause-myelofibrosis
#11
T Maekawa, Y Osawa, T Izumi, S Nagao, K Takano, Y Okada, N Tachi, M Teramoto, T Kawamura, T Horiuchi, R Saga, S Kato, T Yamamura, J Watanabe, A Kobayashi, S Kobayashi, K Sato, M Hashimoto, S Suzu, F Kimura
Myelofibrosis (MF) may be caused by various pathogenic mechanisms such as elevation in circulating cytokine levels, cellular interactions, and genetic mutations. However, the underlying mechanism of MF still remains unknown. Recent studies have revealed that fibrocytes, the spindle-shaped fibroblast-like hematopoietic cells, and the thrombopoietin (TPO)/myeloproliferative leukemia protein (MPL; TPO receptor) signaling pathway play a certain role in the development of MF. In the present study, we aimed to investigate the relationship between fibrocytes and MPL activation...
April 7, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28370306/is-allogeneic-stem-cell-transplantation-for-myelofibrosis-still-indicated-at-the-time-of-molecular-markers-and-jak-inhibitors-era
#12
Elsa Lestang, Pierre Peterlin, Yannick Le Bris, Viviane Dubruille, Jacques Delaunay, Catherine Godon, Olivier Theisen, Nicolas Blin, Beatrice Mahe, Thomas Gastinne, Alice Garnier, Cyrille Touzeau, Maud Voldoire, Marie C Bene, Steven Le Gouill, Noel Milpied, Mohamad Mohty, Philippe Moreau, Thierry Guillaume, Patrice Chevallier
OBJECTIVE: The role of allogenic stem cell transplantation (ASCT) is still debated in myelofibrosis. METHOD: A retrospective analyzed was performed to compare the outcome of 71 patients with intermediate-2 or high-risk Dynamic International Prognosis Scoring System+ (DIPSS+) primary (PMF) or secondary (SMF) myelofibrosis with an indication of ASCT as they ultimately underwent the procedure (n=34) or not (n=37). RESULTS: Five-year overall survival (OS) was not statistically different between both groups (allograft: 52% vs no allograft: 34%, p=0,12)...
March 31, 2017: European Journal of Haematology
https://www.readbyqxmd.com/read/28356514/cytokine-receptor-signaling-is-required-for-the-survival-of-alk-anaplastic-large-cell-lymphoma-even-in-the-presence-of-jak1-stat3-mutations
#13
Jing Chen, Yong Zhang, Michael N Petrus, Wenming Xiao, Alina Nicolae, Mark Raffeld, Stefania Pittaluga, Richard N Bamford, Masao Nakagawa, Sunny Tianyi Ouyang, Alan L Epstein, Marshall E Kadin, Annarose Del Mistro, Richard Woessner, Elaine S Jaffe, Thomas A Waldmann
Activating Janus kinase (JAK) and signal transducer and activator of transcription (STAT) mutations have been discovered in many T-cell malignancies, including anaplastic lymphoma kinase (ALK)(-) anaplastic large cell lymphomas (ALCLs). However, such mutations occur in a minority of patients. To investigate the clinical application of targeting JAK for ALK- ALCL, we treated ALK- cell lines of various histological origins with JAK inhibitors. Interestingly, most exogenous cytokine-independent cell lines responded to JAK inhibition regardless of JAK mutation status...
April 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28344057/ruxolitinib-as-salvage-therapy-in-steroid-refractory-acute-graft-versus-host-disease-in-pediatric-hematopoietic-stem-cell-transplant-patients
#14
Pooja Khandelwal, Ashley Teusink-Cross, Adam S Nelson, Christopher E Dandoy, Javier El-Bietar, Rebecca A Marsh, Ashish R Kumar, Michael S Grimley, Stella M Davies, Sonata Jodele, Kasiani C Myers
We describe our retrospective clinical experience with ruxolitinib for steroid-refractory acute graft versus host disease (GVHD) in pediatric allogeneic hematopoietic stem cell transplant (HSCT) patients. Ruxolitinib was administered orally at 5 mg twice daily for children ≥ 25 kg or 2.5 mg twice daily if < 25 kg. We excluded patients who received new immune suppressive agents within two weeks before initiation of ruxolitinib from response analysis. Patients were called a treatment failure if ruxolitinib was stopped before completion of 4 weeks of therapy due to adverse effects and not because of progression of acute GVHD...
March 23, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/28339658/acute-cell-volume-regulation-by-janus-kinase-2-mediated-sodium-hydrogen-exchange-activation-develops-at-the-late-one-cell-stage-in-mouse-preimplantation-embryos
#15
Baozeng Xu, Chenxi Zhou, Megan Meredith, Jay M Baltz
Early preimplantation embryos are extremely sensitive to dysregulation of cell volume, which can lead to developmental arrest. It was previously shown that mouse embryos at the two-cell stage respond to a cell volume decrease by quickly activating Na+/H+ exchange via a signaling mechanism that involves the tyrosine kinase Janus kinase 2 (JAK2). However, it was not known whether this mechanism is active at the one-cell stage, when embryos are most sensitive to perturbed cell volume. Na+/H+ exchanger activity elicited by an induced cell volume decrease was significantly lower at the mid one-cell stage than at the late one-cell stage or during the two-cell stage...
March 1, 2017: Biology of Reproduction
https://www.readbyqxmd.com/read/28331226/the-histone-deacetylase-inhibitor-givinostat-itf2357-exhibits-potent-anti-tumor-activity-against-crlf2-rearranged-bcp-all
#16
A M Savino, J Sarno, L Trentin, M Vieri, G Fazio, M Bardini, C Bugarin, G Fossati, K Davis, G Gaipa, S Izraeli, L H Meyer, G P Nolan, A Biondi, G Te Kronnie, C Palmi, G Cazzaniga
Leukemias bearing CRLF2 and JAK2 gene alterations are characterized by aberrant JAK/STAT signaling and poor prognosis. The HDAC inhibitor givinostat/ITF2357 has been shown to exert antineoplastic activity against both systemic juvenile idiopathic arthritis and myeloproliferative neoplasms through inhibition of the JAK/STAT pathway. These findings led us to hypothesize that givinostat might also act against CRLF2-rearranged BCP-ALL, which lack effective therapies. Here, we found that givinostat inhibited proliferation and induced apoptosis of BCP-ALL CRLF2-rearranged cell lines, positive for exon 16 JAK2 mutations...
March 23, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28322434/two-cases-of-alopecia-areata-treated-with-ruxolitinib-a%C3%A2-discussion-of-ideal-dosing-and-laboratory-monitoring
#17
Amy Vandiver, Nicholas Girardi, Jihad Alhariri, Luis A Garza
BACKGROUND: Alopecia areata is a relatively common condition affecting patients seen in community dermatology clinics. A 2014 study implicated the JAK1/JAK2 inhibitor, ruxolitinib in short-term treatment of alopecia, however little information exists about the long-term use in otherwise healthy individuals in the community setting. METHODS: A patient with chronic alopecia areata and a patient with acute onset alopecia universalis were treated with oral ruxolitinib for over a year...
March 21, 2017: International Journal of Dermatology
https://www.readbyqxmd.com/read/28302714/ruxolitinib-a-potent-jak1-jak2-inhibitor-induces-temporary-reductions-in-the-allelic-burden-of-concurrent-csf3r-mutations-in-chronic-neutrophilic-leukemia
#18
Arief S Gunawan, Donal P McLornan, Bridget Wilkins, Katherine Waghorn, Yvette Hoade, Nick C P Cross, Claire N Harrison
No abstract text is available yet for this article.
March 16, 2017: Haematologica
https://www.readbyqxmd.com/read/28279039/-regulation-of-ruxolitinib-on-matrix-metalloproteinase-in-jak2v617f-positive-myeloroliferative-neoplasms-cells
#19
G M Liu, L J Zhang, J Z Fu, W T Liang, Z Y Cheng, P Bai, Y S Bian, J S Wan
Objective: To investigate the regulation of JAK2 tyrosine kinase inhibitor ruxolitinib on extracellular matrix metalloproteinase (MMP in JAK2V617F positive myeloproliferative neoplasms (MPN) cells. Methods: ①Forty cases of newly diagnosed JAK2V617F positive MPN patients and 15 healthy volunteers as control in Baoding No.1 Hospital between January 2012 and December 2015 were enrolled in this study. JAK2V617F/JAK2 ratio was detected by real-time-PCR; the expression levels of phosphorylation protein tyrosine kinase 2 (p-JAK2) , MMP-2 and MMP-9 in pathological tissues of bone marrow were detected by immunohistochemistry...
February 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/28277287/the-promise-of-janus-kinase-inhibitors-in-the-treatment-of-hematological-malignancies
#20
REVIEW
Emilee Senkevitch, Scott Durum
The Janus kinases (JAK) are a family of kinases that play an essential role in cytokine signaling and are implicated in the pathogenesis of autoimmune diseases and hematological malignancies. As a result, the JAKs have become attractive therapeutic targets. The discovery of a JAK2 point mutation (JAK2 V617F) as the main cause of polycythemia vera lead to the development and FDA approval of a JAK1/2 inhibitor, ruxolitinib, in 2011. This review focuses on the various JAK and associated components aberrations implicated in myeloproliferative neoplasms, leukemias, and lymphomas...
October 27, 2016: Cytokine
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