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https://www.readbyqxmd.com/read/29465625/spinal-bromodomain-containing-protein-4-contributes-to-neuropathic-pain-induced-by-hiv-glycoprotein-120-with-morphine-in-rats
#1
Keiya Takahashi, Hyun Yi, Ching-Hang Liu, Shue Liu, Yuta Kashiwagi, Dennis J Patin, Shuanglin Hao
The symptoms of HIV-sensory neuropathy are dominated by neuropathic pain. Recent data show that repeated use of opiates enhances the chronic pain states in HIV patients. Limited attention has so far been devoted to exploring the exact pathogenesis of HIV painful disorder and opiate abuse in vivo, for which there is no effective treatment. Bromodomain-containing protein 4 (Brd4) is a member of the bromodomain and extraterminal domain protein (BET) family and functions as a chromatin 'reader' that binds acetylated lysines in histones in brain neurons to mediate the transcriptional regulation underlying learning and memory...
February 20, 2018: Neuroreport
https://www.readbyqxmd.com/read/29463565/an-fgfr3-myc-positive-feedback-loop-provides-new-opportunities-for-targeted-therapies-in-bladder-cancers
#2
Mélanie Mahe, Florent Dufour, Hélène Neyret-Kahn, Aura Moreno-Vega, Claire Beraud, Mingjun Shi, Imene Hamaidi, Virginia Sanchez-Quiles, Clementine Krucker, Marion Dorland-Galliot, Elodie Chapeaublanc, Remy Nicolle, Hervé Lang, Celio Pouponnot, Thierry Massfelder, François Radvanyi, Isabelle Bernard-Pierrot
FGFR3 alterations (mutations or translocation) are among the most frequent genetic events in bladder carcinoma. They lead to an aberrant activation of FGFR3 signaling, conferring an oncogenic dependence, which we studied here. We discovered a positive feedback loop, in which the activation of p38 and AKT downstream from the altered FGFR3 upregulates MYC mRNA levels and stabilizes MYC protein, respectively, leading to the accumulation of MYC, which directly upregulates FGFR3 expression by binding to active enhancers upstream from FGFR3 Disruption of this FGFR3/MYC loop in bladder cancer cell lines by treatment with FGFR3, p38, AKT, or BET bromodomain inhibitors (JQ1) preventing MYC transcription decreased cell viability in vitro and tumor growth in vivo A relevance of this loop to human bladder tumors was supported by the positive correlation between FGFR3 and MYC levels in tumors bearing FGFR3 mutations, and the decrease in FGFR3 and MYC levels following anti-FGFR treatment in a PDX model bearing an FGFR3 mutation...
February 20, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29454094/synergistic-activity-of-bet-inhibitor-bi-894999-with-plk-inhibitor-volasertib-in-aml-in-vitro-and-in-vivo
#3
Ulrike Tontsch-Grunt, Dorothea Rudolph, Irene Waizenegger, Anke Baum, Daniel Gerlach, Harald Engelhardt, Melanie Wurm, Fabio Savarese, Norbert Schweifer, Norbert Kraut
Interactions between a new potent Bromodomain and extraterminal domain (BET) inhibitor BI 894999 and the polo-like kinase (PLK) inhibitor volasertib were studied in acute myeloid leukemia cell lines in vitro and in vivo. We provide data for the distinct mechanisms of action of these two compounds with a potential utility in AML based on gene expression, cell cycle profile and modulation of PD biomarkers such as MYC and HEXIM1. In contrast to BI 894999, volasertib treatment neither affects MYC nor HEXIM1 expression, but augments and prolongs the decrease of MYC expression caused by BI 894999 treatment...
February 14, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29440272/antagonistic-effects-of-nitric-oxide-in-a-glioblastoma-photodynamic-therapy-model-mitigation-by-bet-bromodomain-inhibitor-jq1
#4
Jonathan M Fahey, Jennifer S Stancill, Brian C Smith, Albert W Girotti
Endogenous nitric oxide (NO) generated by inducible NO synthase (iNOS) promotes glioblastoma cell proliferation and invasion, and also plays a key role in glioblastoma resistance to chemotherapy and radiotherapy. Non-ionizing photodynamic therapy (PDT) has anti-tumor advantages over conventional glioblastoma therapies. Our previous studies revealed that glioblastoma U87 cells upregulate iNOS after a photodynamic challenge and that resulting NO not only increased resistance to apoptosis, but rendered surviving cells more proliferative and invasive...
February 12, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29437854/bet-proteins-exhibit-transcriptional-and-functional-opposition-in-the-epithelial-to-mesenchymal-transition
#5
Guillaume P Andrieu, Gerald V Denis
Transcriptional programs in embryogenesis and cancer, such as the epithelial-to-mesenchymal transition (EMT), ensure cellular plasticity, an essential feature of carcinoma progression. As effectors of signal transduction, the bromodomain and extraterminal (BET) proteins are well suited to support plasticity because they function as co-activators or co-repressors of mammalian transcriptomes. Here, using both hormone-sensitive and triple-negative breast cancer (TNBC) model systems, we systematically altered EMT transcriptional profiles by manipulating individual BET proteins and found that BRD2 positively regulates EMT, whereas BRD3 and BRD4 repress this program...
February 7, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29434197/brd4-regulates-cellular-senescence-in-gastric-cancer-cells-via-e2f-mir-106b-p21-axis
#6
Xingchen Dong, Xiangming Hu, Jinjing Chen, Dan Hu, Lin-Feng Chen
Small molecules targeting bromodomains of BET proteins possess strong anti-tumor activities and have emerged as potential therapeutics for cancer. However, the underlying mechanisms for the anti-proliferative activity of these inhibitors are still not fully characterized. In this study, we demonstrated that BET inhibitor JQ1 suppressed the proliferation and invasiveness of gastric cancer cells by inducing cellular senescence. Depletion of BRD4, which was overexpressed in gastric cancer tissues, but not other BET proteins recapitulated JQ1-induced cellular senescence with increased cellular SA-β-Gal activity and elevated p21 levels...
February 12, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29415456/bet-family-protein-brd4-an-emerging-actor-in-nf%C3%AE%C2%BAb-signaling-in-inflammation-and-cancer
#7
REVIEW
Azadeh Hajmirza, Anouk Emadali, Arnaud Gauthier, Olivier Casasnovas, Rémy Gressin, Mary B Callanan
NFκB (Nuclear Factor- κ -light-chain-enhancer of activated B cells) signaling elicits global transcriptional changes by activating cognate promoters and through genome-wide remodeling of cognate regulatory elements called "super enhancers". BET (Bromodomain and Extra-Terminal domain) protein family inhibitor studies have implicated BET protein member BRD4 and possibly other BET proteins in NFκB-dependent promoter and super-enhancer modulation. Members of the BET protein family are known to bind acetylated chromatin to facilitate access by transcriptional regulators to chromatin, as well as to assist the activity of transcription elongation complexes via CDK9/pTEFb...
February 6, 2018: Biomedicines
https://www.readbyqxmd.com/read/29386193/brd4-profiling-identifies-critical-chronic-lymphocytic-leukemia-oncogenic-circuits-and-reveals-sensitivity-to-plx51107-a-novel-structurally-distinct-bet-inhibitor
#8
Hatice Gulcin Ozer, Dalia El-Gamal, Ben Powell, Zachary A Hing, James S Blachly, Bonnie Harrington, Shaneice Mitchell, Nicole R Grieselhuber, Katie Williams, Tzung-Huei Lai, Lapo Alinari, Robert A Baiocchi, Lindsey Brinton, Elizabeth Baskin, Matthew Cannon, Larry Beaver, Virginia M Goettl, David M Lucas, Jennifer A Woyach, Deepa Sampath, Amy M Lehman, Lianbo Yu, Jiazhong Zhang, Yan Ma, Ying Zhang, Wayne Spevak, Songyuan Shi, Paul Severson, Rafe Shellooe, Heidi Carias, Garson Tsang, Ken Dong, Todd Ewing, Adhirai Marimuthu, Christina Tantoy, Jason Walters, Laura Sanftner, Hamid Rezaei, Marika Nespi, Bernice Matusow, Gaston Habets, Prabha Ibrahim, Chao Zhang, Ewy A Mathé, Gideon Bollag, John C Byrd, Rosa Lapalombella
Bromodomain and extra-terminal (BET) family proteins are key regulators of gene expression in cancer. Herein, we utilize BRD4 profiling to identify critical pathways involved in pathogenesis of chronic lymphocytic leukemia (CLL). BRD4 is over-expressed in CLL and is enriched proximal to genes up-regulated or de novo expressed in CLL with known function in disease pathogenesis and progression. These genes, including key members of the BCR signaling pathway, provide rationale for this therapeutic approach to identify new targets in alternative types of cancer...
January 31, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29356890/patterns-of-care-and-impact-of-prognostic-factors-in-the-outcome-of-nut-midline-carcinoma-a-systematic-review-and-individual-patient-data-analysis-of-119-cases
#9
Prashanth Giridhar, Supriya Mallick, Lakhan Kashyap, Goura Kishor Rath
INTRODUCTION: NUT midline carcinoma is a rare tumour occurring in young adults which is frequently misdiagnosed as poorly differentiated squamous cell carcinoma or germ cell tumour. Though considered highly aggressive, there is limited information about the clinical behaviour of such patients. We intended to perform this review of published literature to assess the demographic profile, pattern of care and assess survival outcomes. METHODS: Two authors independently searched PubMed and Google search for eligible studies from 1950 till July 1 2017 published in English language using MESH terms NUT midline carcinoma; NUT midline carcinoma and radiotherapy and translocation 15:19 tumour...
January 22, 2018: European Archives of Oto-rhino-laryngology
https://www.readbyqxmd.com/read/29353886/the-bet-bromodomain-inhibitor-cpi203-overcomes-resistance-to-abt-199-venetoclax-by-downregulation-of-bfl-1-a1-in-in-vitro-and-in-vivo-models-of-myc-bcl2-double-hit-lymphoma
#10
A Esteve-Arenys, J G Valero, A Chamorro-Jorganes, D Gonzalez, V Rodriguez, I Dlouhy, I Salaverria, E Campo, D Colomer, A Martinez, G Rymkiewicz, P Pérez-Galán, A Lopez-Guillermo, G Roué
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, mostly known as double-hit lymphoma (DHL), is a rare entity characterized by morphologic and molecular features between Burkitt lymphoma and the clinically manageable diffuse large B-cell lymphoma (DLBCL). DHL patients usually undergo a rapidly progressing clinical course associated with resistance to standard chemo-immunotherapy. As a consequence, the prognosis of this entity is particularly poor with a median overall survival inferior to 1 year...
January 22, 2018: Oncogene
https://www.readbyqxmd.com/read/29351440/jq1-is-a-potential-therapeutic-option-for-copd-patients-with-agrin-overexpression
#11
Zhen Xiao, Jing Shu, Feng Zhou, Yong Han
Chronic Obstructive Pulmonary Disease (COPD) is one of the leading cause of morbidity and death worldwide. It is characterized by chronic pulmonary inflammation and obstructed airflow from the lungs. To date, there is no effective treatments for COPD. The activation of Agrin (AGRN) - YAP pathway can promote heart regeneration. Since Agrin can only induce mild cardiomyocyte (CM) proliferation compare to ERBB2 pathway activation, it might exert pleiotropic effects, such as mitigation of innate inflammation, immune response and fibrosis...
December 28, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/29346775/brd4-promotes-dna-repair-and-mediates-the-formation-of-tmprss2-erg-gene-rearrangements-in-prostate-cancer
#12
Xiangyi Li, GuemHee Baek, Susmita G Ramanand, Adam Sharp, Yunpeng Gao, Wei Yuan, Jon Welti, Daniel N Rodrigues, David Dolling, Ines Figueiredo, Semini Sumanasuriya, Mateus Crespo, Adam Aslam, Rui Li, Yi Yin, Bipasha Mukherjee, Mohammed Kanchwala, Ashley M Hughes, Wendy S Halsey, Cheng-Ming Chiang, Chao Xing, Ganesh V Raj, Sandeep Burma, Johann de Bono, Ram S Mani
BRD4 belongs to the bromodomain and extraterminal (BET) family of chromatin reader proteins that bind acetylated histones and regulate gene expression. Pharmacological inhibition of BRD4 by BET inhibitors (BETi) has indicated antitumor activity against multiple cancer types. We show that BRD4 is essential for the repair of DNA double-strand breaks (DSBs) and mediates the formation of oncogenic gene rearrangements by engaging the non-homologous end joining (NHEJ) pathway. Mechanistically, genome-wide DNA breaks are associated with enhanced acetylation of histone H4, leading to BRD4 recruitment, and stable establishment of the DNA repair complex...
January 16, 2018: Cell Reports
https://www.readbyqxmd.com/read/29343723/pharmacological-targeting-of-bet-proteins-attenuates-radiation-induced-lung-fibrosis
#13
Jian Wang, Fangzheng Zhou, Zhenyu Li, Hong Mei, Ye Wang, Hong Ma, Liangliang Shi, Ai Huang, Tao Zhang, Zhenyu Lin, Gang Wu
Radiation-induced lung injury has restricted radiotherapy for thoracic cancer. The purpose of this study was to investigate the radioprotective effects of bromodomain and extra terminal (BET) inhibitor JQ1 in a murine model of pulmonary damage. Chest computed tomography (CT) was performed in a rat model after 20 Gy radiation of the right thorax. And histological evaluation and protein expressions of irradiated tissue were analyzed to confirm the potential anti-fibrosis effect of JQ1 and its underlying mechanisms...
January 17, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29343578/a-new-quinoline-brd4-inhibitor-targets-a-distinct-latent-hiv-1-reservoir-for-re-activation-from-other-shock-drugs
#14
Erik Abner, Mateusz Stoszko, Lei Zeng, Heng-Chang Chen, Andrea Izquierdo-Bouldstridge, Tsuyoshi Konuma, Eduard Zorita, Elisa Fanunza, Qiang Zhang, Tokameh Mahmoudi, Ming-Ming Zhou, Guillaume J Filion, Albert Jordan
Upon HIV-1 infection, a reservoir of latently infected resting T cells prevents the eradication of the virus from patients. To achieve complete depletion, the existing virus-suppressing antiretroviral therapy must be combined with drugs that reactivate the dormant viruses. We previously described a novel chemical scaffold compound, MMQO (8-methoxy-6-methylquinolin-4-ol) that is able to reactivate viral transcription in several models of HIV latency including J-Lat cells through an unknown mechanism. MMQO potentiates the activity of known latency-reversing agents (LRAs) or 'shock' drugs such as PKC agonists or HDAC inhibitors...
January 17, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29342458/glucocorticoids-modulate-th1-and-th2-responses-in-asthmatic-mouse-models-by-inhibition-of-notch1-signaling
#15
Chengping Hu, Zhifang Li, Juntao Feng, Yongjun Tang, Ling Qin, Xinyue Hu, Yan Zhang, Ruoxi He
BACKGROUND: Notch1 has been linked to the pathogenesis of asthma due to its contribution on Th1/Th2 imbalance. γ-Secretase inhibitor (GSI) acts as an effective blocker of Notch1 signaling. Glucocorticoids (GCs) are the most effective anti-inflammatory drugs for asthma. The present study investigated the involvement of the Notch1 pathway in the anti-inflammatory effect of GCs and its association with Th1/Th2 balance. METHODS: The asthma model was established in BALB/c mice by sensitization with ovalbumin (OVA)...
January 18, 2018: International Archives of Allergy and Immunology
https://www.readbyqxmd.com/read/29334172/silica-nanoparticle-induced-cytokine-responses-in-beas-2b-and-hbec3-kt-cells-significance-of-particle-size-and-signalling-pathways-in-different-lung-cell-cultures
#16
Marit Låg, Tonje Skuland, Anna Godymchuk, Thu H T Nguyen, Hang L T Pham, Magne Refsnes
We have previously reported that silica nanoparticles (SiNPs) of nominal size 50 nm (Si50) induce the pro-inflammatory cytokines CXCL8 and IL-6 in BEAS-2B cells, via mechanisms involving MAPK p38, TACE-mediated TGFα release and the NFκB pathway. In the present study, we examined whether these findings are cell-specific or might be extended to another epithelial lung cell model, HBEC3-KT, and also to SiNPs of a smaller size (nominal size of 10 nm; Si10). The TEM average size of Si10 and Si50 was 10.9 nm and 34...
January 15, 2018: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29333921/targeting-brd4-proteins-suppresses-the-growth-of-nsclc-through-downregulation-of-eif4e-expression
#17
Zhongyuan Gao, Ting Yuan, Xiao Zhou, Ping Ni, Geng Sun, Ping Li, Zhixiang Cheng, Xuerong Wang
Lung cancer is the leading cause of cancer-related death worldwide. Bromodomain and extraterminal domain (BET) proteins act as epigenome readers for gene transcriptional regulation. Among BET family members, BRD4 was well studied, but for its mechanism in non-small cell lung carcinoma has not been elucidated. eIF4E regulates gene translation and has been proved to play an important role in the progression of lung cancer. In this study, we first confirmed that BET inhibitors JQ1 and I-BET151 suppressed the growth of NSCLCs, in parallel with downregulated eIF4E expression...
January 15, 2018: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/29312470/combined-inhibition-of-bet-proteins-and-class-i-hdacs-synergistically-induces-apoptosis-in-urothelial-carcinoma-cell-lines
#18
Alexander S Hölscher, Wolfgang A Schulz, Maria Pinkerneil, Günter Niegisch, Michèle J Hoffmann
Background: New efficient therapies for urothelial carcinoma (UC) are urgently required. Small-molecule drugs targeting chromatin regulators are reasonable candidates because these regulators are frequently mutated or deregulated in UC. Indeed, in previous work, Romidepsin, which targets class I histone deacetylases (HDAC), efficiently killed UC cells, but did not elicit canonical apoptosis and affected benign urothelial cells indiscriminately. Combinations of HDAC inhibitors with JQ1, an inhibitor of bromodomain-containing acetylation reader proteins like BRD4, which promote especially the transcription of pro-tumorigenic genes, have shown efficacy in several tumor types...
2018: Clinical Epigenetics
https://www.readbyqxmd.com/read/29303513/in-vitro-modeling-of-hepatocellular-carcinoma-molecular-subtypes-for-anti-cancer-drug-assessment
#19
Hadassa Hirschfield, C Billie Bian, Takaaki Higashi, Shigeki Nakagawa, Tizita Z Zeleke, Venugopalan D Nair, Bryan C Fuchs, Yujin Hoshida
Tractable experimental model that accounts for inter-tumor molecular heterogeneity is a key element of anti-cancer drug development. Hepatocellular carcinoma is known to exhibit highly heterogeneous molecular aberrations across the tumors, including somatic genetic and epigenetic alterations. Previous studies showed that molecular tumor subtypes determined by transcriptome, as a comprehensive functional readout, are reproducibly observed across global patient populations irrespective of geographic and etiological variations...
January 5, 2018: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29298799/targeting-her2-aberrations-in-non-small-cell-lung-cancer-with-osimertinib
#20
Shengwu Liu, Shuai Li, Josephine Hai, Xiaoen Wang, Ting Chen, Max M Quinn, Peng Gao, Yanxi Zhang, Hongbin Ji, Darren Cross, Kwok-Kin Wong
PURPOSE: HER2 (or ERBB2) aberrations, including both amplification and mutations, have been classified as oncogenic drivers that contribute to 2-6 percent of lung adenocarcinomas. HER2 amplification is also an important mechanism for acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). However, due to limited preclinical studies and clinical trials, currently there is still no available standard of care for lung cancer patients with HER2 aberrations. To fulfill the clinical need for targeting HER2 in non-small cell lung cancer (NSCLC) patients, we performed a comprehensive pre-clinical study to evaluate the efficacy of a third-generation TKI, osimertinib (AZD9291)...
January 3, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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