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https://www.readbyqxmd.com/read/29156772/stat3-and-stat5a-are-potential-therapeutic-targets-in-castration-resistant-prostate-cancer
#1
Sambit K Mohanty, Kader Yagiz, Dinesh Pradhan, Daniel J Luthringer, Mahul B Amin, Serhan Alkan, Bekir Cinar
Mechanisms of castration-resistant prostate cancer (CRPC) are not well understood, thus hindering rational-based drug design. Activation of STAT3/5A, key components of the JAK/STAT pathway, is implicated in aggressive PC, yet their clinical relevance in CRPC remains elusive. Here, we evaluated the possible role of STAT3/5A in CRPC using immunological, quantitative mRNA expression profiling, and pharmacological methods. We observed a strong nuclear immunoreactivity for STAT3 and STAT5A in 93% (n=14/15) and 80% (n=12/15) of CRPC cases, respectively, compared with benign prostatic hyperplasia (BPH)...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29154500/structure-activity-studies-of-peptidomimetics-based-on-kinase-inhibitory-region-of-suppressors-of-cytokine-signaling-1
#2
Sara La Manna, Laura Lopez-Sanz, Marilisa Leone, Paola Brandi, Pasqualina Liana Scognamiglio, Giancarlo Morelli, Ettore Novellino, Carmen Gomez-Guerrero, Daniela Marasco
Suppressors of Cytokine Signaling (SOCS) proteins are negative regulators of JAK proteins that are receptor-associated tyrosine kinases, which play key roles in the phosphorylation and subsequent activation of several transcription factors named STATs. Unlike the other SOCS proteins, SOCS1 and 3 show, in the N-terminal portion, a small kinase inhibitory region (KIR) involved in the inhibition of JAK kinases. Drug discovery processes of compounds based on KIR sequence demonstrated promising in functional in vitro and in inflammatory animal models and we recently developed a peptidomimetic called PS5, as lead compound...
November 20, 2017: Biopolymers
https://www.readbyqxmd.com/read/29150291/ruxolitinib-conjugated-gold-nanoparticles-for-topical-administration-an-alternative-for-treating-alopecia
#3
Sanda Boca, Cristian Berce, Ancuta Jurj, Bobe Petrushev, Laura Pop, Grigore-Aristide Gafencu, Sonia Selicean, Vlad Moisoiu, Daiana Temian, Wilhelm-Thomas Micu, Simion Astilean, Cornelia Braicu, Ciprian Tomuleasa, Ioana Berindan-Neagoe
Alopecia is a dermatological condition for which Janus kinase (JAK) inhibitors have recently emerged as potential therapy options, but with limited practical use because of the systemic side effects. The topical use of Ruxolitinib in alopecia universalis has been demonstrated, but little is known about the pharmacodynamics and pharmacokinetics of this way of administration. Nanomedicine provides improved therapeutics. In the current paper we present preliminary data regarding the potential use of Ruxolitinib-conjugated gold nanoparticles (GNPs) in dermatological conditions, as GNPs have been proven to have a reduced absorption rate into the systemic blood flow for cutaneous administration...
November 2017: Medical Hypotheses
https://www.readbyqxmd.com/read/29149532/exploitation-of-micrornas-by-japanese-encephalitis-virus-in-human-microglial-cells
#4
Meghana Rastogi, Neha Srivastava, Sunit K Singh
JEV infection in CNS leads to the JE neuroinflammation. Children and old age individual have been reported to be more prone to JEV infection. MicroRNAs are endogenous, small non-coding RNAs, which regulate the gene expression. These are ∼22 nucleotide long, conserved RNA sequence that binds at the 3'UTR of a target mRNA and regulate the post-transcriptional gene expression. The role of microRNAs has been reported in several diseases like cancer, viral infection, neuro-degeneration, diabetes etc. In the present study, the human microglial cells were infected with JEV (JaOAr strain)...
November 17, 2017: Journal of Medical Virology
https://www.readbyqxmd.com/read/29148847/emerging-therapeutic-targets-in-myeloproliferative-neoplasms-and-peripheral-t-cell-leukemia-and-lymphomas
#5
Anna Orlova, Bettina Wingelhofer, Heidi A Neubauer, Barbara Maurer, Angelika Berger-Becvar, György Miklós Keserű, Patrick T Gunning, Peter Valent, Richard Moriggl
Hematopoietic neoplasms are often driven by gain-of-function mutations of the JAK-STAT pathway together with mutations of chromatin remodeling and DNA damage control pathways. The interconnection between the JAK-STAT pathway, epigenetic regulation or DNA damage control is still poorly understood in cancer cell biology. Areas covered: Here, we focus on a broader description of mutational insights into myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas, since sequencing efforts have identified similar combinations of driver mutations in these diseases covering different lineages...
November 17, 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/29148541/integrated-genomic-analysis-identifies-deregulated-jak-stat-myc-biosynthesis-axis-in-aggressive-nk-cell-leukemia
#6
Liang Huang, Dan Liu, Na Wang, Shaoping Ling, Yuting Tang, Jun Wu, Lingtong Hao, Hui Luo, Xuelian Hu, Lingshuang Sheng, Lijun Zhu, Di Wang, Yi Luo, Zhen Shang, Min Xiao, Xia Mao, Kuangguo Zhou, Lihua Cao, Lili Dong, Xinchang Zheng, Pinpin Sui, Jianlin He, Shanlan Mo, Jin Yan, Qilin Ao, Lugui Qiu, Hongsheng Zhou, Qifa Liu, Hongyu Zhang, Jianyong Li, Jie Jin, Li Fu, Weili Zhao, Jieping Chen, Xin Du, Guoliang Qing, Hudan Liu, Xin Liu, Gang Huang, Ding Ma, Jianfeng Zhou, Qian-Fei Wang
Aggressive NK-cell leukemia (ANKL) is a rare form of NK cell neoplasm that is more prevalent among people from Asia and Central and South America. Patients usually die within days to months, even after receiving prompt therapeutic management. Here we performed the first comprehensive study of ANKL by integrating whole genome, transcriptome and targeted sequencing, cytokine array as well as functional assays. Mutations in the JAK-STAT pathway were identified in 48% (14/29) of ANKL patients, while the extracellular STAT3 stimulator IL10 was elevated by an average of 56-fold (P < 0...
November 17, 2017: Cell Research
https://www.readbyqxmd.com/read/29146985/drosophila-muscles-regulate-the-immune-response-against-wasp-infection-via-carbohydrate-metabolism
#7
Hairu Yang, Dan Hultmark
We recently found that JAK/STAT signaling in skeletal muscles is important for the immune response of Drosophila larvae against wasp infection, but it was not clear how muscles could affect the immune response. Here we show that insulin signaling is required in muscles, but not in fat body or hemocytes, during larval development for an efficient encapsulation response and for the formation of lamellocytes. This effect requires TOR signaling. We show that muscle tissue affects the immune response by acting as a master regulator of carbohydrate metabolism in the infected animal, via JAK/STAT and insulin signaling in the muscles, and that there is indirect positive feedback between JAK/STAT and insulin signaling in the muscles...
November 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29145319/primary-myelofibrosis-and-pregnancy-outcomes-after-low-molecular-weight-heparin-administration-a-case-report-and-literature-review
#8
Roxana Elena Bohîlţea, Monica Mihaela Cîrstoiu, Crîngu Antoniu Ionescu, Emilia Niculescu-Mizil, Ana Maria Vlădăreanu, Irina Voican, Mihai Dimitriu, Natalia Turcan
RATIONALE: Primary myelofibrosis is encountered with the myeloproliferative diseases and is the least prevalent among women of childbearing age. The prognosis is guided by pancytopenia, leukemic transformation and thrombosis which are the dominant complications. PATIENT CONCERNS: Data regarding protocol management during pregnancy in the context of myelofibrosis are insufficient. Fewer than ten cases have been described until now and half of this cases have resulted in fetal death due to placental infarction during the second and third trimesters...
November 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/29142473/genetic-associations-with-adverse-events-from-anti-tumor-necrosis-factor-therapy-in-inflammatory-bowel-disease-patients
#9
Daniel Lew, Soon Man Yoon, Xiaofei Yan, Lori Robbins, Talin Haritunians, Zhenqiu Liu, Dalin Li, Dermot Pb McGovern
AIM: To study the type and frequency of adverse events associated with anti-tumor necrosis factor (TNF) therapy and evaluate for any serologic and genetic associations. METHODS: This study was a retrospective review of patients attending the inflammatory bowel disease (IBD) centers at Cedars-Sinai IBD Center from 2005-2016. Adverse events were identified via chart review. IBD serologies were measured by ELISA. DNA samples were genotyped at Cedars-Sinai using Illumina Infinium Immunochipv1 array per manufacturer's protocol...
October 28, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/29142070/gfap-and-osmr-regulation-by-brg1-and-stat3-via-interchromosomal-gene-clustering-in-astrocytes
#10
Kenji Ito, Azumi Noguchi, Yuichi Uosaki, Testuya Taga, Hirokazu Arakawa, Takumi Takizawa
Long-range chromatin interactions between gene loci in the cell nucleus are important for many biological processes including transcriptional regulation. Previously, we demonstrated that several genes specifically cluster with the astrocyte-specific gene glial fibrillary acidic protein (Gfap) during astrocyte differentiation; however, the molecular mechanisms for gene clustering remain largely unknown. Here we show that brahma-related gene 1 (BRG1), an ATP-dependent chromatin remodeling factor, and the transcription factor STAT3 are required for Gfap and Osmr clustering and enhanced expression through recruitment to STAT3 recognition sequences and that gene clustering occurs prior to transcriptional upregulation...
November 15, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/29141533/targeting-cancer-stem-cells-and-non-stem-cancer-cells-the-potential-of-lipid-based-nanoparticles
#11
Ana Filipa Cruz, Nuno Andre Fonseca, Vera Moura, Sergio Simoes, Joao Nuno Moreira
Background Cancer stem cells (CSCs) have been described as a relevant contributor to tumorigenicity, metastasis, tumor recurrence and drug resistance, making this cell population a relevant target in solid tumors. METHODS: This has stimulated the development of different therapeutic strategies often targeting surface markers (CD44, epithelial cell adhesion molecule (EpCAM), aldehyde dehydrogenase (ALDH) and nucleolin) and/or signaling pathways that are aberrantly activated and contribute to CSCs proliferation and survival...
November 14, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/29140564/%C3%AE-catenin-and-il-1%C3%AE-dependent-cxcl10-production-drives-progression-of-disease-in-a-mouse-model-of-congenital-hepatic-fibrosis
#12
Eleanna Kaffe, Romina Fiorotto, Francesca Pellegrino, Valeria Mariotti, Mariangela Amenduni, Massimiliano Cadamuro, Luca Fabris, Mario Strazzabosco, Carlo Spirli
Congenital Hepatic Fibrosis (CHF), a genetic disease caused by mutations in the PKHD1 gene, encoding for the protein fibrocystin (FPC), is characterized by biliary dysgenesis, progressive portal fibrosis, and by a PKA-mediated activating phosphorylation of β-Catenin at Ser675. Biliary structures of Pkhd1(del4/del4) mice, a mouse model of CHF, secrete CXCL10 a chemokine able to recruit macrophages. The aim of this study is to clarify whether CXCL10 plays a pathogenetic role in disease progression in CHF/CD and to understand the mechanisms leading to increased CXCL10 secretion...
November 15, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29140428/hpv-negative-but-not-hpv-positive-oropharyngeal-carcinomas-induce-fibroblasts-to-support-tumour-invasion-through-micro-environmental-release-of-hgf-and-il-6
#13
Robert Bolt, Bernadette Foran, Craig Murdoch, Daniel W Lambert, Sally Thomas, Keith D Hunter
Human papillomavirus (HPV) infection is causally related to a subset of oropharyngeal carcinomas (OPC) and is linked to a more favourable prognosis compared to HPV-negative OPC. The mechanisms underlying this effect on prognosis are not fully understood, but interactions with the tumour microenvironment may be pivotal. Here, we investigated the role of the tumour microenvironment in HPV-positive compared to HPV-negative cancer using 2D and 3D modelling of OPC interactions with stromal fibroblasts. HPV-negative, but not HPV-positive, OPC-derived cell lines induced a rapid fibroblast secretory response that supported 2D cancer cell migration and invasion in vitro...
November 13, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/29139090/tofacitinib-a-review-in-rheumatoid-arthritis
#14
Sohita Dhillon
Tofacitinib (Xeljanz(®)) is a potent, selective JAK inhibitor that preferentially inhibits Janus kinase (JAK) 1 and JAK3. In the EU, oral tofacitinib 5 mg twice daily is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who have responded inadequately to, or who are intolerant of, one or more DMARDs. Several clinical studies of ≤ 24 months' duration showed that tofacitinib monotherapy (as first- or second-line treatment) and combination therapy with a conventional synthetic DMARD (csDMARD; as second- or third-line treatment) was effective in reducing signs and symptoms of disease and improving health-related quality of life (HR-QOL), with benefits sustained during long-term therapy (≤ 96 months)...
November 14, 2017: Drugs
https://www.readbyqxmd.com/read/29138331/correction-for-wang-et-al-mitogen-activated-protein-kinase-kinase-2-a-novel-e2-interacting-protein-promotes-the-growth-of-classical-swine-fever-virus-via-attenuation-of-the-jak-stat-signaling-pathway
#15
Jinghan Wang, Shucheng Chen, Yajin Liao, Enyu Zhang, Shuo Feng, Shaoxiong Yu, Lian-Feng Li, Wen-Rui He, Yongfeng Li, Yuzi Luo, Yuan Sun, Mo Zhou, Xiao Wang, Muhammad Munir, Su Li, Hua-Ji Qiu
No abstract text is available yet for this article.
December 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/29135282/genome-wide-dna-methylation-drives-human-embryonic-stem-cell-erythropoiesis-by-remodeling-gene-expression-dynamics
#16
Zhijing Liu, Qiang Feng, Pengpeng Sun, Yan Lu, Minlan Yang, Xiaowei Zhang, Xiangshu Jin, Yulin Li, Shi-Jiang Lu, Chengshi Quan
AIM: To investigate the role of DNA methylation during erythrocyte production by human embryonic stem cells (hESCs). METHODS: We employed an erythroid differentiation model from hESCs, and then tracked the genome-wide DNA methylation maps and gene expression patterns through an Infinium HumanMethylation450K BeadChip and an Ilumina Human HT-12 v4 Expression Beadchip, respectively. RESULTS: A negative correlation between DNA methylation and gene expression was substantially enriched during the later differentiation stage and was present in both the promoter and the gene body...
November 14, 2017: Epigenomics
https://www.readbyqxmd.com/read/29134817/the-bcr-abl1-negative-myeloproliferative-neoplasms-a-review-of-jak-inhibitors-in-the-therapeutic-armamentarium
#17
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
#18
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/29133913/nitric-oxide-mediated-inhibition-of-antigen-presentation-from-dcs-to-cd4-t-cells-in-cancer-and-measurement-of-stat1-nitration
#19
Joseph Markowitz, Jiang Wang, Zach Vangundy, Jia You, Vedat Yildiz, Lianbo Yu, Isaac P Foote, Owen E Branson, Andrew R Stiff, Taylor R Brooks, Brandon Biesiadecki, Thomas Olencki, Susheela Tridandapani, Michael A Freitas, Tracey Papenfuss, Mitch A Phelps, William E Carson
Myeloid derived suppressor cells (MDSC) produce nitric oxide (NO) and inhibit dendritic cell (DC) immune responses in cancer. DCs present cancer cell antigens to CD4(+) T cells through Jak-STAT signal transduction. In this study, NO donors (SNAP and DETA-NONOate) inhibited DC antigen presentation. As expected, MDSC isolated from peripheral blood mononuclear cells (PBMC) from cancer patients produced high NO levels. We hypothesized that NO producing MDSC in tumor-bearing hosts would inhibit DC antigen presentation...
November 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29132481/inhibitory-effect-of-ag490-on-stat3-signal-transduction-pathway-in-nasopharyngeal-carcinoma-cells
#20
Kai Li, Han Bao, Panying Zhang, Li Chen
OBJECTIVE: To determine the effect of JAK kinase inhibitor AG490 on proliferation and apoptosis of nasopharyngeal carcinoma cell line C666-1 and explore the inhibitory effect of AG490 on STAT3 signal transduction pathway. STUDY DESIGN: An experimental study. PLACE AND DURATION OF STUDY: Xi'an Ninth Hospital, Xi'an, China, from May 2015 to December 2016. METHODOLOGY: AG490 was applied to C666-1 cells. Cell proliferation was detected by MTTassay...
November 2017: Journal of the College of Physicians and Surgeons—Pakistan: JCPSP
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