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https://www.readbyqxmd.com/read/28647356/optimizing-bone-morphogenic-protein-4-mediated-human-embryonic-stem-cell-differentiation-into-trophoblast-like-cells-using-fibroblast-growth-factor-2-and-transforming-growth-factor-%C3%AE-activin-nodal-signalling-inhibition
#1
Mariann Koel, Urmo Võsa, Kaarel Krjutškov, Elisabet Einarsdottir, Juha Kere, Juha Tapanainen, Shintaro Katayama, Sulev Ingerpuu, Viljar Jaks, Ulf-Hakan Stenman, Karolina Lundin, Timo Tuuri, Andres Salumets
Several studies have demonstrated that human embryonic stem cells (hESC) can be differentiated into trophoblast-like cells if exposed to bone morphogenic protein 4 (BMP4) and/or inhibitors of fibroblast growth factor 2 (FGF2) and the transforming growth factor beta (TGF-β)/activin/nodal signalling pathways. The goal of this study was to investigate how the inhibitors of these pathways improve the efficiency of hESC differentiation when compared with basic BMP4 treatment. RNA sequencing was used to analyse the effects of all possible inhibitor combinations on the differentiation of hESC into trophoblast-like cells over 12 days...
June 12, 2017: Reproductive Biomedicine Online
https://www.readbyqxmd.com/read/28646676/multicenter-phase-2-study-of-combination-therapy-with-ruxolitinib-and-danazol-in-patients-with-myelofibrosis
#2
K Gowin, H Kosiorek, A Dueck, J Mascarenhas, R Hoffman, C Reeder, J Camoriano, R Tibes, K Gano, J Palmer, R Mesa
Myelofibrosis is a myeloproliferative neoplasm that is characterized by splenomegaly, profound symptom burden, and cytopenias. JAK inhibitor therapy offers improvements in splenomegaly, symptom burden, and potentially survival; however, cytopenias remain a significant challenge. Danazol has previously demonstrated improvements in myelofibrosis-associated anemia. We conducted a phase II clinical trial evaluating the efficacy and tolerability of combination therapy with ruxolitinib, an oral JAK inhibitor, and danazol...
June 13, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28646516/tofacitinib-restores-the-inhibition-of-reverse-cholesterol-transport-induced-by-inflammation-understanding-the-lipid-paradox-associated-with-rheumatoid-arthritis
#3
S Pérez-Baos, J I Barrasa, P Gratal, A Larrañaga-Vera, I Prieto-Potin, G Herrero-Beaumont, R Largo
BACKGROUND AND PURPOSE: Patients with active rheumatoid arthritis (RA) have increased cardiovascular mortality, paradoxically associated with reduced circulating lipid levels. The Janus kinase (Jak) inhibitor tofacitinib ameliorates systemic and joint inflammation in RA with a concomitant increase in serum lipids. We analyzed the effect of tofacitinib on the lipid profile of hyperlipidemic rabbits with chronic arthritis (CA) and on the regulation of reverse cholesterol transport (RCT) during chronic inflammation...
June 23, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28646393/the-changing-landscape-of-alopecia-areata-the-therapeutic-paradigm
#4
REVIEW
Yael Renert-Yuval, Emma Guttman-Yassky
Alopecia areata (AA), a prevalent inflammatory cause of hair loss, lacks FDA-approved therapeutics for extensive cases, which are associated with very poor rates of spontaneous hair regrowth and major psychological distress. Current treatments for severe cases include broad immune-suppressants, which are associated with significant adverse effects, precluding long-term use, with rapid hair loss following treatment termination. As a result of the extent of the disease in severe cases, topical contact sensitizers and intralesional treatments are of limited use...
June 23, 2017: Advances in Therapy
https://www.readbyqxmd.com/read/28642467/targeting-coronaviral-replication-and-cellular-jak2-mediated-dominant-nf-%C3%AE%C2%BAb-activation-for-comprehensive-and-ultimate-inhibition-of-coronaviral-activity
#5
Cheng-Wei Yang, Yue-Zhi Lee, Hsing-Yu Hsu, Chuan Shih, Yu-Sheng Chao, Hwan-You Chang, Shiow-Ju Lee
Tylophorine-based compounds exert broad spectral, potent inhibition of coronaviruses. NF-κB activation is a common pro-inflammatory response of host cells to viral infection. The aims of this study were to (i) find an effective combination treatment for coronaviral infections through targeting of the virus per se and cellular NF-κB activity; and (ii) to study the underling mechanisms. We found that tylophorine-based compounds target the TGEV viral RNA and effectively inhibit TGEV replication. NF-κB inhibition also leads to anti-TGEV replication...
June 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28637459/the-role-of-jak-stat-signaling-pathway-and-its-regulators-in-the-fate-of-t-helper-cells
#6
REVIEW
Farhad Seif, Majid Khoshmirsafa, Hossein Aazami, Monireh Mohsenzadegan, Gholamreza Sedighi, Mohammadali Bahar
The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays critical roles in orchestrating of immune system, especially cytokine receptors and they can modulate the polarization of T helper cells. This pathway is regulated by an array of regulator proteins, including Suppressors of Cytokine Signaling (SOCS), Protein Inhibitors of Activated STATs (PIAS) and Protein Tyrosine Phosphatases (PTPs) determining the initiation, duration and termination of the signaling cascades. Dysregulation of the JAK-STAT pathway in T helper cells may result in various immune disorders...
June 21, 2017: Cell Communication and Signaling: CCS
https://www.readbyqxmd.com/read/28635319/a-case-of-topical-ruxolitinib-treatment-failure-in-alopecia-areata
#7
Maya Deeb, Renée A Beach
Alopecia areata (AA) is an autoimmune-mediated, nonscarring form of hair loss. Despite its prevalence, current management options are limited, especially when the disease has progressed to alopecia totalis (AT) or alopecia universalis (AU). Recent evidence that janus kinase (JAK) signaling contributes to AA pathogenesis prompted the investigation of JAK inhibitors such as tofacitinib and ruxolitinib as possible oral treatments. However, the potential for significant adverse effects with systemic JAK inhibition makes local administration a more attractive option...
June 1, 2017: Journal of Cutaneous Medicine and Surgery
https://www.readbyqxmd.com/read/28632888/excellent-response-to-tofacitinib-in-a-patient-with-alopecia-universalis
#8
Funda Erduran, Esra Adışen, Ahmet Burhan Aksakal
EAlopecia universalis (AU) is generally considered a variant of alopecia areata (AA), in which the treatment options seldom provide satisfactory results. However, successful treatment of several cases of AA and its variants with oral Janus kinase (JAK) inhibitors have been reported recently. Here we report a 23-year-old female patient with AU successfully treated with tofacitinib, a selective JAK-3 inhibitor. The initial tofacitinib dose was 5 mg twice daily. After 2 months of treatment, partial hair regrowth was seen on the scalp and eyebrows...
June 2017: Acta Dermatovenerologica Alpina, Panonica, et Adriatica
https://www.readbyqxmd.com/read/28631441/genetic-landscape-and-deregulated-pathways-in-b-cell-lymphoid-malignancies
#9
R Rosenquist, S Beà, M-Q Du, B Nadel, Q Pan-Hammarström
With the introduction of next-generation sequencing, the genetic landscape of the complex group of B-cell lymphoid malignancies has rapidly been unravelled in recent years. This has provided important information about recurrent genetic events and identified key pathways deregulated in each lymphoma subtype. In parallel, there has been intense search and development of novel types of targeted therapy that 'hit' central mechanisms in lymphoma pathobiology, such as BTK, PI3K or BCL2 inhibitors. In this review, we will outline the current view of the genetic landscape of selected entities: follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, chronic lymphocytic leukaemia and marginal zone lymphoma...
June 20, 2017: Journal of Internal Medicine
https://www.readbyqxmd.com/read/28630047/update-on-anti-tumor-necrosis-factor-agents-and-other-new-drugs-for-inflammatory-bowel-disease
#10
REVIEW
Benjamin L Cohen, David B Sachar
The treatment of inflammatory bowel disease (IBD)-ulcerative colitis (UC) and Crohn's disease (CD)-has evolved beyond surgery with the introduction of biologic agents, primarily antibodies against mediators of inflammation and cell attraction. Anti-tumor necrosis factor (TNF) agents have been the first line treatment for moderate to severe ulcerative colitis and Crohn's disease for more than 15 years. During that time much has been learnt about how best to use these agents. This review will assess the evidence on how to optimize the use of anti-TNF agents; when and how to start treatment; how to monitor treatment and when to de-escalate it; and the potential adverse effects of these drugs...
June 19, 2017: BMJ: British Medical Journal
https://www.readbyqxmd.com/read/28628689/aggressive-skin-cancers-occurring-in-patients-treated-with-the-janus-kinase-inhibitor-ruxolitinib
#11
Adam B Blechman, Christine E Cabell, Christine H Weinberger, Anna Duckworth, Justin J Leitenberger, Fiona O Zwald, Mark A Russell
<p>The Food and Drug Administration approved Ruxolitinib in 2011 for the treatment of primary myelofibrosis. Five-year safety data showed a higher incidence of skin cancer in patients treated with Ruxolitinib compared to best available therapy for myelofibrosis. This report presents a series of five patients with history of myelofibrosis treated with Ruxolitinib who subsequently developed numerous skin cancers with aggressive biological behavior. Each patient in this report was treated by a Mohs surgeon affiliated with an academic institution...
May 1, 2017: Journal of Drugs in Dermatology: JDD
https://www.readbyqxmd.com/read/28622463/efficacy-safety-pharmacokinetics-and-pharmacodynamics-of-filgotinib-a-selective-janus-kinase-1-inhibitor-after-short-term-treatment-of-rheumatoid-arthritis-results-of-two-randomized-phase-iia-trials
#12
Frédéric Vanhoutte, Minodora Mazur, Oleksandr Voloshyn, Mykola Stanislavchuk, Annegret Van der Aa, Florence Namour, René Galien, Luc Meuleners, Gerben van 't Klooster
OBJECTIVE: Janus kinase (JAK) inhibitors have shown efficacy in rheumatoid arthritis (RA). We hypothesized that selective inhibition of JAK1 would combine good efficacy with a differentiated safety profile versus less selective JAK inhibitors. METHODS: In two 4-week exploratory, double-blind, placebo-controlled Phase IIA trials, 127 RA patients with insufficient response to methotrexate received filgotinib (GLPG0634, GS-6034) oral capsules (twice-daily 100 mg, or once-daily 30, 75, 150, 200, or 300 mg) or placebo, added on to a stable regimen of methotrexate, to evaluate safety, efficacy, pharmacokinetics and pharmacodynamics of filgotinib...
June 16, 2017: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/28622305/the-thrombopoietin-mpl-axis-is-activated-in-the-gata1-low-mouse-model-of-myelofibrosis-and-is-associated-with-a-defective-rps14-signature
#13
M Zingariello, L Sancillo, F Martelli, F Ciaffoni, M Marra, L Varricchio, R A Rana, C Zhao, J D Crispino, A R Migliaccio
Myelofibrosis (MF) is characterized by hyperactivation of thrombopoietin (TPO) signaling, which induces a RPS14 deficiency that de-regulates GATA1 in megakaryocytes by hampering its mRNA translation. As mice carrying the hypomorphic Gata1(low) mutation, which reduces the levels of Gata1 mRNA in megakaryocytes, develop MF, we investigated whether the TPO axis is hyperactive in this model. Gata1(low) mice contained two times more Tpo mRNA in liver and TPO in plasma than wild-type littermates. Furthermore, Gata1(low) LSKs expressed levels of Mpl mRNA (five times greater than normal) and protein (two times lower than normal) similar to those expressed by LSKs from TPO-treated wild-type mice...
June 16, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/28619982/jak1-2-and-bcl2-inhibitors-synergize-to-counteract-bone-marrow-stromal-cell-induced-protection-of-aml
#14
Riikka Karjalainen, Tea Pemovska, Mihaela Popa, Minxia Liu, Komal K Javarappa, Muntasir M Majumder, Bhagwan Yadav, David Tamborero, Jing Tang, Dmitrii Bychkov, Mika Kontro, Alun Parsons, Minna Suvela, Mireia Mayoral Safont, Kimmo Porkka, Tero Aittokallio, Olli Kallioniemi, Emmet McCormack, Bjørn T Gjertsen, Krister Wennerberg, Jonathan Knowles, Caroline A Heckman
The bone marrow (BM) provides a protective microenvironment to support the survival of leukemic cells and influence their response to therapeutic agents. In acute myeloid leukemia (AML), the high rate of relapse may in part be due to the inability of current treatment to effectively overcome the protective influence of the BM niche. To better understand the impact of the BM microenvironment on drug responses in AML, we conducted a comprehensive evaluation of 304 inhibitors, including approved and investigational agents, comparing ex vivo responses of primary AML cells in BM stroma-derived and standard culture conditions...
June 15, 2017: Blood
https://www.readbyqxmd.com/read/28612747/pathogenetic-insights-from-the-treatment-of-rheumatoid-arthritis
#15
REVIEW
Iain B McInnes, Georg Schett
Rheumatoid arthritis is a chronic autoimmune disease that causes progressive articular damage, functional loss, and comorbidity. The development of effective biologics and small-molecule kinase inhibitors in the past two decades has substantially improved clinical outcomes. Just as understanding of pathogenesis has led in large part to the development of drugs, so have mode-of-action studies of these specific immune-targeted agents revealed which immune pathways drive articular inflammation and related comorbidities...
June 10, 2017: Lancet
https://www.readbyqxmd.com/read/28611190/cbl-family-e3-ubiquitin-ligases-control-jak2-ubiquitination-and-stability-in-hematopoietic-stem-cells-and-myeloid-malignancies
#16
Kaosheng Lv, Jing Jiang, Ryan Donaghy, Christopher R Riling, Ying Cheng, Vemika Chandra, Krasimira Rozenova, Wei An, Bhopal C Mohapatra, Benjamin T Goetz, Vinodh Pillai, Xu Han, Emily A Todd, Grace R Jeschke, Wallace Y Langdon, Suresh Kumar, Elizabeth O Hexner, Hamid Band, Wei Tong
Janus kinase 2 (JAK2) is a central kinase in hematopoietic stem/progenitor cells (HSPCs), and its uncontrolled activation is a prominent oncogenic driver of hematopoietic neoplasms. However, molecular mechanisms underlying the regulation of JAK2 have remained elusive. Here we report that the Casitas B-cell lymphoma (CBL) family E3 ubiquitin ligases down-regulate JAK2 stability and signaling via the adaptor protein LNK/SH2B3. We demonstrated that depletion of CBL/CBL-B or LNK abrogated JAK2 ubiquitination, extended JAK2 half-life, and enhanced JAK2 signaling and cell growth in human cell lines as well as primary murine HSPCs...
June 13, 2017: Genes & Development
https://www.readbyqxmd.com/read/28609676/hepatocellular-differentiation-status-is-characterized-by-distinct-subnuclear-localization-and-form-of-the-chanzyme-trpm7
#17
Adenike Ogunrinde, Robyn D Pereira, Natalie Beaton, D Hung Lam, Christiane Whetstone, Ceredwyn E Hill
The channel-kinase TRPM7 is important for the survival, proliferation, and differentiation, of many cell types. Both plasma membrane channel activity and kinase function are implicated in these roles. Channel activity is greater in less differentiated hepatoma cells compared with non-dividing, terminally differentiated adult hepatocytes, suggesting differences in protein expression and/or localization. We used electrophysiological and immunofluorescence approaches to establish whether hepatocellular differentiation is associated with altered TRPM7 expression...
June 10, 2017: Differentiation; Research in Biological Diversity
https://www.readbyqxmd.com/read/28606598/practical-measures-of-clinical-benefit-with-ruxolitinib-therapy-an-exploratory-analysis-of-comfort-i
#18
Carole B Miller, Rami S Komrokji, Ruben A Mesa, William Sun, Michael Montgomery, Srdan Verstovsek
BACKGROUND: The phase III COMFORT (Controlled Myelofibrosis Study With Oral JAK inhibitor Treatment)-I and COMFORT-II trials in patients with intermediate-2 or high-risk myelofibrosis (MF) showed that ruxolitinib was superior to placebo and best available therapy, respectively, for improvements in spleen volume, MF-related symptoms, and overall survival (OS). However, patients managed in community settings might not have access to the methods used in the COMFORT trials. In this exploratory analysis we summarize efficacy findings of COMFORT-I using practical, community-oriented measures of patient outcomes...
May 12, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28602584/how-to-define-treatment-failure-for-jak-inhibitors
#19
Hans Michael Kvasnicka
No abstract text is available yet for this article.
June 8, 2017: Lancet Haematology
https://www.readbyqxmd.com/read/28586756/inhibitors-of-the-pi3k-mtor-pathway-prevent-stat5-phosphorylation-in-jak2v617f-mutated-cells-through-pp2a-cip2a-axis
#20
Niccolò Bartalucci, Laura Calabresi, Manjola Balliu, Serena Martinelli, Maria Caterina Rossi, Jean Luc Villeval, Francesco Annunziato, Paola Guglielmelli, Alessandro M Vannucchi
Inhibition of the constitutively activated JAK/STAT pathway in JAK2V617F mutated cells by the JAK1/JAK2 inhibitor ruxolitinib resulted in clinical benefits in patients with myeloproliferative neoplasms. However, evidence of disease-modifying effects remains scanty; furthermore, some patients do not respond adequately to ruxolitinib, or have transient responses, thus novel treatment strategies are needed. Here we demonstrate that ruxolitinib causes incomplete inhibition of STAT5 in JAK2V617F mutated cells due to persistence of phosphorylated serine residues of STAT5b, that conversely are targeted by PI3K and mTORC1 inhibitors...
May 22, 2017: Oncotarget
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