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https://www.readbyqxmd.com/read/29162613/the-jak1-2-inhibitor-ruxolitinib-reverses-interleukin-6-mediated-suppression-of-drug-detoxifying-proteins-in-cultured-human-hepatocytes
#1
Marie Febvre-James, Arnaud Bruyere, Marc Le Vee, Olivier Fardel
The inflammatory cytokine interleukin (IL)-6, which basically activates the JAK/STAT signaling pathway, is well-known to repress expression of hepatic cytochromes P-450 (CYPs) and transporters. Therapeutic proteins, like mAbs targeting IL-6 or its receptor, have been consequently demonstrated to restore full hepatic detoxification capacity, which results in inflammatory disease-related drug-drug interactions (idDDIs). In the present study, we investigated whether ruxolitinib, a small drug acting as a JAK1/2 inhibitor and currently used in the treatment of myeloproliferative neoplasms, may also counteract IL-6 repressing effects towards hepatic detoxifying systems...
November 21, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29156136/the-discovery-of-3-4-chloro-3-methoxyphenyl-amino-1-3r-4s-4-cyanotetrahydro-2h-pyran-3-yl-1h-pyrazole-4-carboxamide-a-highly-ligand-efficient-and-efficacious-jak1-selective-inhibitor-with-favorable-pharmacokinetic-properties
#2
Tony Siu, Jason Brubaker, Peter Fuller, Luis Torres, Hongbo Zeng, Joshua Close, Dawn M Mampreian, Feng Shi, Duan Liu, Xavier Fradera, Kevin Johnson, Nathan Bays, Elma Kadic, Fang He, Peter Goldenblatt, Lynsey Shaffer, Sangita B Patel, Charles A Lesburg, Carla Alpert, Lauren Dorosh, Sujal V Deskmukh, Hongshi Yu, Joel Klappenbach, Fiona Elwood, Christopher J Dinsmore, Rafael Fernandez, Lily Moy, Jonathan R Young
The discovery of a potent selective low dose JAK1 inhibitor suitable for clinical evaluation is described. As part of an overall goal to minimize dose, we pursued a medicinal chemistry strategy focused on optimization of key parameters that influence dose size, including lowering human Clint and increasing intrinsic potency, bioavailability, and solubility. To impact these multiple parameters simultaneously, we used lipophilic ligand efficiency as a key metric to track changes in the physicochemical properties of our analogs, which led to improvements in overall compound quality...
November 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29155422/secretion-mediated-stat3-activation-promotes-self-renewal-of-glioma-stem-like-cells-during-hypoxia
#3
D A Almiron Bonnin, M C Havrda, M C Lee, H Liu, Z Zhang, L N Nguyen, L X Harrington, S Hassanpour, C Cheng, M A Israel
High-grade gliomas (HGGs) include the most common and the most aggressive primary brain tumor of adults and children. Despite multimodality treatment, most high-grade gliomas eventually recur and are ultimately incurable. Several studies suggest that the initiation, progression, and recurrence of gliomas are driven, at least partly, by cancer stem-like cells. A defining characteristic of these cancer stem-like cells is their capacity to self-renew. We have identified a hypoxia-induced pathway that utilizes the Hypoxia Inducible Factor 1α (HIF-1α) transcription factor and the JAK1/2-STAT3 (Janus Kinase 1/2 - Signal Transducer and Activator of Transcription 3) axis to enhance the self-renewal of glioma stem-like cells...
November 20, 2017: Oncogene
https://www.readbyqxmd.com/read/29150430/interferon-%C3%A1%C2%B5-2-signaling-in-melanocytes-and-melanoma-cells-regulates-expression-of-ctla-4
#4
Xuan Mo, Hanghang Zhang, Sarah Preston, Kayla Martin, Bo Zhou, Nish Vadalia, Ana M Gamero, Jonathan Soboloff, Italo Tempera, M Raza Zaidi
CTLA-4 is a cell surface receptor on T cells that functions as an immune checkpoint molecule to enforce tolerance to cognate antigens. Anti-CTLA-4 immunotherapy is highly effective at reactivating T cell responses against melanoma, which is postulated to be due to targeting CTLA-4 on T cells. Here we report that CTLA-4 is also highly expressed by most human melanoma cell lines, as well as in normal human melanocytes. Interferon-gamma (IFNG) signaling activated the expression of the human CTLA-4 gene in a melanocyte and melanoma cell-specific manner...
November 17, 2017: Cancer Research
https://www.readbyqxmd.com/read/29140408/philadelphia-chromosome-like-mixed-phenotype-acute-leukemia-demonstrating-p2ry8-crlf2-fusion-and-jak1-mutation
#5
Sarah M Choi, John K Frederiksen, Charles W Ross, Dale L Bixby, Lina Shao
Objectives: Philadelphia chromosome-like (Ph-like) genetic alterations define a subset of B lymphoblastic leukemia/lymphoma (B-ALL), which represents a separate provisional entity in the World Health Organization 2016 updated classification. However, these alterations have not been described outside the context of B-ALL. Methods: Cytogenomic array and molecular analysis identified a Ph-like signature in a mixed-phenotype acute leukemia (MPAL), B/myeloid, confirmed using conventional immunophenotypic and cytochemical analysis...
November 11, 2017: American Journal of Clinical Pathology
https://www.readbyqxmd.com/read/29137428/pten-loss-is-associated-with-prostate-cancer-recurrence-and-alterations-in-tumor-dna-methylation-profiles
#6
Milan S Geybels, Min Fang, Jonathan L Wright, Xiaoyu Qu, Marina Bibikova, Brandy Klotzle, Jian-Bing Fan, Ziding Feng, Elaine A Ostrander, Peter S Nelson, Janet L Stanford
Background: Prostate cancer (PCa) with loss of the tumor suppressor gene PTEN has an unfavorable prognosis. DNA methylation profiles associated with PTEN loss may provide further insights into the mechanisms underlying these more aggressive, clinically relevant tumors. Methods: The cohort included patients with clinically localized PCa. Samples taken from the primary tumor were used to determine PTEN genomic deletions using FISH, and to analyze epigenome-wide DNA methylation profiles...
October 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/29134817/the-bcr-abl1-negative-myeloproliferative-neoplasms-a-review-of-jak-inhibitors-in-the-therapeutic-armamentarium
#7
Martin Griesshammer, Parvis Sadjadian
The classical BCR-ABL1-negative myeloproliferative neoplasms (MPN) include primary myelofibrosis (PMF), polycythaemia vera (PV) and essential thrombocythaemia (ET). They are characterized by stem cell-derived clonal proliferation, harbour Janus kinase 2 (JAK2), or calreticulin (CALR), or myeloproliferative leukaemia virus oncogene (MPL) driver mutations and exert an over activated JAK-signal transducer and activator of transcription (STAT) pathway. Therefore JAK inhibiting strategies have been successfully investigated in MPN clinical trials...
November 14, 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/29134648/pharmacokinetics-pharmacodynamics-and-proposed-dosing-of-the-oral-jak1-and-jak2-inhibitor-baricitinib-in-pediatric-and-young-adult-candle-and-savi-patients
#8
Hanna Kim, Kristina M Brooks, Cheng Cai Tang, Paul Wakim, Mary Blake, Stephen R Brooks, Gina A Montealegre Sanchez, Adriana A de Jesus, Yan Huang, Wanxia Li Tsai, Massimo Gadina, Apurva Prakash, Jonathan Marcus Janes, Xin Zhang, William L Macias, Parag Kumar, Raphaela Goldbach-Mansky
Population pharmacokinetic (popPK) modeling was used to characterize the PK profile of the oral janus kinase (JAK)1/JAK2 inhibitor, baricitinib, in 18 patients with Mendelian interferonopathies who are enrolled in a compassionate use program. Patients received doses between 0.1 to 17 mg per day. Covariates of weight and renal function significantly influenced volume-of-distribution and clearance respectively. The half-life of baricitinib in patients less than 40kg was substantially shorter than in adult populations, requiring the need for dosing up to 4 times daily...
November 14, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29130827/association-of-single-nucleotide-polymorphisms-in-immune-related-genes-with-development-of-dengue-hemorrhagic-fever-in-a-mexican-population
#9
Angélica Berenice Vargas-Castillo, Karina Ruiz-Tovar, Héctor Vivanco-Cid, Sarai Quiroz-Cruz, Alejandro Escobar-Gutiérrez, Jorge Francisco Cerna-Cortes, Gilberto Vaughan, Salvador Fonseca-Coronado
Single-nucleotide polymorphisms (SNPs) occurring in immune-related genes have been associated with risk or protection for development of dengue, depending on ethnicity. Here, we genotyped seven SNPs located in immune response-related genes to identify their association with severe forms of dengue in patients from an endemic region in Mexico. One hundred and thirty-eight patients with dengue fever (DF), thirty-one dengue hemorrhagic fever (DHF) patients, as well as 304 healthy donors were genotyped by using a TaqMan-based approach...
November 13, 2017: Viral Immunology
https://www.readbyqxmd.com/read/29128627/inhibition-of-jak1-by-microrna-708-promotes-sh-sy5y-neuronal-cell-survival-after-oxygen-and-glucose-deprivation-and-reoxygenation
#10
Chao Huang, Haitao Zhou, Xiangyang Ren, Junfang Teng
MicroRNAs mediates gene expression in various diseases. Studies have shown that aberrant expression of miRNAs affected cerebral protection. In this study, we have investigated the effects of microRNA-708 (miR-708) on cell survival of oxygen and glucose-deprived reoxygenation (OGD/R) human neuroblastoma cells (SH-SY5Y) and explored whether miR-708 inhibited neuronal death by targeting JAK1. In vitro model of ischemia was used to investigate the neuroprotective functions of miR-708. MiR-708 mimics/siJAK1 transfected SH-SY5Y cells were treated with OGD...
November 9, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/29127481/expression-of-janus-kinase-1-in-vitiligo-psoriasis-before-and-after-narrow-band-uvb-a-case-control-study
#11
Hanan Rabea Nada, Dina Ahmed El Sharkawy, Maha Fathy Elmasry, Laila Ahmed Rashed, Sally Mamdouh
Janus kinases (JAKs) are non-receptor protein tyrosine kinases that are expressed in many tissues. Once the JAKs are activated, a cascade of further signaling events is triggered involving phosphorylation of selected receptor chain tyrosines, binding of signal transducer and activator of transcription (STAT) proteins and phosphorylation of these STATs. Due to their ability to selectively modulate immune function, targeted JAK inhibitors are promising candidates for some skin diseases such as psoriasis and atopic dermatitis...
November 10, 2017: Archives of Dermatological Research
https://www.readbyqxmd.com/read/29121062/loss-of-function-jak1-mutations-occur-at-high-frequency-in-cancers-with-microsatellite-instability-and-are-suggestive-of-immune-evasion
#12
Lee A Albacker, Jeremy Wu, Peter Smith, Markus Warmuth, Philip J Stephens, Ping Zhu, Lihua Yu, Juliann Chmielecki
Immune evasion is a well-recognized hallmark of cancer and recent studies with immunotherapy agents have suggested that tumors with increased numbers of neoantigens elicit greater immune responses. We hypothesized that the immune system presents a common selective pressure on high mutation burden tumors and therefore immune evasion mutations would be enriched in high mutation burden tumors. The JAK family of kinases is required for the signaling of a host of immune modulators in tumor, stromal, and immune cells...
2017: PloS One
https://www.readbyqxmd.com/read/29117539/hsa_circ_0009910-promotes-carcinogenesis-by-promoting-the-expression-of-mir-449a-target-il6r-in-osteosarcoma
#13
Nian Deng, Longyang Li, Jinghao Gao, Jun Zhou, Yan Wang, Chao Wang, Yong Liu
Circular RNAs (circRNAs) have recently shown capabilities as gene regulators in mammals. Some of them interact with microRNAs (miRNAs) and function as sponges to affect related miRNAs' activities. In this study, the molecular function of circRNA_0009910 and its potential downstream miRNA targets were explored. The expression levels of hsa_circ_0009910 were found to be overexpressed in osteosarcoma (OS) cells. Knockdown of circ_0009910 induced cell proliferation inhibition, cell cycle arrest, and apoptosis in OS cells...
November 5, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29111217/ruxolitinib-partially-reverses-functional-nk-cell-deficiency-in-patients-with-stat1-gain-of-function-mutations
#14
Alexander Vargas-Hernandez, Emily M Mace, Ofer Zimmerman, Christa S Zerbe, Alexandra F Freeman, Sergio Rosenzweig, Jennifer W Leiding, Troy Torgerson, Matthew C Altman, Edith Schussler, Charlotte Cunningham-Rundles, Ivan K Chinn, Alexandre F Carisey, Imelda C Hanson, Nicholas L Rider, Steven M Holland, Jordan S Orange, Lisa R Forbes
BACKGROUND: Natural Killer (NK) cells are critical innate effector cells whose development is dependent on the JAK-STAT pathway. NK deficiency can result in severe or refractory viral infections. Patients with Signal Transducer and Activator of Transcription (STAT)1 gain of function (GOF) mutations have increased viral susceptibility. OBJECTIVE: We sought to investigate NK cell function in STAT1 GOF patients. METHODS: NK cell phenotype and function were determined in 16 STAT1 GOF patients...
October 27, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29100426/phytosphingosine-exhibits-an-anti-epithelial-mesenchymal-transition-function-by-the-inhibition-of-egfr-signaling-in-human-breast-cancer-cells
#15
Hye-Min Kang, Han-Sun Son, Yan-Hong Cui, BuHyun Youn, Beomseok Son, Nagendra Kumar Kaushik, Nizam Uddin, Jae-Seong Lee, Jie-Young Song, Neha Kaushik, Su-Jae Lee
The lack of effective anti-metastatic drugs for the eradication of breast cancer stem cells within tumors, which are often resistant to chemotherapy and radiotherapy, creates a major obstacle during metastatic breast cancer therapy. Although D-ribo-phytosphingosine (PHS) is well known to activate protein kinase (MAPK)-mediated apoptosis, its possible role towards the metastasis signaling mechanisms underlying the epithelial-mesenchymal transition (EMT) remains largely unknown. In this report, we investigate the anti-metastatic potential of the natural sphingolipid PHS for the targeting of breast cancer cells as well as breast stem-like cells in vitro...
September 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29098608/novel-therapies-for-myelofibrosis
#16
REVIEW
Kristen Pettit, Olatoyosi Odenike
PURPOSE OF REVIEW: The purpose of the review was to provide a contemporary update of novel agents and targets under investigation in myelofibrosis in the Janus kinase (JAK) inhibitor era. RECENT FINDINGS: Myelofibrosis (MF) is a clonal stem cell disease characterized by marrow fibrosis and a heterogeneous disease phenotype with a variable degree of splenomegaly, cytopenias, and constitutional symptoms that significantly impact quality of life and survival. Overactive JAK/STAT signaling is a hallmark of MF...
November 2, 2017: Current Hematologic Malignancy Reports
https://www.readbyqxmd.com/read/29074595/ruxolitinib-vs-best-available-therapy-for-et-intolerant-or-resistant-to-hydroxycarbamide
#17
RANDOMIZED CONTROLLED TRIAL
Claire N Harrison, Adam J Mead, Anesh Panchal, Sonia Fox, Christina Yap, Emmanouela Gbandi, Aimee Houlton, Samah Alimam, Joanne Ewing, Marion Wood, Frederick Chen, Jason Coppell, Nicki Panoskaltsis, Steven Knapper, Sahra Ali, Angela Hamblin, Robyn Scherber, Amylou C Dueck, Nicholas C P Cross, Ruben Mesa, Mary Frances McMullin
Treatments for high-risk essential thrombocythemia (ET) address thrombocytosis, disease-related symptoms, as well as risks of thrombosis, hemorrhage, transformation to myelofibrosis, and leukemia. Patients resistant/intolerant to hydroxycarbamide (HC) have a poor outlook. MAJIC (ISRCTN61925716) is a randomized phase 2 trial of ruxolitinib (JAK1/2 inhibitor) vs best available therapy (BAT) in ET and polycythemia vera patients resistant or intolerant to HC. Here, findings of MAJIC-ET are reported, where the modified intention-to-treat population included 58 and 52 patients randomized to receive ruxolitinib or BAT, respectively...
October 26, 2017: Blood
https://www.readbyqxmd.com/read/29062282/model-based-targeting-of-il-6-induced-inflammatory-responses-in-cultured-primary-hepatocytes-to-improve-application-of-the-jak-inhibitor-ruxolitinib
#18
Svantje Sobotta, Andreas Raue, Xiaoyun Huang, Joep Vanlier, Anja Jünger, Sebastian Bohl, Ute Albrecht, Maximilian J Hahnel, Stephanie Wolf, Nikola S Mueller, Lorenza A D'Alessandro, Stephanie Mueller-Bohl, Martin E Boehm, Philippe Lucarelli, Sandra Bonefas, Georg Damm, Daniel Seehofer, Wolf D Lehmann, Stefan Rose-John, Frank van der Hoeven, Norbert Gretz, Fabian J Theis, Christian Ehlting, Johannes G Bode, Jens Timmer, Marcel Schilling, Ursula Klingmüller
IL-6 is a central mediator of the immediate induction of hepatic acute phase proteins (APP) in the liver during infection and after injury, but increased IL-6 activity has been associated with multiple pathological conditions. In hepatocytes, IL-6 activates JAK1-STAT3 signaling that induces the negative feedback regulator SOCS3 and expression of APPs. While different inhibitors of IL-6-induced JAK1-STAT3-signaling have been developed, understanding their precise impact on signaling dynamics requires a systems biology approach...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/29056075/an-updated-review-of-the-jak1-2-inhibitor-ruxolitininb-in-the-philadelphia-negative-myeloproliferative-neoplasms
#19
Natalia Curto-Garcia, Claire N Harrison
Ruxolitinib (Rux), a JAK1/2 inhibitor, has been approved for patients with myelofibrosis and in polycythemia vera with inadequate response/intolerance to hydroxycarbamide. Studies have demonstrated that Rux improves disease-related symptoms and splenomegaly. A late emerging observation from two Phase III trials was that Rux was associated with survival advantage in comparison with placebo or other available therapies in myelofibrosis. Important data suggest that for polycythemia vera Rux improved control of blood counts...
October 23, 2017: Future Oncology
https://www.readbyqxmd.com/read/29054137/il-35-gene-modified-mesenchymal-stem-cells-protect-the-con-a-induced-fulminant-hepatitis-through-decreasing-the-ifn-g-level
#20
Wei Wang, Hao Guo, Hongyue Li, Yongjia Yan, Chao Wu, Xiaodong Wang, Xianghui He, Na Zhao
Interleukin 35 (IL-35) is a relatively newly identified cytokine required for the regulatory and suppressive functions of regulatory T cells(Treg), playing an important role in the prevention of autoimmune diseases. In this study, we used the MSCs as the gene-delivery vehicles for IL-35 gene therapy and investigated their protective effects in Con A-induced autoimmune hepatitis. Results showed that IL-35 gene modified MSCs(IL-35-MSCs) can specifically migrate to the injured liver tissues and significantly narrow the necrosis areas and reduce the hepatocytes apoptosis...
October 20, 2017: Human Gene Therapy
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