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https://www.readbyqxmd.com/read/28229364/molecular-subtyping-in-diffuse-large-b-cell-lymphoma-closer-to-an-approach-of-precision-therapy
#1
REVIEW
Reem Karmali, Leo I Gordon
It has become clear that there is immense biological heterogeneity in diffuse large B cell lymphoma (DLBCL). Developing technology has allowed better characterization of patient subsets at a molecular level, allowing for a link of phenotype and clinical outcomes to oncogenic mechanisms and biologic signatures. Cell of origin and double hit status are able to identify aggressive subsets, with molecular profiling allowing for a clearer understanding of biologic pathways that contribute to cellular resistance to conventional treatment in these subsets...
February 2017: Current Treatment Options in Oncology
https://www.readbyqxmd.com/read/28214951/inhibition-of-jak-stat-pathway-restrains-tslp-activated-dendritic-cells-mediated-inflammatory-t-helper-type-2-cell-response-in-allergic-rhinitis
#2
Zhaohui Shi, Weihong Jiang, Min Wang, Xiaocheng Wang, Xiaoyuan Li, Xiaodong Chen, Li Qiao
Thymic stromal lymphopoietin (TSLP) has recently been implicated as a key molecule for initiating allergic rhinitis (AR) at the cell-dendritic cell (DC) interface. Previous studies demonstrated that TSLP activated DCs to express more OX40 ligand (OX40L), which is associated with the initiation of T helper type 2 (Th2) cell responses. STAT phosphorylation has been reported to be promoted by TSLP. Thus, we investigated if the JAK/STAT pathway inhibitor CYT387 could affect TSLP-DC-mediated Th2 cell response in naive T cell and AR mice model...
February 18, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28214886/adenovirus-vector-harboring-the-hbcag-and-tripeptidyl-peptidase-ii-genes-induces-potent-cellular-immune-responses-in-vivo
#3
Quanhui Tan, Siyuan Ma, Jianjun Hu, Xiaohua Chen, Yongsheng Yu, Zhenghao Tang, Guoqin Zang
BACKGROUND: Chronic hepatitis B virus (HBV) infection is associated with a weak but specific cellular immune response of the host to HBV. Tripeptidyl peptidaseⅡ (TPPⅡ), an intracellular macromolecule and proteolytic enzyme, plays an important complementary and compensatory role for the proteasome during viral protein degradation and major histocompatibility complex class I antigen presentation by inducing a specific cellular immune response in vivo. Based on a previous study, we aimed to explore the role of MHC class I antigen presentation in vivo and the mechanisms that may be involved...
January 27, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28214593/jak-stat-pathway-directed-therapy-of-t-cell-leukemia-lymphoma-inspired-by-functional-and-structural-genomics
#4
REVIEW
Thomas A Waldmann
Abnormal activation of the γc cytokine JAK/STAT signaling pathway assessed by STAT3 or STAT5b phosphorylation was present in a proportion of many T-cell malignancies. Activating mutations of STAT3/STAT5b and JAK1/3 were present in some but not in all cases with constitutive signaling pathway activation. Using shRNA analysis pSTAT malignant T-cell lines were addicted to JAKs/STATs whether they were mutated or not. Activating JAK/STAT mutations were not sufficient to support leukemic cell proliferation but only augmented upstream pathway signals...
February 15, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28202754/jak-stat-signaling-pathways-and-inhibitors-affect-reversion-of-envelope-mutated-hiv-1
#5
Yudong Quan, Hongtao Xu, Yingshan Han, Thibault Mesplède, Mark A Wainberg
HIV can spread by both cell-free and cell-to-cell transmission. Here, we show that numerous of the amino acid changes in Env that are close to the CD4 binding pocket can affect HIV replication. We generated a number of mutant viruses that were unable to infect T cells as cell-free viruses but were nevertheless able to infect certain T cell lines as cell-associated viruses, followed by reversion to wild type. However, the activation of JAK-STAT signaling pathways caused inhibition of such cell-to-cell infection as well as the reversion of multiple HIV Env mutants that displayed differences in ability to bind to the CD4 receptor...
February 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28193636/evaluation-of-jak3-biology-in-autoimmune-disease-using-a-highly-selective-irreversible-jak3-inhibitor
#6
Fiona Elwood, David Witter, Jennifer Piesvaux, Brian Kraybill, Nathan Bays, Carla Alpert, Peter Goldenblatt, Yujie Qu, Irena Ivanovska, Hyun-Hee Lee, Chi-Sung Chiu, Hao Tang, Mark E Scott, Sujal Deshmukh, Mark Zielstorff, Alan Byford, Kalyan Chakravarty, Lauren Dorosh, Alexy Rivkin, Joel Klappenbach, Bo-Sheng Pan, Ilona Kariv, Christopher Dinsmore, Deborah Slipetz, Peter Dandliker
Reversible Janus kinase (JAK) inhibitors such as Tofacitinib(Changelian, et al., 2003;Flanagan, et al., 2010) and Decernotinib(Farmer, et al., 2015;Mahajan, et al., 2015) block cytokine signaling and are efficacious in treating autoimmune diseases (Kremer, et al., 2009;Fleischmann, et al., 2015;Fleischmann, et al., 2015;Krueger, et al., 2016;Sandborn, et al., 2012). However therapeutic doses are limited due to inhibition of other JAK/STAT pathways associated with hematopoiesis, lipid biogenesis, infection and immune responses(Kahn C, 2012)...
February 13, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28186964/il-6-secreted-by-cancer-associated-fibroblasts-promotes-epithelial-mesenchymal-transition-and-metastasis-of-gastric-cancer-via-jak2-stat3-signaling-pathway
#7
Xiongyan Wu, Pan Tao, Quan Zhou, Jie Li, Zhenjia Yu, Xiaofeng Wang, Jiaanfang Li, Chen Li, Min Yan, Zhenggang Zhu, Bingya Liu, Liping Su
Cancer-associated fibroblasts (CAFs), as the activated fibroblasts in tumor stroma, are important modifiers of tumor progression. However, the molecular mechanisms underlying the tumor-promoting properties of CAFs in gastric cancer remain unclear. Here, we show that CAFs isolated from gastric cancer produce significant amounts of interleukin-6 (IL-6). CAFs enhances the migration and EMT of gastric cancer cells through the secretion of IL-6 that activates Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT3) pathway in gastric cancer cells, while deprivation of IL-6 using a neutralizing antibody or inhibition of JAK/STAT3 pathway with specific inhibitor AG490 markedly attenuates these phenotypes in gastric cancer cells induced by CAFs...
February 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28179884/cellular-signaling-pathways-in-insulin-resistance-systems-biology-analyses-of-microarray-dataset-reveals-new-drug-target-gene-signatures-of-type-2-diabetes-mellitus
#8
Syed Aun Muhammad, Waseem Raza, Thanh Nguyen, Baogang Bai, Xiaogang Wu, Jake Chen
Purpose: Type 2 diabetes mellitus (T2DM) is a chronic and metabolic disorder affecting large set of population of the world. To widen the scope of understanding of genetic causes of this disease, we performed interactive and toxicogenomic based systems biology study to find potential T2DM related genes after cDNA differential analysis. Methods: From the list of 50-differential expressed genes (p < 0.05), we found 9-T2DM related genes using extensive data mapping. In our constructed gene-network, T2DM-related differentially expressed seeder genes (9-genes) are found to interact with functionally related gene signatures (31-genes)...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28179120/novel-therapeutic-approaches-for-disease-modification-of-epileptogenesis-for-curing-epilepsy
#9
REVIEW
Bryan L Clossen, Doodipala Samba Reddy
This article describes the recent advances in epileptogenesis and novel therapeutic approaches for the prevention of epilepsy, with a special emphasis on the pharmacological basis of disease-modification of epileptogenesis for curing epilepsy. Here we assess animal studies and human clinical trials of epilepsy spanning 1982-2016. Epilepsy arises from a number of neuronal factors that trigger epileptogenesis, which is the process by which a brain shifts from a normal physiologic state to an epileptic condition...
February 4, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28177684/aegle-marmelos-l-corr-impedes-onset-of-insulin-resistance-syndrome-in-rats-provided-with-drinking-fructose-from-weaning-to-adulthood-stages-of-development-a-mechanistic-study
#10
Rajani Mathur, Ratika Sehgal, Preeti Rajora, Shveta Sharma, Rajesh Kumar, Sandeep Mathur
To explore the effect of aqueous extract of leaves of Aegle marmelos (AM) on hepatic carbohydrate metabolism and insulin downstream signalling in rats provided with drinking fructose (15%) from weaning to adulthood. Wistar albino rats (4week) were randomly divided into Normal Control (NC), Fructose Control (FC) and treatment (AMT) groups and provided over 8 weeks, chow + water, chow + fructose (15%) and chow + fructose (15%) + AM (500 mg/kg/d, p.o.), respectively. Significantly (p<0.05) raised levels of Fasting Blood Glucose, lipid, visceral weight, plasma insulin and leptin, glycogen, gluconeogenesis enzyme levels but decreased glycolytic enzyme activity was recorded in FC as compared to NC...
December 17, 2016: Canadian Journal of Physiology and Pharmacology
https://www.readbyqxmd.com/read/28167612/jak-mutations-as-escape-mechanisms-to-anti-pd-1-therapy
#11
Aurelien Marabelle, Sandrine Aspeslagh, Sophie Postel-Vinay, Jean-Charles Soria
JAK mutations could be one of the primary escape mechanisms to anti-PD-1/PD-L1 immunotherapy via impaired IFNγ signaling in cancer cells and could be used to identify patients unlikely to benefit from these treatments. Cancer Discov; 7(2); 128-30. ©2017 AACR.See related article by Shin et al., p. 188.
February 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28167449/curcumin-and-treatment-of-melanoma-the-potential-role-of-micrornas
#12
REVIEW
Diana Lelli, Claudio Pedone, Amirhosssein Sahebkar
Melanoma is the most aggressive type of skin cancer and is characterized by poor prognosis in its advanced stages because treatments are poorly effective and burdened with severe adverse effects. MicroRNAs (miRNAs) are small non-coding RNAs that are implicated in several cellular processes; they are categorized as oncogenic and tumor suppressor miRNAs. Several miRNAs are implicated in the pathogenesis and progression of melanoma, such as the tumor suppressor miR-let7b that targets cyclin D and regulates cell cycle...
February 3, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28157215/identification-of-a-genetically-defined-ultra-high-risk-group-in-relapsed-pediatric-t-lymphoblastic-leukemia
#13
P Richter-Pechańska, J B Kunz, J Hof, M Zimmermann, T Rausch, O R Bandapalli, E Orlova, G Scapinello, J C Sagi, M Stanulla, M Schrappe, G Cario, R Kirschner-Schwabe, C Eckert, V Benes, J O Korbel, M U Muckenthaler, A E Kulozik
In the search for genes that define critical steps of relapse in pediatric T-cell acute lymphoblastic leukemia (T-ALL) and can serve as prognostic markers, we performed targeted sequencing of 313 leukemia-related genes in 214 patients: 67 samples collected at the time of relapse and 147 at initial diagnosis. As relapse-specific genetic events, we identified activating mutations in NT5C2 (P=0.0001, Fisher's exact test), inactivation of TP53 (P=0.0007, Fisher's exact test) and duplication of chr17:q11.2-24.3 (P=0...
February 3, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/28139931/design-of-a-janus-kinase-3-jak3-specific-inhibitor-1-2s-5r-5-7h-pyrrolo-2-3-d-pyrimidin-4-yl-amino-2-methylpiperidin-1-yl-prop-2-en-1-one-pf-06651600-allowing-for-the-interrogation-of-jak3-signaling-in-humans
#14
Atli Thorarensen, Martin E Dowty, Mary Ellen Banker, Brian Juba, Jason Jussif, Tsung Lin, Fabien Vincent, Robert M Czerwinski, Agustin Casimiro-Garcia, Ray Unwalla, John I Trujillo, Sidney Liang, Paul Balbo, Ye Che, Adam M Gilbert, Matthew F Brown, Matthew Hayward, Justin Montgomery, Louis Leung, Xin Yang, Sarah Soucy, Martin Hegen, Jotham Coe, Jonathan Langille, Felix Vajdos, Jill Chrencik, Jean-Baptiste Telliez
Significant work has been dedicated to the discovery of JAK kinase inhibitors resulting in several compounds entering clinical development and two FDA approved NMEs. However, despite significant effort during the past 2 decades, identification of highly selective JAK3 inhibitors has eluded the scientific community. A significant effort within our research organization has resulted in the identification of the first orally active JAK3 specific inhibitor, which achieves JAK isoform specificity through covalent interaction with a unique JAK3 residue Cys-909...
February 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28128670/large-granular-lymphocytic-leukemia-current-diagnostic-and-therapeutic-approaches-and-novel-treatment-options
#15
Estella Matutes
Large granular lymphocytic leukemia (LGLL) is a low grade lymphoproliferative disorder characterized by the clonal proliferation of large granular lymphocytes (LGL) and recognised by the WHO. The diagnosis and management of these patients is challenging due to the limited information from prospective studies. Guidelines for front-line therapy have not been established. The prognosis is favourable with median overall survivals greater than 10 years. Areas covered: This manuscript is a review of the clinical features, diagnosis, pathogenesis and, in particular, the various available therapeutic options for this rare lymphoid leukemia...
January 29, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28122987/mmp-9-facilitates-hepatitis-b-virus-replication-through-binding-with-ifnar1-to-repress-ifn-jak-stat-signaling
#16
Junbo Chen, Wei Xu, Yanni Chen, Xueping Xie, Yecheng Zhang, Chunqiang Ma, Qingyu Yang, Yang Han, Chengliang Zhu, Ying Xiong, Kailang Wu, Fang Liu, Yingle Liu, Jianguo Wu
: Hepatitis B virus (HBV) infection may cause acute hepatitis B (AHB), chronic hepatitis B (CHB), liver cirrhosis (LC) and hepatocellular carcinoma (HCC). However, the mechanisms by which HBV evades host immunity and maintains chronic infection are largely unknown. Here, we revealed that matrix metalloproteinase-9 (MMP-9) is activated in peripheral blood mononuclear cells (PBMCs) of HBV-infected patients, and HBV stimulates MMP-9 expression in macrophages and PBMCs isolated from healthy individuals...
January 25, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28122045/negative-immune-regulator-tipe2-promotes-m2-macrophage-differentiation-through-the-activation-of-pi3k-akt-signaling-pathway
#17
Ruiling Liu, Tingting Fan, Wenwen Geng, Youhai H Chen, Qingguo Ruan, Cui Zhang
Macrophages play important roles in the regulation of the innate and adaptive immune responses. Classically activated macrophages and alternatively activated macrophages are the two major forms of macrophages and have opposing functionalities. Tumor necrosis factor-α-induced protein 8-2 is expressed primarily by immune cells and negatively regulates type 1 innate and adaptive immune responses to maintain immune tolerance. While previous studies indicate that TIPE2 promotes M2 but inhibits M1 macrophage differentiation, the underlying molecular mechanism by which TIPE2 promotes M2 macrophage differentiation remains unclear...
2017: PloS One
https://www.readbyqxmd.com/read/28118538/peficitinib-a-jak-inhibitor-in-combination-with-limited-conventional-synthetic-dmards-in-the-treatment-of-moderate-to-severe-rheumatoid-arthritis
#18
Mark C Genovese, Maria Greenwald, Christine Codding, Anna Zubrzycka-Sienkiewicz, Alan J Kivitz, Annie Wang, Kathyjo Shay, Xuegong Wang, Jay P Garg, Mario H Cardiel
OBJECTIVE: To evaluate the efficacy and safety of orally administered once-daily peficitinib in patients with moderate-to-severe rheumatoid arthritis (RA) in combination with limited conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). METHODS: In this double-blind, randomized, phase IIb trial, patients with RA (N=289) were treated with peficitinib 25 mg, 50 mg, 100 mg, 150 mg, or matching placebo once daily for 12 weeks. Primary endpoint was the percentage of patients achieving an American College of Rheumatology (ACR) 20% response at Week 12...
January 24, 2017: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/28117214/a-novel-jak-inhibitor-peficitinib-demonstrates-potent-efficacy-in-a-rat-adjuvant-induced-arthritis-model
#19
Misato Ito, Shunji Yamazaki, Kaoru Yamagami, Masako Kuno, Yoshiaki Morita, Kenji Okuma, Koji Nakamura, Noboru Chida, Masamichi Inami, Takayuki Inoue, Shohei Shirakami, Yasuyuki Higashi
The Janus kinase (JAK) family of tyrosine kinases is associated with various cytokine receptors. JAK1 and JAK3 play particularly important roles in the immune response, and their inhibition is expected to provide targeted immune modulation. Several oral JAK inhibitors have recently been developed for treating autoimmune diseases, including rheumatoid arthritis (RA). Here, we investigated the pharmacological effects of peficitinib (formerly known as ASP015K), a novel, chemically synthesized JAK inhibitor. We found that peficitinib inhibited JAK1 and JAK3 with 50% inhibitory concentrations of 3...
December 23, 2016: Journal of Pharmacological Sciences
https://www.readbyqxmd.com/read/28112370/the-jak-stat-pathway-is-involved-in-the-upregulation-of-pd-l1-expression-in-pancreatic-cancer-cell-lines
#20
Toshifumi Doi, Takeshi Ishikawa, Tetsuya Okayama, Kaname Oka, Katsura Mizushima, Tomoyo Yasuda, Naoyuki Sakamoto, Kazuhiro Katada, Kazuhiro Kamada, Kazuhiko Uchiyama, Osamu Handa, Tomohisa Takagi, Yuji Naito, Yoshito Itoh
Although improvements in the chemotherapy modalities for pancreatic cancer have been realized, pancreatic cancer remains one of the most lethal malignancies. New-generation cancer immunotherapy methods, such as blocking of the PD-1/PD-L1 pathway, are consistently being investigated to improve the survival of pancreatic cancer patients. In the present study, we evaluated the influence of anticancer agents 5-fluorouracil, gemcitabine and paclitaxel on PD-L1 expression in human pancreatic cancer cell lines MIA PaCa-2 and AsPC-1 and in murine pancreatic cancer cell line Pan02...
January 23, 2017: Oncology Reports
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