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Ruxolitinib

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https://www.readbyqxmd.com/read/29042365/ruxolitinib-induced-defects-in-dna-repair-cause-sensitivity-to-parp-inhibitors-in-myeloproliferative-neoplasms
#1
Margaret Nieborowska-Skorska, Silvia Maifrede, Yashodhara Dasgupta, Katherine Sullivan, Sylwia Flis, Bac Viet Le, Martyna Solecka, Elizaveta A Belyaeva, Lucia Kubovcakova, Morgan Nawrocki, Martin Kirschner, Huaqing Zhao, Josef T Prchal, Katarzyna Piwocka, Alison R Moliterno, Mariusz Wasik, Steffen Koschmieder, Tony R Green, Radek C Skoda, Tomasz Skorski
Myeloproliferative neoplasms (MPNs) often carry JAK2(V617F), MPL(W515L), or CALR(del52) mutations. Current treatment options for MPNs include cytoreduction by hydroxyurea and JAK1/2 inhibition by ruxolitinib, both of which are not curative. We show here that cell lines expressing JAK2(V617F), MPL(W515L) or CALR(del52) accumulated reactive oxygen species-induced DNA double-strand breaks (DSBs) and were modestly sensitive to poly-ADP-ribose polymerase (PARP) inhibitors olaparib and BMN673. At the same time primary MPN cell samples from individual patients displayed a high degree of variability in the sensitivity to these drugs...
October 17, 2017: Blood
https://www.readbyqxmd.com/read/29034260/clodronate-improves-survival-of-transplanted-hoxb8-myeloid-progenitors-with-constitutively-active-gmcsfr-in-immunocompetent-mice
#2
Simon Lee, Saul Kivimäe, Francis C Szoka
New methods to produce large numbers of myeloid progenitor cells, precursors to macrophages (MΦs), by maintaining Hoxb8 transcription factor activity(1) has reinvigorated interest in MΦ cell therapies. We generated Hoxb8-dependent myeloid progenitors (HDPs) by transducing lineage-negative bone marrow cells with a constitutively expressed Hoxb8 flanked by loxP. HDPs proliferate indefinitely and differentiate into MΦ when Hoxb8 is removed by a tamoxifen-inducible Cre. We genetically modified HDPs with a constitutively active GMCSF receptor and the tamoxifen-induced transcription factor IRF8, which we have termed "HDP-on...
December 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29030706/rare-adar-and-rnaseh2b-variants-and-a-type-i-interferon-signature-in-glioma-and-prostate-carcinoma-risk-and-tumorigenesis
#3
Ulrike Beyer, Frank Brand, Helge Martens, Julia Weder, Arne Christians, Natalie Elyan, Bettina Hentschel, Manfred Westphal, Gabriele Schackert, Torsten Pietsch, Bujung Hong, Joachim K Krauss, Amir Samii, Peter Raab, Anibh Das, Claudia A Dumitru, I Erol Sandalcioglu, Oliver W Hakenberg, Andreas Erbersdobler, Ulrich Lehmann, Guido Reifenberger, Michael Weller, Martin A M Reijns, Matthias Preller, Bettina Wiese, Christian Hartmann, Ruthild G Weber
In search of novel germline alterations predisposing to tumors, in particular to gliomas, we studied a family with two brothers affected by anaplastic gliomas, and their father and paternal great-uncle diagnosed with prostate carcinoma. In this family, whole-exome sequencing yielded rare, simultaneously heterozygous variants in the Aicardi-Goutières syndrome (AGS) genes ADAR and RNASEH2B co-segregating with the tumor phenotype. AGS is a genetically induced inflammatory disease particularly of the brain, which has not been associated with a consistently increased cancer risk to date...
October 13, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/29026328/phosphorylation-of-stat-proteins-by-recombinant-human-il-6-in-immortalized-human-chondrocyte-cell-lines-t-c28a2-and-c28-i2
#4
Evan C Meszaros, Charles J Malemud
Two immortalized human juvenile chondrocyte cell lines, T/C28a2 and C28/I2, were employed to determine the extent to which recombinant human (rh) IL-6, a known cytokine activator of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway in many cell types, caused STAT proteins to be phosphorylated. The results showed that STAT3 was constitutively phosphorylated in the absence of rhIL-6 in T/C28a2 chondrocytes. However, C28/I2 chondrocytes treated with rhIL-6 caused STAT1, STAT3, and STAT5 to be phosphorylated without altering total unphosphorylated STAT proteins...
2017: Journal of Inflammation Research
https://www.readbyqxmd.com/read/29025600/a-novel-somatic-jak2-kinase-domain-mutation-in-pediatric-acute-lymphoblastic-leukemia-with-rapid-on-treatment-development-of-loh
#5
Teresa Sadras, Susan L Heatley, Chung H Kok, Barbara J McClure, David Yeung, Timothy P Hughes, Rosemary Sutton, David S Ziegler, Deborah L White
We report a novel somatic mutation in the kinase domain of JAK2 (R938Q) in a high-risk pediatric case of B-cell acute lymphoblastic leukemia (ALL). The patient developed on-therapy relapse at 12 months, and interestingly, the JAK2 locus acquired loss of heterozygosity during treatment resulting in 100% mutation load. Furthermore, we show that primary ALL mononuclear cells harboring the JAK2 R938Q mutation display reduced sensitivity to the JAK1/2 ATP-competitive inhibitor ruxolitinib in vitro, compared to ALL cells that carry a more common JAK2 pseudokinase domain mutation...
October 2017: Cancer Genetics
https://www.readbyqxmd.com/read/29024842/peritoneal-carcinomatosis-like-implants-of-extramedullary-hematopoiesis-an-insolite-occurrence-during-splenectomy-for-myelofibrosis
#6
Marco Casaccia, Rosario Fornaro, Marco Frascio, Denise Palombo, Cesare Stabilini, Emma Firpo, Ezio Gianetta
INTRODUCTION: Primary myelofibrosis (MF) is a myeloproliferative neoplasm that results in debilitating constitutional symptoms, splenomegaly, and cytopenias. In patients with symptomatic splenomegaly, splenectomy remains a viable treatment option for MF patients with medically refractory symptomatic splenomegaly that precludes the use of ruxolitinib. CASE PRESENTATION: We present the clinical case of a patient who was admitted to our Department to perform a splenectomy in MF as a therapeutic step prior to an allogeneic stem cell transplantation (ASCT)...
October 5, 2017: International Journal of Surgery Case Reports
https://www.readbyqxmd.com/read/29022420/recommendations-on-the-use-of-ruxolitinib-for-the-treatment-of-myelofibrosis
#7
Timothy Devos, Dominik Selleslag, Pierre Zachée, Fleur Samantha Benghiat
OBJECTIVES: Myelofibrosis (MF) is a severe disease, with decreased life expectancy and heavy symptom burden. Ruxolitinib is the only approved pharmacotherapy for the treatment of MF patients. In Belgium, ruxolitinib is only reimbursed for MF patients with splenomegaly for whom the disease is categorized as intermediate-2 or high risk. The improvement of symptoms without spleen volume reduction is not considered sufficient to continue treatment. The aim of this manuscript is to provide guidance for the safe and effective administration of ruxolitinib, considering the particularities of the Belgian reimbursement criteria...
October 12, 2017: Hematology (Amsterdam, Netherlands)
https://www.readbyqxmd.com/read/28994166/newer-treatments-of-psoriasis-regarding-il-23-inhibitors-phosphodiesterase-4-inhibitors-and-janus-kinase-inhibitors
#8
REVIEW
Dominika Wcisło-Dziadecka, Martyna Zbiciak-Nylec, Ligia Brzezińska-Wcisło, Katarzyna Bebenek, Agata Kaźmierczak
The rapid progress of genetic engineering furthermore opens up new prospects in the therapy of this difficult-to-treat disease. IL-23 inhibitors, phosphodiesterase 4 (PDE4) inhibitors, and Janus kinase (JAK) inhibitors are currently encouraging further research. Two drugs which are IL-23 inhibitors are now in phase III of clinical trials. The aim of the action of both drugs is selective IL-23 inhibition by targeting the p19 subunit. Guselkumab is a fully human monoclonal antibody. Tildrakizumab is a humanized monoclonal antibody, which also belongs to IgG class and is targeted to subunit p19 of interleukin 23 (IL-23)...
October 10, 2017: Dermatologic Therapy
https://www.readbyqxmd.com/read/28986762/evaluation-of-the-dose-and-efficacy-of-ruxolitinib-in-japanese-patients-with-myelofibrosis
#9
Keita Kirito, Shinichiro Okamoto, Kohshi Ohishi, Tetsuzo Tauchi, Hiroshi Handa, Shigeki Saito, Katsuto Takenaka, Kazuya Shimoda, Kenji Oritani, Koichi Akashi, Hikaru Okada, Taro Amagasaki, Kazuyuki Suzuki, Toshio Yonezu, Norio Komatsu
Ruxolitinib, a potent JAK1/JAK2 inhibitor, improved splenomegaly and myelofibrosis-associated symptoms and prolonged survival compared with placebo and best available therapy in the phase 3 COMFORT studies. Although cytopenias were the most common adverse events associated with ruxolitinib treatment, a COMFORT-I analysis showed that they were managed effectively with dose modifications, without a negative impact on the efficacy of ruxolitinib. Subsequently, studies A2202 and AJP01 showed that ruxolitinib is an effective treatment for Japanese patients with myelofibrosis...
October 6, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28970999/acute-respiratory-distress-syndrome-a-rare-complication-caused-by-usage-of-ruxolitinib
#10
Bugra Kerget, Omer Araz, Elif Yilmazel Ucar, Metin Akgun, Leyla Sağlam
Ruxolitinib-associated acute respiratory distress has rarely been reported, mostly due to discontinuation of treatment. Herein we report a 58-year-old male patient with primary myelofibrosis who presented with malaise and dyspnea 15 days after initiation of the treatment. The patient was diagnosed as mild acute respiratory distress syndrome (ARDS). After excluding other potential causes such as infection and cardiac pathologies, it was considered secondary to ruxolitinib use. The medication was discontinued and 1 mg/kg methylprednisolone was given to prevent cytokine rebound syndrome and continuous positive airway pressure therapy was prescribed for ARDS...
2017: Respiratory Medicine Case Reports
https://www.readbyqxmd.com/read/28969943/deciphering-the-pathways-that-protect-from-il-13-mediated-potentiation-of-oxidative-stress-induced-dopaminergic-nerve-cell-death
#11
Pamela Maher, Bruno Conti
The majority of Parkinson's disease (PD) cases are sporadic with only about 10% of PD patients having a family history of the disease suggesting that this neurodegenerative disorder is the result of both environmental and genetic factors. Both oxidative stress and neuroinflammation are thought to contribute to PD. Previously, we showed that the activation of interleukin 13 receptor alpha 1 (IL-13Rα1) increases the sensitivity of dopaminergic neurons to oxidative damage both in cultured cells and in animals...
September 30, 2017: Cytokine
https://www.readbyqxmd.com/read/28962635/long-term-survival-in-patients-treated-with-ruxolitinib-for-myelofibrosis-comfort-i-and-ii-pooled-analyses
#12
Srdan Verstovsek, Jason Gotlib, Ruben A Mesa, Alessandro M Vannucchi, Jean-Jacques Kiladjian, Francisco Cervantes, Claire N Harrison, Ronald Paquette, William Sun, Ahmad Naim, Peter Langmuir, Tuochuan Dong, Prashanth Gopalakrishna, Vikas Gupta
BACKGROUND: Myelofibrosis (MF) is associated with a variety of burdensome symptoms and reduced survival compared with age-/sex-matched controls. This analysis evaluated the long-term survival benefit with ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, in patients with intermediate-2 (int-2) or high-risk MF. METHODS: This was an exploratory analysis of 5-year data pooled from the phase 3 COMFORT-I and -II trials. In both trials, patients could cross over to ruxolitinib from the control group (COMFORT-I, placebo; COMFORT-II, best available therapy)...
September 29, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28956263/ruxolitinib-is-effective-and-safe-in-japanese-patients-with-hydroxyurea-resistant-or-hydroxyurea-intolerant-polycythemia-vera-with-splenomegaly
#13
Keita Kirito, Kenshi Suzuki, Koichi Miyamura, Masahiro Takeuchi, Hiroshi Handa, Shinichiro Okamoto, Brian Gadbaw, Kyosuke Yamauchi, Taro Amagasaki, Kazuo Ito, Masayuki Hino
Ruxolitinib, a potent JAK1/JAK2 inhibitor, was found to be superior to the best available therapy (BAT) in controlling hematocrit, reducing splenomegaly, and improving symptoms in the phase 3 RESPONSE study of patients with polycythemia vera with splenomegaly who experienced an inadequate response to or adverse effects from hydroxyurea. We report findings from a subgroup analysis of Japanese patients in RESPONSE (n = 18). The composite response rate (hematocrit control and spleen response) was higher in patients receiving ruxolitinib (50...
September 27, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28953386/design-and-synthesis-of-ligand-efficient-dual-inhibitors-of-janus-kinase-jak-and-histone-deacetylase-hdac-based-on-ruxolitinib-and-vorinostat
#14
Lianbin Yao, Nurulhuda Mustafa, Eng Chong Tan, Anders Poulsen, Prachi Singh, Minh-Dao Duong-Thi, Jeannie X T Lee, Pondy Murugappan Ramanujulu, Wee Joo Chng, Jeffrey J Y Yen, Sten Ohlson, Brian W Dymock
Concomitant inhibition of multiple oncogenic pathways is a desirable goal in cancer therapy. To achieve such an outcome with a single molecule would simplify treatment regimes. Herein the core features of ruxolitinib (1), a marketed JAK1/2 inhibitor, have been merged with the HDAC inhibitor vorinostat (2), leading to new molecules which are bispecific targeted JAK/HDAC inhibitors. A preferred pyrazole substituted pyrrolopyrimidine, 24, inhibits JAK1 and HDACs 1,2,3,6 and 10 with IC50s of less than 20 nM, is <100 nM potent against JAK2 and HDAC11 and is selective for the JAK family against a panel of 97 kinases...
September 27, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28949941/polycythemia-vera-from-new-modified-diagnostic-criteria-to-new-therapeutic-approaches
#15
Margherita Maffioli, Barbara Mora, Francesco Passamonti
Polycythemia vera (PV) is a Philadelphia chromosome-negative chronic myeloproliferative neoplasm that is associated with a Janus kinase 2 (JAK2) mutation in most cases. The most recent update to the World Health Organization diagnostic criteria for PV was published in 2016. These were the modifications with the greatest effect: (1) lowering the hemoglobin threshold, allowing a diagnosis of PV at 16.5 g/dL in males and at 16.0 g/dL in females and (2) introducing a hematocrit cutoff (49% in males and 48% in females)...
September 2017: Clinical Advances in Hematology & Oncology: H&O
https://www.readbyqxmd.com/read/28930494/simplify-1-a-phase-iii-randomized-trial-of-momelotinib-versus-ruxolitinib-in-janus-kinase-inhibitor-na%C3%A3-ve-patients-with-myelofibrosis
#16
Ruben A Mesa, Jean-Jacques Kiladjian, John V Catalano, Timothy Devos, Miklos Egyed, Andrzei Hellmann, Donal McLornan, Kazuya Shimoda, Elliott F Winton, Wei Deng, Ronald L Dubowy, Julia D Maltzman, Francisco Cervantes, Jason Gotlib
Purpose We evaluated the efficacy and safety of momelotinib, a potent and selective Janus kinase 1 and 2 inhibitor (JAKi), compared with ruxolitinib, in JAKi-naïve patients with myelofibrosis. Patients and Methods Patients (N = 432) with high risk or intermediate-2 risk or symptomatic intermediate-1 risk myelofibrosis were randomly assigned to receive 24 weeks of treatment with momelotinib 200 mg once daily or ruxolitinib 20 mg twice a day (or per label), after which all patients could receive open-label momelotinib...
September 20, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28869184/the-treatment-landscape-of-myelofibrosis-before-and-after-ruxolitinib-approval
#17
Andrew T Kuykendall, Chetasi Talati, Najla Al Ali, Kendra Sweet, Eric Padron, David A Sallman, Jeffrey E Lancet, Alan F List, Kenneth S Zuckerman, Rami S Komrokji
INTRODUCTION/BACKGROUND: Myelofibrosis (MF) is a chronic myeloproliferative neoplasm that presents with a heterogeneous clinical phenotype and prognosis. Before the US Food and Drug Administration approval of ruxolitinib, treatment options were varied and had limited effect. The increased use of ruxolitinib has drastically altered the MF treatment landscape. In this study, we aimed to clarify the clinical situations in which ruxolitinib is being used and analyze its effect on this landscape...
August 5, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28860323/traffic-lights-for-ruxolitinib
#18
Alessandro M Vannucchi, Paola Guglielmelli
No abstract text is available yet for this article.
August 31, 2017: Blood
https://www.readbyqxmd.com/read/28854975/ruxolitinib-nilotinib-cotreatment-inhibits-leukemia-propagating-cells-in-philadelphia-chromosome-positive-all
#19
Yuan Kong, Yi-Lin Wu, Yang Song, Min-Min Shi, Xie-Na Cao, Hong-Yan Zhao, Ya-Zhen Qin, Yue-Yun Lai, Hao Jiang, Qian Jiang, Xiao-Jun Huang
BACKGROUND: As one of the major treatment obstacles in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL), relapse of Ph(+)ALL may result from the persistence of leukemia-propagating cells (LPCs). Research using a xenograft mouse assay recently determined that LPCs were enriched in the CD34(+)CD38(-)CD58(-) fraction in human Ph(+)ALL. Additionally, a cohort study demonstrated that Ph(+)ALL patients with a LPCs phenotype at diagnosis exhibited a significantly higher cumulative incidence of relapse than those with the other cell phenotypes even with uniform front-line imatinib-based therapy pre- and post-allotransplant, thus highlighting the need for novel LPCs-based therapeutic strategies...
August 30, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28852199/mutant-jak3-phosphoproteomic-profiling-predicts-synergism-between-jak3-inhibitors-and-mek-bcl2-inhibitors-for-the-treatment-of-t-cell-acute-lymphoblastic-leukemia
#20
S Degryse, C E de Bock, S Demeyer, I Govaerts, S Bornschein, D Verbeke, K Jacobs, S Binos, D A Skerrett-Byrne, H C Murray, N M Verrills, P Van Vlierberghe, J Cools, M D Dun
Mutations in the interleukin-7 receptor (IL7R) or the JAK3 kinase occur frequently in T-cell acute lymphoblastic leukemia (T-ALL) and both are able to drive cellular transformation and the development of T-ALL in mouse models. However, the signal transduction pathways downstream of JAK3 mutations remain poorly characterized. Here, we describe the phosphoproteome downstream of the JAK3(L857Q)/(M511I) activating mutations in transformed Ba/F3 lymphocyte cells. Signaling pathways regulated by JAK3 mutants were assessed following acute inhibition of JAK1/JAK3 using the JAK kinase inhibitors ruxolitinib or tofacitinib...
August 30, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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