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https://www.readbyqxmd.com/read/28646676/multicenter-phase-2-study-of-combination-therapy-with-ruxolitinib-and-danazol-in-patients-with-myelofibrosis
#1
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/28642467/targeting-coronaviral-replication-and-cellular-jak2-mediated-dominant-nf-%C3%AE%C2%BAb-activation-for-comprehensive-and-ultimate-inhibition-of-coronaviral-activity
#2
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/28634059/a-pumpkin-polysaccharide-induces-apoptosis-by-inhibiting-the-jak2-stat3-pathway-in-human-hepatoma-hepg2-cells
#3
Weixi Shen, Chunhong Chen, Yuanyuan Guan, Xiaowei Song, Yinghua Jin, Jingfang Wang, Yu Hu, Tao Xin, Qiuying Jiang, Li Zhong
The purpose of this study is to investigate the effect of a purified polysaccharide (PPPF) from pumpkin fruit on the Janus activated kinase (JAK)/signal transducer and activator of transcription (STAT) signaling during apoptotic process. The results showed that PPPF or STAT3 siRNA inhibits the cell growth of HepG2 cells via induction of apoptosis. Moreover, PPPF is able to suppress both constitutive and IL-6-induced phosphorylation of STAT3 (on Tyr705) and subsequent nuclear translocation in cancer cells. Such inhibition is found to be achieved through down-regulation of constitutive phosphorylation of JAK2, but not JAk1, c-Src, ERK1/2, and Akt, which means STAT3 tyrosine phosphorylation in HepG2 cells following PPPF treatment is associated with a reduction in JAK2 activity...
June 17, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28632888/excellent-response-to-tofacitinib-in-a-patient-with-alopecia-universalis
#4
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/28620241/tgf-beta-atra-induced-tregs-express-a-selected-set-of-micrornas-involved-in-the-repression-of-transcripts-related-to-th17-differentiation
#5
Josiane Lilian Dos Santos Schiavinato, Rodrigo Haddad, Felipe Saldanha-Araujo, João Baiochi, Amélia Goes Araujo, Priscila Santos Scheucher, Dimas Tadeu Covas, Marco Antonio Zago, Rodrigo Alexandre Panepucci
Regulatory T cells (Tregs) are essential regulators of immune tolerance. atRA and TGF-β can inhibit the polarization of naïve T cells into inflammatory Th17 cells, favoring the generation of stable iTregs, however the regulatory mechanisms involved are not fully understood. In this context, the roles of individual microRNAs in Tregs are largely unexplored. Naïve T cells were immunomagnetically isolated from umbilical cord blood and activated with anti-human CD2/CD3/CD28 beads in the presence of IL-2 alone (CD4Med) or with the addition of TGF-β and atRA (CD4TGF/atRA)...
June 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28619982/jak1-2-and-bcl2-inhibitors-synergize-to-counteract-bone-marrow-stromal-cell-induced-protection-of-aml
#6
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/28617942/withasteroid-b-from-d-metel-l-regulates-immune-responses-by-modulating-the-jak-stat-pathway-and-the-il-17-ror%C3%AE-t-il-10-foxp3-ratio
#7
Yang Su, Qiuhong Wang, Bingyou Yang, Lun Wu, Genhong Cheng, Haixue Kuang
Datura metel L. is a medicinal herb that contains withasteroids and has a wide range of biological activities. We isolated 7 withasteroids from the flowers of D. metel L(1) . and examined their ability to inhibit immune responses in vitro and in vivo. Among the withasteroids, B2(2) exhibited the strongest inhibitory effect on immune responses comparing B2 with other isolated compounds from D. metel L., including suppressing the differentiation of CD4(+3) T cells by inhibiting the expression and production of T cell lineage-specific master regulators and cytokines and directly suppressing the cytokine-induced JAK/STAT(4) signaling pathways...
June 15, 2017: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/28617558/up-regulation-of-mir-124-inhibits-invasion-and-proliferation-of-prostate-cancer-cells-through-mediating-jak-stat3-signaling-pathway
#8
Z Wu, W Huang, B Chen, P-D Bai, X-G Wang, J-C Xing
OBJECTIVE: Signal transducer and activator of transcription 3 (STAT3) is an important protein in Janus kinase (JAK)-STAT signaling pathway, and can facilitate expression of Bcl-2 and Cyclin D1 gene, thus playing a role in tumor pathogenesis. Bioinformatics analysis revealed targeted binding sites between mircroRNA-124 (miR-124) and 3'-UTR of STAT3 mRNA. This study aims to investigate the role of miR-124 in regulating STAT3 expression and proliferation, cycle, apoptosis and invasion of prostate cancer cells...
May 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/28611190/cbl-family-e3-ubiquitin-ligases-control-jak2-ubiquitination-and-stability-in-hematopoietic-stem-cells-and-myeloid-malignancies
#9
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/28608623/guar-gum-fiber-increases-suppressor-of-cytokine-signaling-1-expression-via-toll-like-receptor-2-and-dectin-1-pathways-regulating-inflammatory-response-in-small-intestinal-epithelial-cells
#10
Tran Van Hung, Takuya Suzuki
SCOPE: Direct regulation of intestinal inflammation by intact dietary fibers is still unclear. Here, the anti-inflammatory regulation by intact guar gum (GG) was investigated using mice and human intestinal Caco-2 cells. METHODS AND RESULTS: Administration of dextran sodium sulfate (DSS) increased myeloperoxidase activity and CXC motif chemokine ligand2 (an IL-8 homologue) expression in the small intestines of mice, while supplemental GG reduced these increases...
June 13, 2017: Molecular Nutrition & Food Research
https://www.readbyqxmd.com/read/28606598/practical-measures-of-clinical-benefit-with-ruxolitinib-therapy-an-exploratory-analysis-of-comfort-i
#11
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/28606122/anterior-tibial-curved-cortex-is-a-reliable-landmark-for-tibial-rotational-alignment-in-total-knee-arthroplasty
#12
Joong Il Kim, Jak Jang, Ki Woong Lee, Hyuk Soo Han, Sahnghoon Lee, Myung Chul Lee
BACKGROUND: Rotational alignment of the tibial component is important for long-term success of total knee arthroplasty (TKA). This study aimed to compare five axes in normal and osteoarthritic (OA) knees to determine a reliable landmark for tibial rotational alignment in TKA. METHODS: One hundred twenty patients with OA knees and 40 with normal knees were included. The angle between a line perpendicular to the surgical transepicondylar axis and each of five axes were measured on preoperative computed tomography...
June 12, 2017: BMC Musculoskeletal Disorders
https://www.readbyqxmd.com/read/28601384/polycystin-and-calcium-signaling-in-cell-death-and-survival
#13
REVIEW
Fernanda O Lemos, Barbara E Ehrlich
Mutations in polycystin-1 (PC1) and polycystin-2 (PC2) result in a commonly occurring genetic disorder, called Autosomal Dominant Polycystic Kidney Disease (ADPKD), that is characterized by the formation and development of kidney cysts. Epithelial cells with loss-of-function of PC1 or PC2 show higher rates of proliferation and apoptosis and reduced autophagy. PC1 is a large multifunctional transmembrane protein that serves as a sensor that is usually found in complex with PC2, a calcium (Ca(2+))-permeable cation channel...
May 24, 2017: Cell Calcium
https://www.readbyqxmd.com/read/28599489/maslinic-acid-suppresses-the-growth-of-human-gastric-cells-by-inducing-apoptosis-via-inhibition-of-the-interleukin-6-mediated-janus-kinase-signal-transducer-and-activator-of-transcription-3-signaling-pathway
#14
Deyou Wang, Sifeng Tang, Qiwen Zhang
The present study aimed to determine whether maslinic acid effectively inhibits the proliferation of MKN28 cells, and to investigate the mechanisms underlying its antitumor functions. MKN28 cell viability was evaluated using a Cell Counting Kit-8, cell proliferation was analyzed by a colony formation assay and flow cytometry was used to investigate the rate of apoptosis. Western blot analysis was performed in order to determine the differential expression levels of Janus kinase (JAK), signal transducer and activator of transcription 3 (STAT3) and apoptosis associated proteins B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein (Bax) and Bcl-2 associated agonist of cell death (Bad)...
June 2017: Oncology Letters
https://www.readbyqxmd.com/read/28596648/the-impact-of-mean-platelet-volume-mpv-and-jak-2-mutation-on-thrombosis-in-chronic-myeloproliferative-diseases
#15
Mesut Ayer, İlhan Menken, Mehmet Yamak, Fatma Aylin Ayer, Onur Kırkızlar, M Burak Aktuğlu
Thrombosis and bleeding are the main complications of chronic myeloproliferative diseases. Mean platelet volume (MPV) is an important indicator of the platelet activation. The aim of the present study was to assess the interrelationships between MPV, JAK-2 gene mutation and thromboembolic events in patients with ET and PV. Patients with ET (n = 60) and PV (n = 46) were compared to the secondary erythrocytosis group (n = 19); and a control group of age and sex matched healthy volunteers (n = 52). Besides demographic, clinical and laboratory data; thrombotic and hemorrhagic events were recorded for each patient...
June 2017: Indian Journal of Hematology & Blood Transfusion
https://www.readbyqxmd.com/read/28587386/socs3-overexpression-inhibits-advanced-glycation-end-product-induced-emt-in-proximal-tubule-epithelial-cells
#16
Lin Yu, Ying Zhang, Huimin Zhang, Yingtao Li
Diabetic nephropathy (DN) is among the most severe complications of diabetes mellitus, and may lead to end-stage renal disease. Sustained exposure to advanced glycation end products (AGEs) typically causes renal tubular epithelial cells (TECs) to suffer from an epithelial-to-mesenchymal transition (EMT). However, there remains no consensus regarding the mechanism underlying the cause of EMT in TECs as induced by AGEs. In the present study, we investigated the promotion of EMT in TECs by AGEs, and the activation of Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling...
June 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28574510/rip4-inhibits-stat3-signaling-to-sustain-lung-adenocarcinoma-differentiation
#17
Jawahar Kopparam, Johanna Chiffelle, Paolo Angelino, Alessandra Piersigilli, Nadine Zangger, Mauro Delorenzi, Etienne Meylan
Loss of epithelial differentiation and extracellular matrix (ECM) remodeling are known to facilitate cancer progression and are associated with poor prognosis in patients with lung cancer. We have identified Receptor-interacting serine/threonine protein kinase 4 (RIP4) as a regulator of tumor differentiation in lung adenocarcinoma (AC). Bioinformatics analyses of human lung AC samples showed that poorly differentiated tumors express low levels of RIP4, whereas high levels are associated with better overall survival...
June 2, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28569589/cytokine-signal-suppressor-socs-1-1478-ca-del-gene-polymorphism-in-turkish-patients-with-polycystic-ovary-syndrome
#18
Ozen Oz Gul, Soner Cander, Cuma Bulent Gul, Ferah Budak, Barbaros Oral, Canan Ersoy
Eighty-four subjects, premenopausal female patients (n = 42, mean (SD) age: 26.4 (4.2) years) diagnosed with polycystic ovary syndrome (PCOS) and age-matched healthy volunteers (n = 42, mean (SD) age: 27.6(3.4) years), were included in this study. Data on physical examination, anthropometric measurements and blood biochemistry analysis were recorded for each subject along with analysis for SOCS1-1478 CA/del polymorphism by polymerase chain reaction-restriction fragment length polymorphism. The relation of SOCS1-1478 CA/del polymorphism to PCOS status and insulin resistance was analysed via logistic regression analysis...
June 1, 2017: Journal of Obstetrics and Gynaecology: the Journal of the Institute of Obstetrics and Gynaecology
https://www.readbyqxmd.com/read/28569433/ascochlorin-suppresses-mmp-2-mediated-migration-and-invasion-by-targeting-fak-and-jak-stat-signaling-cascades
#19
Hyun-Ji Cho, Ji-Hyun Park, Jin Han Nam, Young-Chae Chang, Byoungduck Park, Hyang-Sook Hoe
Human glioblastomas express higher levels of matrix metalloprotease-2 (MMP-2) than low-grade brain tumors and normal brain tissues. Ascochlorin (ASC) has anti-metastatic, anti-angiogenic, and synergistic effect in various types of cancer cells. However, it remains unknown whether ASC can affect cell migration and invasion in malignant human glioma cells. In this study, we found that ASC indeed inhibits cell migration and invasion in U373MG and A172. ASC significantly suppresses the MMP-2 gelatinolytic activity and expression in U373MG and A172...
June 1, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28566376/ruxolitinib-and-polycation-combination-treatment-overcomes-multiple-mechanisms-of-resistance-of-pancreatic-cancer-cells-to-oncolytic-vesicular-stomatitis-virus
#20
Sébastien A Felt, Gaith N Droby, Valery Z Grdzelishvili
Vesicular stomatitis virus (VSV) is a promising oncolytic virus (OV). Although VSV is effective against a majority of pancreatic ductal adenocarcinoma (PDAC) cell lines, some PDAC cell lines are highly resistant to VSV, and the mechanisms of the resistance are still unclear. JAK 1/2 inhibitors (such as ruxolitinib and JAK Inhibitor 1) strongly stimulate VSV replication and oncolysis in all resistant cell lines, but only partially improve susceptibility of resistant PDACs to VSV. VSV tumor tropism is generally dependent on the permissiveness of malignant cells to viral replication, rather than on receptor specificity, with several ubiquitously expressed cell-surface molecules to play a role in VSV attachment to host cells...
May 31, 2017: Journal of Virology
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