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https://www.readbyqxmd.com/read/29785143/pilot-study-of-the-antifibrotic-effects-of-the-multikinase-inhibitor-pacritinib-in-a-mouse-model-of-liver-fibrosis
#1
Suliman Al-Fayoumi, Taishi Hashiguchi, Yuka Shirakata, John Mascarenhas, Jack W Singer
Background: Fibrotic diseases result from an exuberant response to chronic inflammation. Myelofibrosis is the end result of inflammation in bone, caused by an inflammatory process triggered by production of abnormal myeloid cells driven by mutations affecting the JAK-STAT pathway. Inflammatory cytokine overproduction leads to increased mesenchymal cell proliferation, culminating in fibrosis. Although JAK2 inhibitors, such as the JAK1/2 inhibitor ruxolitinib and the JAK2/FLT3/CSF1R/IRAK1 inhibitor pacritinib suppress abnormal clone expansion in myelofibrosis, ruxolitinib does not appear to prevent or reverse bone-marrow fibrosis in most patients...
2018: Journal of Experimental Pharmacology
https://www.readbyqxmd.com/read/29778097/hyperprolactinemia-inducing-antipsychotics-increase-breast-cancer-risk-by-activating-jak-stat5-in-precancerous-lesions
#2
A N Johnston, W Bu, S Hein, S Garcia, L Camacho, L Xue, L Qin, C Nagi, S G Hilsenbeck, J Kapali, K Podsypanina, J Nangia, Y Li
BACKGROUND: Psychiatric medications are widely prescribed in the USA. Many antipsychotics cause serum hyperprolactinemia as an adverse side effect; prolactin-Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5) signaling both induces cell differentiation and suppresses apoptosis. It is controversial whether these antipsychotics increase breast cancer risk. METHODS: We investigated the impact of several antipsychotics on mammary tumorigenesis initiated by retrovirus-mediated delivery of either ErbB2 or HRas or by transgenic expression of Wnt-1...
May 19, 2018: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/29761158/phase-ii-study-of-ruxolitinib-a-selective-jak1-2-inhibitor-in-patients-with-metastatic-triple-negative-breast-cancer
#3
Daniel G Stover, Carlos R Gil Del Alcazar, Jane Brock, Hao Guo, Beth Overmoyer, Justin Balko, Qiong Xu, Aditya Bardia, Sara M Tolaney, Rebecca Gelman, Maxwell Lloyd, Yu Wang, Yaomin Xu, Franziska Michor, Vivian Wang, Eric P Winer, Kornelia Polyak, Nancy U Lin
Preclinical data support a role for the IL-6/JAK2/STAT3 signaling pathway in breast cancer. Ruxolitinib is an orally bioavailable receptor tyrosine inhibitor targeting JAK1 and JAK2. We evaluated the safety and efficacy of ruxolitinib in patients with metastatic breast cancer. This was a non-randomized phase II study enrolling patients with refractory, metastatic triple-negative breast cancer. The primary endpoint was objective response by RECIST 1.1. The study was designed to enroll patients whose archival tumor tissue was pSTAT3-positive ( T -score >5) by central immunohistochemistry...
2018: NPJ Breast Cancer
https://www.readbyqxmd.com/read/29750040/a-phase-ib-study-of-ruxolitinib-gemcitabine-%C3%A2-nab-paclitaxel-in-patients-with-advanced-solid-tumors
#4
Todd M Bauer, Manish R Patel, Andres Forero-Torres, Thomas J George, Albert Assad, Yining Du, Herbert Hurwitz
Purpose: Aberrant activation of the Janus-associated kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is associated with increased malignant cell proliferation and survival. This Phase Ib study evaluated ruxolitinib, a potent JAK1/2 inhibitor, in combination with gemcitabine with or without nab-paclitaxel in patients with advanced solid tumors. Patients and methods: Patients received ruxolitinib + gemcitabine (regimen A) or ruxolitinib + gemcitabine + nab-paclitaxel (regimen B)...
2018: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29743719/inhibition-of-interleukin-1-receptor-associated-kinase-1-is-a-therapeutic-strategy-for-acute-myeloid-leukemia-subtypes
#5
Mona M Hosseini, Stephen E Kurtz, Sherif Abdelhamed, Shawn Mahmood, Monika A Davare, Andy Kaempf, Johannes Elferich, Jason E McDermott, Tao Liu, Samuel H Payne, Ujwal Shinde, Karin D Rodland, Motomi Mori, Brian J Druker, Jack W Singer, Anupriya Agarwal
Interleukin-1 receptor-associated kinase 1 (IRAK1), an essential mediator of innate immunity and inflammatory responses, is constitutively active in multiple cancers. We evaluated the role of IRAK1 in acute myeloid leukemia (AML) and assessed the inhibitory activity of multikinase inhibitor pacritinib on IRAK1 in AML. We demonstrated that IRAK1 is overexpressed in AML and provides a survival signal to AML cells. Genetic knockdown of IRAK1 in primary AML samples and xenograft model showed a significant reduction in leukemia burden...
March 29, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29741513/myelofibrosis-clinicopathologic-features-prognosis-and-management
#6
Jennifer M O'Sullivan, Claire N Harrison
Myelofibrosis is one of the BCR-ABL-negative clonal disorders that collectively are known as myeloproliferative neoplasms (MPNs). It is caused by the proliferation of clonal hematopoietic stem cells, which over time leads to characteristic clinical features. The disease presentation is heterogeneous, however, with 30% of patients initially asymptomatic. This variation in clinical phenotype warrants careful risk stratification to guide appropriate management, and prognostic risk scores are continually being refined...
February 2018: Clinical Advances in Hematology & Oncology: H&O
https://www.readbyqxmd.com/read/29737494/the-effect-of-moderate-weight-loss-with-or-without-1-3-1-6-%C3%AE-glucan-addition-on-subcutaneous-adipose-tissue-inflammatory-gene-expression-in-young-subjects-with-uncomplicated-obesity
#7
Marek Strączkowski, Agnieszka Nikołajuk, Radosław Majewski, Remigiusz Filarski, Magdalena Stefanowicz, Natalia Matulewicz, Monika Karczewska-Kupczewska
PURPOSE: Obesity is characterized by insulin resistance and low-grade systemic and adipose tissue (AT) inflammation. It remains unclear whether beneficial effects of weight loss are related to AT inflammation. We aimed to assess the effect of weight loss during low-calorie diet on insulin sensitivity, AT expression of genes associated with inflammation in young subjects with obesity. Furthermore, we estimated the effects of immunomodulatory (1, 3)(1, 6)-β-glucan (BG) on the above parameters...
May 8, 2018: Endocrine
https://www.readbyqxmd.com/read/29736209/microrna-214-inhibits-the-proliferation-and-invasion-of-lung-carcinoma-cells-by-targeting-jak1
#8
Xiaofeng Chen, Jiangyuan Du, Rui Jiang, Ling Li
Increasing evidence suggests that microRNAs (miRNAs) play a crucial role in the pathogenesis of tumor. In this study, miR-214 was found to be significantly down-regulated in lung tumor tissues and lung cell lines. From the gain-of-function experiment results, we found that ectopic expression of miR-214 in lung cancer cell lines significantly inhibited cell growth, as evidenced by cell viability and colony formation assays, and suppressed tumor growth in vivo . Besides, further investigations showed that miR-214 inhibited cell migration and invasion...
2018: American Journal of Translational Research
https://www.readbyqxmd.com/read/29735884/polysaccharides-extracted-from-rhizoma-pleionis-have-antitumor-properties-in-vitro-and-in-an-h22-mouse-hepatoma-ascites-model-in-vivo
#9
Yukun Fang, Anhong Ning, Sha Li, Shaozheng Zhou, Lei Liu, Thomson Patrick Joseph, Mintao Zhong, Jilong Jiao, Wei Zhang, Yonghui Shi, Meishan Zhang, Min Huang
Malignant ascites is a highly severe and intractable complication of advanced or recurrent malignant tumors that is often immunotherapy-resistant. Rhizoma Pleionis is widely used in traditional medicine as an antimicrobial and anticancer agent, but its effectiveness in treating malignant ascites is unclear. In the current study, we investigated the effect of polysaccharides isolated from Rhizoma Pleionis (PRP) on murine hepatocarcinoma H22 cells in an ascites model. We have found that the main components of PRP, that presented a relative molecular weight of 383...
May 7, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29731916/an-indel-polymorphism-in-the-3-untranslated-region-of-jak1-confers-risk-for-hepatocellular-carcinoma-possibly-by-regulating-jak1-transcriptional-activity-in-a-chinese-population
#10
Qiang Yu, Weifeng Qian, Jian Wang, Yejiao Wu, Jinkun Zhang, Weichang Chen
The purpose of the present study was to assess whether the rs112395617 polymorphism located in the Janus kinase 1 ( JAK1 ) 3' untranslated region (3' UTR) was associated with the risk of hepatocellular carcinoma (HCC), and to explore the potential mechanism of action. Genomic DNA was extracted from peripheral blood of 290 patients with HCC and 320 controls. A polymerase chain reaction-polyacrylamide gel electrophoresis assay was used to genotype the rs112395617 polymorphism. Quantitative (q)PCR was used to detect the genotype-phenotype association between HCC tissues and different genotypes...
May 2018: Oncology Letters
https://www.readbyqxmd.com/read/29731870/igf-1-induced-mmp-11-expression-promotes-the-proliferation-and-invasion-of-gastric-cancer-cells-through-the-jak1-stat3-signaling-pathway
#11
Chao Su, Wenchang Wang, Cunchuan Wang
The present study aimed to investigate the association between insulin-like growth factor-1 (IGF-1) and matrix metalloproteinase-11 (MMP-11) expression in gastric cancer (GC) and the underlying mechanisms in SGC-7901 cells. Reverse transcription-quantitative polymerase chain reaction analysis revealed that the expression of IGF-1 and MMP-11 was significantly upregulated in GC tissues compared with normal gastric tissue. Furthermore, IGF-1 significantly and dose-dependently promoted MMP-11. Western blotting revealed that the addition of IGF-1 to SGC-7901 cells led to an evident enhancement in signal transducer and activator of transcription 3 (STAT3), IGF-1R and Janus kinase 1 (JAK1) phosphorylation at 20 and 40 min...
May 2018: Oncology Letters
https://www.readbyqxmd.com/read/29714141/blocking-il-6-gp130-signaling-inhibits-cell-viability-proliferation-glycolysis-and-colony-forming-activity-in-human-pancreatic-cancer-cells
#12
Xiang Chen, Jilai Tian, Gloria H Su, Jiayuh Lin
BACKGROUND: Elevated production of the pro-inflammatory cytokine interleukin-6 (IL-6) and dysfunctions of IL-6 signaling promotes tumorigenesis and are associated with poor survival outcomes in multiple cancer types. Recent studies showed that the IL-6/GP130/STAT3 signaling pathway plays a pivotal role in pancreatic cancer development and maintenance. OBJECTIVE: We aim to develop effective treatments through inhibition of IL-6/GP130 signaling in pancreatic cancer...
April 30, 2018: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/29713323/implication-of-interleukin-12-15-18-and-ruxolitinib-in-the-phenotype-proliferation-and-polyfunctionality-of-human-cytokine-preactivated-natural-killer-cells
#13
Iñigo Terrén, Idoia Mikelez, Irati Odriozola, Andrea Gredilla, Javier González, Ane Orrantia, Joana Vitallé, Olatz Zenarruzabeitia, Francisco Borrego
A brief in vitro stimulation of natural killer (NK) cells with interleukin (IL)-12, IL-15, and IL-18 endow them a memory-like behavior, characterized by higher effector responses when they are restimulated after a resting period of time. These preactivated NK cells, also known as cytokine-induced memory-like (CIML) NK cells, have several properties that make them a promising tool in cancer immunotherapy. In the present study, we have described the effect that different combinations of IL-12, IL-15, and IL-18 have on the generation of human CIML NK cells...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29703908/a-side-effect-free-method-for-identifying-cancer-drug-targets
#14
Md Izhar Ashraf, Seng-Kai Ong, Shama Mujawar, Shrikant Pawar, Pallavi More, Somnath Paul, Chandrajit Lahiri
Identifying effective drug targets, with little or no side effects, remains an ever challenging task. A potential pitfall of failing to uncover the correct drug targets, due to side effect of pleiotropic genes, might lead the potential drugs to be illicit and withdrawn. Simplifying disease complexity, for the investigation of the mechanistic aspects and identification of effective drug targets, have been done through several approaches of protein interactome analysis. Of these, centrality measures have always gained importance in identifying candidate drug targets...
April 27, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29698782/altered-cytokine-profile-under-control-of-the-serotonergic-system-determines-the-regulation-of-cyp2c11-and-cyp3a-isoforms
#15
Marta Kot, Martine Daujat-Chavanieu
The aim of this study is to assess a potential mechanism by which the serotonergic system can control the expression and activity of cytochrome (CYP) 2C11 and CYP3A isoforms during liver insufficiency. A rat model of diethylnitrosamine (DEN)-induced liver insufficiency was developed by administering 50 mg/kg of DEN twice a week for 7 weeks. Dysfunction of the serotonergic system was evoked by feeding the rats with a tryptophan-free diet for three weeks. Dysfunction of the serotonergic system during liver insufficiency decreased the level of proinflammatory cytokines (TGF-β and IL-1β) and increased the level of an anti-inflammatory cytokine (IL-4)...
April 23, 2018: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/29695516/phase-1-study-of-the-pi3k%C3%AE-inhibitor-incb040093-%C3%A2-jak1-inhibitor-itacitinib-in-relapsed-refractory-b-cell-lymphoma
#16
Tycel J Phillips, Andres Forero-Torres, Taimur Sher, Catherine S Diefenbach, Patrick Johnston, Moshe Talpaz, Jennifer Pulini, Li Zhou, Peggy Scherle, Xuejun Chen, Paul M Barr
Because both phosphatidylinositol 3-kinase δ (PI3Kδ) and Janus kinase (JAK)-signal transducer and activator of transcription pathways contribute to tumor cell proliferation and survival in B-cell malignancies, their simultaneous inhibition may provide synergistic treatment efficacy. This phase 1 dose-escalation/expansion study assessed the safety, efficacy, pharmacokinetics, and pharmacodynamics of INCB040093, a selective PI3Kδ inhibitor, as monotherapy or combined with itacitinib (formerly INCB039110), a selective JAK1 inhibitor, in adult patients with relapsed or refractory (R/R) B-cell lymphomas...
April 25, 2018: Blood
https://www.readbyqxmd.com/read/29693289/lncrna-atb-promotes-proliferation-and-metastasis-in-a549-cells-by-down-regulation-of-microrna-494
#17
Yiwei Cao, Xiangjun Luo, Xiaoqian Ding, Shichao Cui, Caihong Guo
Lung cancer is a commonly diagnosed disease with poor prognosis. Novel therapeutic targets and deep understanding of the regulatory mechanisms in lung cancer are of great importance. We aimed to figure out the functional roles of lncRNA-activated by transforming growth factor-β (ATB) in A549 cells as well as the underlying molecular mechanisms. ATB was non-physiologically expressed in A549 cells after cell transfection. Then, cell proliferation, expressions of proteins related to proliferation and epithelial-mesenchymal transition (EMT), migration, and invasion were measured by BrdU incorporation assay, Western blot analysis, and Transwell assay, respectively...
April 25, 2018: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29693186/combined-inhibition-of-jak1-2-stat3%C3%A2-pd%C3%A2-l1-signaling-pathway-suppresses-the-immune-escape-of-castration%C3%A2-resistant-prostate-cancer-to-nk-cells-in-hypoxia
#18
Li-Jun Xu, Qi Ma, Jin Zhu, Jian Li, Bo-Xin Xue, Jie Gao, Chuan-Yang Sun, Ya-Chen Zang, Yi-Bin Zhou, Dong-Rong Yang, Yu-Xi Shan
Castration‑resistant prostate cancer (CRPC) is difficult to treat in current clinical practice. Hypoxia is an important feature of the CRPC microenvironment and is closely associated with the progress of CRPC invasion. However, no research has been performed on the immune escape of CRPC from NK cells. The present study focused on this subject. Firstly, when the CRPC cell lines C4‑2 and CWR22Rv1 were induced by hypoxia, the expression of the UL16 binding protein (ULBP) ligand family of natural killer (NK) group 2D (NKG2D; ULBP‑1, ULBP‑2 and ULBP‑3) and MHC class I chain‑related proteins A and B (MICA/MICB) decreased...
April 20, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29691471/baricitinib-induced-blockade-of-interferon-gamma-receptor-and-interleukin-6-receptor-for-the-prevention-and-treatment-of-graft-versus-host-disease
#19
Jaebok Choi, Matthew L Cooper, Karl Staser, Kidist Ashami, Kiran R Vij, Bing Wang, Lynne Marsala, Jessica Niswonger, Julie Ritchey, Bader Alahmari, Samuel Achilefu, Ikuo Tsunoda, Mark A Schroeder, John F DiPersio
The therapeutic benefits of allogeneic hematopoietic stem cell transplantation (allo-HSCT) are derived from the graft-versus-leukemia (GvL) effects of the procedure. There is a strong association between the GvL effects and graft-versus-host disease (GvHD), a major life-threatening complication of allo-HSCT. The limiting of GvHD while maintaining the GvL effect remains the goal of allo-HSCT. Therefore, identifying optimal therapeutic targets to selectively suppress GvHD while maintaining the GvL effects represents a significant unmet medical need...
April 2, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29689246/il-13-is-produced-by-tumor-cells-in-breast-implant-associated-anaplastic-large-cell-lymphoma-implications-for-pathogenesis
#20
Marshall E Kadin, John Morgan, Haiying Xu, Alan L Epstein, David Sieber, Bradley A Hubbard, William P Adams, Carlos E Bacchi, Joao C S Goes, Mark W Clemens, L Jeffrey Medeiros, Roberto N Miranda
More than 500 women worldwide have developed a CD30+ T-cell lymphoma around breast implants, strongly suggesting a cause and effect relationship, and designated as breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). The mechanism of lymphomagenesis is unknown. Recently, a bacterial biofilm containing gram negative bacilli was discovered on the surface of breast implants associated with ALCL. We and others have described overexpression of the proto-oncogene JUNB and mutations of JAK1/2, TP53 and STAT3 in BIA-ALCL...
April 21, 2018: Human Pathology
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