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https://www.readbyqxmd.com/read/28434881/muramyl-dipeptide-based-postbiotics-mitigate-obesity-induced-insulin-resistance-via-irf4
#1
Joseph F Cavallari, Morgan D Fullerton, Brittany M Duggan, Kevin P Foley, Emmanuel Denou, Brennan K Smith, Eric M Desjardins, Brandyn D Henriksbo, Kalvin J Kim, Brian R Tuinema, Jennifer C Stearns, David Prescott, Philip Rosenstiel, Brian K Coombes, Gregory R Steinberg, Jonathan D Schertzer
Intestinal dysbiosis contributes to obesity and insulin resistance, but intervening with antibiotics, prebiotics, or probiotics can be limited by specificity or sustained changes in microbial composition. Postbiotics include bacterial components such as lipopolysaccharides, which have been shown to promote insulin resistance during metabolic endotoxemia. We found that bacterial cell wall-derived muramyl dipeptide (MDP) is an insulin-sensitizing postbiotic that requires NOD2. Injecting MDP lowered adipose inflammation and reduced glucose intolerance in obese mice without causing weight loss or altering the composition of the microbiome...
April 6, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/28420429/deptor-maintains-plasma-cell-differentiation-and-favorably-affects-prognosis-in-multiple-myeloma
#2
Dalia Quwaider, Luis A Corchete, Irena Misiewicz-Krzeminska, María E Sarasquete, José J Pérez, Patryk Krzeminski, Noemí Puig, María Victoria Mateos, Ramón García-Sanz, Ana B Herrero, Norma C Gutiérrez
BACKGROUND: The B cell maturation process involves multiple steps, which are controlled by relevant pathways and transcription factors. The understanding of the final stages of plasma cell (PC) differentiation could provide new insights for therapeutic strategies in multiple myeloma (MM). Here, we explore the role of DEPTOR, an mTOR inhibitor, in the terminal differentiation of myeloma cells, and its potential impact on patient survival. METHODS: The expression level of DEPTOR in MM cell lines and B cell populations was measured by real-time RT-PCR, and/or Western blot analysis...
April 18, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28418867/early-detection-of-gastric-cancer-using-global-genome-wide-and-irf4-elmo1-clip4-and-msc-dna-methylation-in-endoscopic-biopsies
#3
Francesca Pirini, Sassan Noazin, Martha H Jahuira-Arias, Sebastian Rodriguez-Torres, Leah Friess, Christina Michailidi, Jaime Cok, Juan Combe, Gloria Vargas, William Prado, Ethan Soudry, Jimena Pérez, Tikki Yudin, Andrea Mancinelli, Helen Unger, Carmen Ili-Gangas, Priscilla Brebi-Mieville, Douglas E Berg, Masamichi Hayashi, David Sidransky, Robert H Gilman, Rafael Guerrero-Preston
Clinically useful molecular tools to triage gastric cancer patients are not currently available. We aimed to develop a molecular tool to predict gastric cancer risk in endoscopy-driven biopsies obtained from high-risk gastric cancer clinics in low resource settings.We discovered and validated a DNA methylation biomarker panel in endoscopic samples obtained from 362 patients seen between 2004 and 2009 in three high-risk gastric cancer clinics in Lima, Perú, and validated it in 306 samples from the Cancer Genome Atlas project ("TCGA")...
March 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28369050/antagonism-of-b-cell-enhancer-networks-by-stat5-drives-leukemia-and-poor-patient-survival
#4
Casey D S Katerndahl, Lynn M Heltemes-Harris, Mark J L Willette, Christine M Henzler, Seth Frietze, Rendong Yang, Hilde Schjerven, Kevin A T Silverstein, Laura B Ramsey, Gregory Hubbard, Andrew D Wells, Roland P Kuiper, Blanca Scheijen, Frank N van Leeuwen, Markus Müschen, Steven M Kornblau, Michael A Farrar
The transcription factor STAT5 has a critical role in B cell acute lymphoblastic leukemia (B-ALL). How STAT5 mediates this effect is unclear. Here we found that activation of STAT5 worked together with defects in signaling components of the precursor to the B cell antigen receptor (pre-BCR), including defects in BLNK, BTK, PKCβ, NF-κB1 and IKAROS, to initiate B-ALL. STAT5 antagonized the transcription factors NF-κB and IKAROS by opposing regulation of shared target genes. Super-enhancers showed enrichment for STAT5 binding and were associated with an opposing network of transcription factors, including PAX5, EBF1, PU...
April 3, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28368411/pu-1-acts-as-tumor-suppressor-for-myeloma-cells-through-direct-transcriptional-repression-of-irf4
#5
N Ueno, N Nishimura, S Ueno, S Endo, H Tatetsu, S Hirata, H Hata, M Matsuoka, H Mitsuya, Y Okuno
We previously reported that PU.1 is downregulated in the majority of myeloma cell lines and primary myeloma cells of certain myeloma patients, and conditional expression of PU.1 in such myeloma cell lines induced cell cycle arrest and apoptosis. We found downregulation of IRF4 protein in the U266 myeloma cell line following induction of PU.1. Previous studies reported that knockdown of IRF4 in myeloma cell lines induces apoptosis, prompting us to further investigate the role of IRF4 downregulation in PU.1-induced cell cycle arrest and apoptosis in myeloma cells...
April 3, 2017: Oncogene
https://www.readbyqxmd.com/read/28368397/molecular-impact-of-selective-nfkb1-and-nfkb2-signaling-on-dlbcl-phenotype
#6
X Guo, J L Koff, A B Moffitt, M Cinar, S Ramachandiran, Z Chen, J M Switchenko, M Mosunjac, S G Neill, K P Mann, M Bagirov, Y Du, Y Natkunam, H J Khoury, M R Rossi, W Harris, C R Flowers, I S Lossos, L H Boise, S S Dave, J Kowalski, L Bernal-Mizrachi
Diffuse large B-cell lymphoma (DLBCL) has been categorized into two molecular subtypes that have prognostic significance, namely germinal center B-cell like (GCB) and activated B-cell like (ABC). Although ABC-DLBCL has been associated with NF-κB activation, the relationships between activation of specific NF-κB signals and DLBCL phenotype remain unclear. Application of novel gene expression classifiers identified two new DLBCL categories characterized by selective p100 (NF-κB2) and p105 (NF-κB1) signaling...
April 3, 2017: Oncogene
https://www.readbyqxmd.com/read/28359033/regulation-of-memory-b-and-plasma-cell-differentiation
#7
REVIEW
Ryo Shinnakasu, Tomohiro Kurosaki
Memory B cell generation and antibody production result from a differentiation process that begins when the surface BCR on naïve B cells binds an antigen. How the choice between these fates is tempo-spatially regulated is still obscure, but recent advances have reinforced the concept that the combination of B cell-intrinsic heterogeneity and -extrinsic heterogeneity provided by cells such as T cells is a key determinant. As molecular regulators, the transcription factors IRF4 and Bach2, which participate in these fate choices, have been emerging...
March 27, 2017: Current Opinion in Immunology
https://www.readbyqxmd.com/read/28357165/persistent-afebrile-abdominal-pain-an-unusual-case-of-segmental-colitis-in-an-immunocompromised-host
#8
Ilias P Papakonstantinou, Emmanuel A Andreadis
In this report we describe a case of a 66-year-old woman who presented with right upper quadrant abdominal pain and bloody diarrhea. A workup revealed immunodeficiency, an immunologic profile with low complement levels resembling systemic lupus erythematosus, and a circumferential colonic wall lesion located in the ascending colon. After endoscopy and biopsy, the mass lesion was attributed to "double hit" diffuse large B-cell lymphoma, categorized as high grade large B-cell non-Hodgkin lymphoma according to the most recent revised 2016 World Health Organisation classification and considered to be a rare and highly aggressive tumor...
February 16, 2017: Curēus
https://www.readbyqxmd.com/read/28346410/quality-of-tcr-signaling-determined-by-differential-affinities-of-enhancers-for-the-composite-batf-irf4-transcription-factor-complex
#9
Arifumi Iwata, Vivek Durai, Roxane Tussiwand, Carlos G Briseño, Xiaodi Wu, Gary E Grajales-Reyes, Takeshi Egawa, Theresa L Murphy, Kenneth M Murphy
Variable strengths of signaling via the T cell antigen receptor (TCR) can produce divergent outcomes, but the mechanism of this remains obscure. The abundance of the transcription factor IRF4 increases with TCR signal strength, but how this would induce distinct types of responses is unclear. We compared the expression of genes in the TH2 subset of helper T cells to enhancer occupancy by the BATF-IRF4 transcription factor complex at varying strengths of TCR stimulation. Genes dependent on BATF-IRF4 clustered into groups with distinct TCR sensitivities...
May 2017: Nature Immunology
https://www.readbyqxmd.com/read/28338898/the-hematopoietic-cell-specific-transcription-factor-pu-1-is-critical-for-expression-of-cd11c
#10
Takuya Yashiro, Kazumi Kasakura, Yoshihito Oda, Nao Kitamura, Akihito Inoue, Shusuke Nakamura, Hokuto Yokoyama, Kanako Fukuyama, Mutsuko Hara, Hideoki Ogawa, Ko Okumura, Makoto Nishiyama, Chiharu Nishiyama
PU.1 is a hematopoietic cell-specific transcription factor belonging to the Ets family, which plays an important role in the development of dendritic cells (DCs). CD11c (encoded by Itgax) is well established as a characteristic marker of hematopoietic lineages including DCs. In the present study, we analyzed the role of PU.1 (encoded by Spi-1) in the expression of CD11c. When small interfering RNA (siRNA) for Spi-1 was introduced into bone marrow-derived DCs (BMDCs), the mRNA level and cell surface expression of CD11c were dramatically reduced...
February 1, 2017: International Immunology
https://www.readbyqxmd.com/read/28329691/myocardial-infarction-primes-autoreactive-t-cells-through-activation-of-dendritic-cells
#11
Katrien Van der Borght, Charlotte L Scott, Veronika Nindl, Ann Bouché, Liesbet Martens, Dorine Sichien, Justine Van Moorleghem, Manon Vanheerswynghels, Sofie De Prijck, Yvan Saeys, Burkhard Ludewig, Thierry Gillebert, Martin Guilliams, Peter Carmeliet, Bart N Lambrecht
Peripheral tolerance is crucial for avoiding activation of self-reactive T cells to tissue-restricted antigens. Sterile tissue injury can break peripheral tolerance, but it is unclear how autoreactive T cells get activated in response to self. An example of a sterile injury is myocardial infarction (MI). We hypothesized that tissue necrosis is an activator of dendritic cells (DCs), which control tolerance to self-antigens. DC subsets of a murine healthy heart consisted of IRF8-dependent conventional (c)DC1, IRF4-dependent cDC2, and monocyte-derived DCs...
March 21, 2017: Cell Reports
https://www.readbyqxmd.com/read/28320933/activin-a-co-opts-irf4-and-ahr-signaling-to-induce-human-regulatory-t-cells-that-restrain-asthmatic-responses
#12
Sofia Tousa, Maria Semitekolou, Ioannis Morianos, Aggelos Banos, Aikaterini I Trochoutsou, Tess M Brodie, Nikolaos Poulos, Konstantinos Samitas, Maria Kapasa, Dimitris Konstantopoulos, Giannis Paraskevopoulos, Mina Gaga, Catherine M Hawrylowicz, Federica Sallusto, Georgina Xanthou
Type 1 regulatory T (Tr1) cells play a pivotal role in restraining human T-cell responses toward environmental allergens and protecting against allergic diseases. Still, the precise molecular cues that underlie their transcriptional and functional specification remain elusive. Here, we show that the cytokine activin-A instructs the generation of CD4(+) T cells that express the Tr1-cell-associated molecules IL-10, inducible T-Cell costimulator (ICOS), lymphocyte activation gene 3 protein (LAG-3), and CD49b, and exert strongly suppressive functions toward allergic responses induced by naive and in vivo-primed human T helper 2 cells...
April 4, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28273354/mtorc2-controls-th9-polarization-and-allergic-airway-inflammation
#13
H Chen, L Zhang, P Wang, H Su, W Wang, Z Chu, L Zhang, X Zhang, Y Zhao
BACKGROUND: T helper type 9 (Th9) cells, a subpopulation of CD4(+) T cells, play a critical role in the pathogenesis of allergic airway inflammation. However, it remains unknown whether mTORC2 regulates Th9 differentiation or function during allergic inflammation. METHODS: T-cell-specific Rictor-deficient mice, a mouse model of allergic airway inflammation induced by ovalbumin (OVA) sensitization and a mouse model of adoptive transfer of induced Th9 cells, were used to address the roles of mTORC2 in the pathogenesis of allergic airway inflammation...
March 8, 2017: Allergy
https://www.readbyqxmd.com/read/28272467/meta-analysis-identifies-novel-risk-loci-and-yields-systematic-insights-into-the-biology-of-male-pattern-baldness
#14
Stefanie Heilmann-Heimbach, Christine Herold, Lara M Hochfeld, Axel M Hillmer, Dale R Nyholt, Julian Hecker, Asif Javed, Elaine G Y Chew, Sonali Pechlivanis, Dmitriy Drichel, Xiu Ting Heng, Ricardo C-H Del Rosario, Heide L Fier, Ralf Paus, Rico Rueedi, Tessel E Galesloot, Susanne Moebus, Thomas Anhalt, Shyam Prabhakar, Rui Li, Stavroula Kanoni, George Papanikolaou, Zoltán Kutalik, Panos Deloukas, Michael P Philpott, Gérard Waeber, Tim D Spector, Peter Vollenweider, Lambertus A L M Kiemeney, George Dedoussis, J Brent Richards, Michael Nothnagel, Nicholas G Martin, Tim Becker, David A Hinds, Markus M Nöthen
Male-pattern baldness (MPB) is a common and highly heritable trait characterized by androgen-dependent, progressive hair loss from the scalp. Here, we carry out the largest GWAS meta-analysis of MPB to date, comprising 10,846 early-onset cases and 11,672 controls from eight independent cohorts. We identify 63 MPB-associated loci (P<5 × 10(-8), METAL) of which 23 have not been reported previously. The 63 loci explain ∼39% of the phenotypic variance in MPB and highlight several plausible candidate genes (FGF5, IRF4, DKK2) and pathways (melatonin signalling, adipogenesis) that are likely to be implicated in the key-pathophysiological features of MPB and may represent promising targets for the development of novel therapeutic options...
March 8, 2017: Nature Communications
https://www.readbyqxmd.com/read/28264055/enhancement-of-pomalidomide-anti-tumor-response-with-acy-241-a-selective-hdac6-inhibitor
#15
Brian J North, Ingrid Almeciga-Pinto, David Tamang, Min Yang, Simon S Jones, Steven N Quayle
Thalidomide-based Immunomodulatory Drugs (IMiDs®), including lenalidomide and pomalidomide, are effective therapeutics for multiple myeloma. These agents have been approved with, or are under clinical development with, other targeted therapies including proteasome inhibitors, αCD38 monoclonal antibodies, as well as histone deacetylase (HDAC) inhibitors for combination therapy. HDAC inhibitors broadly targeting Class I and IIb HDACs have shown potent preclinical efficacy but have frequently demonstrated an undesirable safety profile in combination therapy approaches in clinical studies...
2017: PloS One
https://www.readbyqxmd.com/read/28263097/transcriptional-and-epigenetic-regulation-of-follicular-t-helper-cells-and-their-role-in-autoimmunity
#16
Hong Qiu, Haijing Wu, Vera Chan, Chak-Sing Lau, Qianjin Lu
T-follicular helper (Tfh) cells are a specialized subset of T cells that provide help to B cells and promote the formation of germinal centers (GCs). Tfh cells transmit important signals to B cells that drive class switch recombination, somatic hyper-mutation, the generation of high-affinity antibodies, immunological memory and their differentiation into plasma cells or memory B cells in the GCs. Tfh-cell differentiation is regulated by the coordinated functions of distinct cytokines, including interleukin (IL)-6, IL-21, IL-12, IL-23, IL-2, IL-7 and transforming growth factor-β (TGF-β), as well as transcription factors, including B-cell lymphoma 6 protein (Bcl-6), Signal transducers and activators of transcription (STAT)1, STAT3, STAT4, B-cell activating transcription factor (Batf), interferon regulatory factor 4 (IRF4), v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (C-Maf), T-cell-specific transcription factor 1 (TCF-1) and Achaete-scute homolog 2 (Acl2), which have been shown to form a complex transcriptional network...
March 2017: Autoimmunity
https://www.readbyqxmd.com/read/28262505/distinct-roles-of-brd2-and-brd4-in-potentiating-the-transcriptional-program-for-th17-cell-differentiation
#17
Ka Lung Cheung, Fan Zhang, Anbalagan Jaganathan, Rajal Sharma, Qiang Zhang, Tsuyoshi Konuma, Tong Shen, June-Yong Lee, Chunyan Ren, Chih-Hung Chen, Geming Lu, Matthew R Olson, Weijia Zhang, Mark H Kaplan, Dan R Littman, Martin J Walsh, Huabao Xiong, Lei Zeng, Ming-Ming Zhou
The BET proteins are major transcriptional regulators and have emerged as new drug targets, but their functional distinction has remained elusive. In this study, we report that the BET family members Brd2 and Brd4 exert distinct genomic functions at genes whose transcription they co-regulate during mouse T helper 17 (Th17) cell differentiation. Brd2 is associated with the chromatin insulator CTCF and the cohesin complex to support cis-regulatory enhancer assembly for gene transcriptional activation. In this context, Brd2 binds the transcription factor Stat3 in an acetylation-sensitive manner and facilitates Stat3 recruitment to active enhancers occupied with transcription factors Irf4 and Batf...
March 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28251349/prognostic-significance-of-interferon-regulating-factor-4-irf4-in-node-negative-breast-cancer
#18
Anne-Sophie Heimes, K Madjar, K Edlund, M J Battista, K Almstedt, S Gebhard, S Foersch, J Rahnenführer, W Brenner, A Hasenburg, J G Hengstler, M Schmidt
PURPOSE: The transcription factor IRF4 regulates immunoglobulin class switch recombination as well as plasma cell differentiation. We examined the prognostic significance of IRF4 expression in node-negative breast cancer (BC). METHODS: IRF4 expression was evaluated by immunostaining in a cohort of 197 node-negative BC patients not treated in adjuvant setting, referred to as Mainz cohort. The prognostic significance of immunohistochemically determined IRF4 expression for metastasis-free survival (MFS) was examined by Kaplan-Meier survival analysis as well as univariate and multivariate Cox analysis adjusted for age, pT stage, histological grade, ER, and HER2 status...
March 1, 2017: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/28245601/distinct-antigen-delivery-systems-induce-dendritic-cells-divergent-transcriptional-response-new-insights-from-a-comparative-and-reproducible-computational-analysis
#19
Valerio Costa, Dario Righelli, Francesco Russo, Piergiuseppe De Berardinis, Claudia Angelini, Luciana D'Apice
Vaccination is the most successful and cost-effective method to prevent infectious diseases. However, many vaccine antigens have poor in vivo immunogenic potential and need adjuvants to enhance immune response. The application of systems biology to immunity and vaccinology has yielded crucial insights about how vaccines and adjuvants work. We have previously characterized two safe and powerful delivery systems derived from non-pathogenic prokaryotic organisms: E2 and fd filamentous bacteriophage systems. They elicit an in vivo immune response inducing CD8+ T-cell responses, even in absence of adjuvants or stimuli for dendritic cells' maturation...
February 25, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28245413/-research-progress-in-transgenic-animal-models-of-chronic-lymphocytic-leukemia-review
#20
Fang-Tian Wu, Wei Xu, Jian-Yong Li
Transgenic mouse models of chronic lymphocytic leukemia (CLL) are crucially required for the elucidation of the underlying pathogenic mechanisms and for finding new therapies. So far, several mouse models have been established, mimicking either genetic aberrations or dysregulated gene expression in CLL. Among all the models, TCL1 transgenic model is the most commonly used one. Additionally, there are also other models, such as 13q14-deletion model. In this review, the major genetically engineered mouse models of CLL in current use are summarized, the main problems include TCL-1 transgenic mice, miR15a/16-1 gene knockdown mice and miR29 transgeneic mice, BAFF and APRIL transgeneic mice, BCL-2:Traf2DN double transgeneic mice, IRF4(-/-)Vh11 transgeneic mice and so on...
February 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
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