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https://www.readbyqxmd.com/read/28814673/human-lung-tumor-foxp-tregs-upregulate-four-treg-locking-transcription-factors
#1
Tatiana Akimova, Tianyi Zhang, Dmitri Negorev, Sunil Singhal, Jason Stadanlick, Abhishek Rao, Michael Annunziata, Matthew H Levine, Ulf H Beier, Joshua M Diamond, Jason D Christie, Steven M Albelda, Evgeniy B Eruslanov, Wayne W Hancock
Experimental data indicate that FOXP3+ Tregs can markedly curtail host antitumor immune responses, but the properties of human intratumoral Tregs are still largely unknown, in part due to significant methodologic problems. We studied the phenotypic, functional, epigenetic, and transcriptional features of Tregs in 92 patients with non-small-cell lung cancer, comparing the features of Tregs within tumors versus corresponding blood, lung, and lymph node samples. Intratumoral Treg numbers and suppressive function were significantly increased compared with all other sites but did not display a distinctive phenotype by flow cytometry...
August 17, 2017: JCI Insight
https://www.readbyqxmd.com/read/28808358/mbd2-regulates-th17-cell-differentiation-and-experimental-severe-asthma-by-affecting-irf4-expression
#2
Aijun Jia, Yueling Wang, Wenjin Sun, Bing Xiao, Yan Wei, Lulu Qiu, Lin Mu, Li Xu, Jianmin Li, Xiufeng Zhang, Da Liu, Cong Peng, Dongshan Zhang, Xudong Xiang
Th17 cells and IL-17 participate in airway neutrophil infiltration characteristics in the pathogenesis of severe asthma. Methyl-CpG binding domain protein 2 (MBD2) expression increased in CD4(+) T cells in peripheral blood samples of asthma patients. However, little is known about that epigenetic regulation of MBD2 in both immunological pathogenesis of experimental severe asthma and CD4(+) T cell differentiation. Here, we established a neutrophil-predominant severe asthma model, which was characterized by airway hyperresponsiveness (AHR), BALF neutrophil granulocyte (NEU) increase, higher NEU and IL-17 protein levels, and more Th17 cell differentiation...
2017: Mediators of Inflammation
https://www.readbyqxmd.com/read/28802050/distinct-dc-subsets-regulate-adaptive-th1-and-2-responses-during-trichuris-muris-infection
#3
Mimoza Demiri, Katarzyna Müller-Luda, William W Agace, Marcus Svensson-Frej
Low and high-dose infections with the murine large-intestinal nematode Trichuris muris are associated with induction of adaptive Th1 and Th2 responses, respectively, in mesenteric lymph nodes (MLN). Classical dendritic cells (cDC) accumulate in the large-intestinal mucosa and MLN upon T. muris infection, yet their role in driving adaptive responses to infection remains largely unknown. We performed low and high-dose T. muris infections of mice deficient in defined cDC subsets to investigate their role in induction of adaptive immune responses...
August 12, 2017: Parasite Immunology
https://www.readbyqxmd.com/read/28791349/ubiquitin-specific-peptidase-4-stabilizes-interferon-regulatory-factor-protein-and-promotes-its-function-to-facilitate-interleukin-4-expression-in-t-helper-type-2-cells
#4
Zhixiang Guo, Peng Xu, Shangqing Ge, Chengxin Zhang, Xiaoyan Zheng, Jinguo Xu, Zhuang Liu, Bin Li, Shenglin Ge
We speculated that ubiquitin specific peptidase 4 (USP4) may deubiquitinate interferon regulatory factor 4 (IRF4) and affect T helper type 2 (Th2) cell function. This study aimed to validate this hypothesis. Here, the interaction between USP4 and IRF4 were analyzed by co-immunoprecipitation assay. The deubiquitin effect of USP4 on IRF4 was analyzed by the Ni-NTA pull down assay. Luciferase reporter gene constructs were used to analyze the effects of USP4, IRF4 and nuclear factor of activated T cell-2 (NFATc2) on the activation of the interleukin-4 (IL-4) promoter...
August 3, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28755520/genetic-variation-in-irf4-expression-modulates-growth-characteristics-tyrosinase-expression-and-interferon-gamma-response-in-melanocytic-cells
#5
Yash Chhabra, Hilary X L Yong, Mitchell E Fane, Arish Soogrim, Wen Lim, Dayana Nur Mahiuddin, Reuben S Q Kim, Melinda Ashcroft, Scott A Beatson, Stephen A Ainger, Darren J Smit, Kasturee Jagirdar, Graeme J Walker, Richard A Sturm, Aaron G Smith
A SNP within intron4 of the Interferon Regulatory Factor4 (IRF4) gene, rs12203592*C/T has been independently associated with pigmentation and age-specific effects on nevus count in European-derived populations. We have characterised the cis-regulatory activity of this intronic region and using human foreskin-derived melanoblast strains we have explored the correlation between IRF4 rs12203592 homozygous C/C and T/T genotypes with TYR enzyme activity, supporting its association with pigmentation traits. Further, higher IRF4 protein levels directed by the rs12203592*C allele were associated with increased basal proliferation but decreased cell viability following UVR, an etiological factor in melanoma development...
July 29, 2017: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/28751557/the-bet-bromodomain-inhibitor-cpi203-improves-lenalidomide-and-dexamethasone-activity-in-in-vitro-and-in-vivo-models-of-multiple-myeloma-by-blockade-of-ikaros-and-myc-signaling
#6
Tania Díaz, Vanina Rodríguez, Ester Lozano, Mari-Pau Mena, Marcos Calderón, Laura Rosiñol, Antonio Martínez, Natalia Tovar, Patricia Pérez-Galán, Joan Bladé, Gaël Roué, Carlos Fernández de Larrea
Most of patients with multiple myeloma treated with current therapies, including immunomodulatory drugs, eventually develop relapsed/refractory disease. Clinical activity of lenalidomide relies on degradation of Ikaros and the consequently reduction on IRF4 expression, both required for myeloma cell survival and involved in the regulation of MYC transcription. Thus, we sought to determine the combinatorial effect of a MYC-interfering therapy with lenalidomide/dexamethasone. We analyzed the potential therapeutic effect of the combination of BET bromodomain inhibitor CPI203 with the lenalidomide/dexamethasone regimen in myeloma cell lines...
July 27, 2017: Haematologica
https://www.readbyqxmd.com/read/28738086/an-essential-ebv-latent-antigen-3c-binds-bcl6-for-targeted-degradation-and-cell-proliferation
#7
Yonggang Pei, Shuvomoy Banerjee, Hem Chandra Jha, Zhiguo Sun, Erle S Robertson
The latent EBV nuclear antigen 3C (EBNA3C) is required for transformation of primary human B lymphocytes. Most mature B-cell malignancies originate from malignant transformation of germinal center (GC) B-cells. The GC reaction appears to have a role in malignant transformation, in which a major player of the GC reaction is Bcl6, a key regulator of this process. We now demonstrate that EBNA3C contributes to B-cell transformation by targeted degradation of Bcl6. We show that EBNA3C can physically associate with Bcl6...
July 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28733463/tlr4-and-c5ar-crosstalk-in-dendritic-cells-induces-a-core-regulatory-network-of-rsk2-pi3k%C3%AE-sgk1-and-foxo-transcription-factors
#8
Anouk Zaal, Benjamin Nota, Kat S Moore, Miranda Dieker, S Marieke van Ham, Anja Ten Brinke
Crosstalk between complement component 5a receptors (C5aRs) and TLRs in dendritic cells (DCs) occurs upon pathogen invasion; however, studies on C5aR and TLR crosstalk mainly focused on the modulating effect of C5a on TLR-induced cytokine production. To elucidate the breadth of C5aR and TLR4 crosstalk, the effect of simultaneous treatment with C5a and LPS was investigated in human monocyte-derived DCs (moDCs) 2 h after stimulation using whole transcriptome sequencing analysis. Although the effect of C5a on hallmark genes defining TLR4-induced DC maturation was limited at this time point, RNA sequencing analysis revealed a great variety of novel C5a targets, of which many interfere with TLR4-mediated immune activation...
July 21, 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28723546/local-modulation-of-antigen-presenting-cell-development-after-resolution-of-pneumonia-induces-long-term-susceptibility-to-secondary-infections
#9
Antoine Roquilly, Hamish E G McWilliam, Cedric Jacqueline, Zehua Tian, Raphael Cinotti, Marie Rimbert, Linda Wakim, Irina Caminschi, Mireille H Lahoud, Gabrielle T Belz, Axel Kallies, Justine D Mintern, Karim Asehnoune, Jose A Villadangos
Lung infections cause prolonged immune alterations and elevated susceptibility to secondary pneumonia. We found that, after resolution of primary viral or bacterial pneumonia, dendritic cells (DC), and macrophages exhibited poor antigen-presentation capacity and secretion of immunogenic cytokines. Development of these "paralyzed" DCs and macrophages depended on the immunosuppressive microenvironment established upon resolution of primary infection, which involved regulatory T (Treg) cells and the cytokine TGF-β...
July 18, 2017: Immunity
https://www.readbyqxmd.com/read/28706201/genotypic-variability-based-association-identifies-novel-non-additive-loci-dhcr7-and-irf4-in-sero-negative-rheumatoid-arthritis
#10
Wen-Hua Wei, Sebastien Viatte, Tony R Merriman, Anne Barton, Jane Worthington
Sero-negative rheumatoid arthritis (RA) is a highly heterogeneous disorder with only a few additive loci identified to date. We report a genotypic variability-based genome-wide association study (vGWAS) of six cohorts of sero-negative RA recruited in Europe and the US that were genotyped with the Immunochip. A two-stage approach was used: (1) a mixed model to partition dichotomous phenotypes into an additive component and non-additive residuals on the liability scale and (2) the Levene's test to assess equality of the residual variances across genotype groups...
July 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28693749/primary-gastrointestinal-anaplastic-large-cell-lymphoma
#11
Yi-Ying Lee, Katsuyoshi Takata, Ren-Ching Wang, Sheau-Fang Yang, Shih-Sung Chuang
Primary gastrointestinal anaplastic large cell lymphoma (GI-ALCL) is rare. We report eight new cases. The median age was 61.5 years (range 10-88), most frequently involving the stomach (n = 3) and small intestine (n = 4). The neoplastic hallmark cells in all cases expressed CD30. Anaplastic lymphoma kinase (ALK) protein was expressed in two cases (25%). By in situ hybridisation, all cases were negative for Epstein-Barr virus and for DUSP22/IRF4 gene translocation. At a median follow-up time of 37.5 months, four patients died of disease, one was alive with disease, and three were disease-free...
August 2017: Pathology
https://www.readbyqxmd.com/read/28689197/nkl-homeobox-gene-msx1-acts-like-a-tumor-suppressor-in-nk-cell-leukemia
#12
Stefan Nagel, Claudia Pommerenke, Corinna Meyer, Maren Kaufmann, Roderick A F MacLeod, Hans G Drexler
NKL homeobox gene MSX1 is physiologically expressed in lymphoid progenitors and subsequently downregulated in developing T- and B-cells. In contrast, elevated expression levels of MSX1 persist in mature natural killer (NK)-cells, indicating a functional role in this compartment. While T-cell acute lymphoblastic leukemia (T-ALL) subsets exhibit aberrant overexpression of MSX1, we show here that in malignant NK-cells the level of MSX1 transcripts is aberrantly downregulated. Chromosomal deletions at 4p16 hosting the MSX1 locus have been described in NK-cell leukemia patients...
June 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/28658623/nod2-suppresses-colorectal-tumorigenesis-via-downregulation-of-the-tlr-pathways
#13
S M Nashir Udden, Lan Peng, Jia-Liang Gan, John M Shelton, James S Malter, Lora V Hooper, Md Hasan Zaki
Although NOD2 is the major inflammatory bowel disease susceptibility gene, its role in colorectal tumorigenesis is poorly defined. Here, we show that Nod2-deficient mice are highly susceptible to experimental colorectal tumorigenesis independent of gut microbial dysbiosis. Interestingly, the expression of inflammatory genes and the activation of inflammatory pathways, including NF-κB, ERK, and STAT3 are significantly higher in Nod2(-/-) mouse colons during colitis and colorectal tumorigenesis, but not at homeostasis...
June 27, 2017: Cell Reports
https://www.readbyqxmd.com/read/28649789/beyond-mitf-multiple-transcription-factors-directly-regulate-the-cellular-phenotype-in-melanocytes-and-melanoma
#14
REVIEW
Hannah E Seberg, Eric Van Otterloo, Robert A Cornell
MITF governs multiple steps in the development of melanocytes, including specification from neural crest, growth, survival, and terminal differentiation. In addition, the level of MITF activity determines the phenotype adopted by melanoma cells, whether invasive, proliferative, or differentiated. However, MITF does not act alone. Here we review literature on the transcription factors that co-regulate MITF-dependent genes. ChIP-seq studies have indicated that the transcription factors SOX10, YY1, and TFAP2A co-occupy subsets of regulatory elements bound by MITF in melanocytes...
June 26, 2017: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/28635957/itk-signalling-via-the-ras-irf4-pathway-regulates-the-development-and-function-of-tr1-cells
#15
Weishan Huang, Sabrina Solouki, Nicholas Koylass, Song-Guo Zheng, Avery August
Type 1 regulatory T (Tr1) cells differentiate in response to signals engaging the T cell receptor (TCR), express high levels of the immunosuppressive cytokine IL-10, but not Foxp3, and can suppress inflammation and promote immune tolerance. Here we show that ITK, an important modulator of TCR signalling, is required for the TCR-induced development of Tr1 cells in various organs, and in the mucosal system during parasitic and viral infections. ITK kinase activity is required for mouse and human Tr1 cell differentiation...
June 21, 2017: Nature Communications
https://www.readbyqxmd.com/read/28627735/genetic-alterations-in-adult-t-cell-leukemia-lymphoma
#16
REVIEW
Yasunori Kogure, Keisuke Kataoka
Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell neoplasm with a dismal prognosis, caused by human T-cell leukemia virus type-1 (HTLV-1) retrovirus. A long latency period from HTLV-1 infection to ATL onset suggests that not only HTLV-1 proteins, such as Tax and HBZ, but also additional genetic and/or epigenetic events are required for ATL development. Although many studies have demonstrated the biological functions of viral genes, alterations of cellular genes associated with ATL have not been fully investigated...
June 19, 2017: Cancer Science
https://www.readbyqxmd.com/read/28619709/loss-of-fam46c-promotes-cell-survival-in-myeloma
#17
Yuan Xiao Zhu, Chang-Xin Shi, Laura A Bruins, Patrick Jedlowski, Xuewei Wang, K Martin Kortüm, Moulun Luo, Jonathan M Ahmann, Esteban Braggio, A Keith Stewart
FAM46C is one of the most recurrently mutated genes in multiple myeloma; however its role in disease pathogenesis has not been determined. Here we demonstrate that wild-type (WT) FAM46C overexpression induces substantial cytotoxicity in multiple myeloma cells. In contrast, FAM46C mutations found in multiple myeloma patients abrogate this cytotoxicity, indicating a survival advantage conferred by the FAM46C mutant phenotype. WT FAM46C overexpression downregulated IRF4, CEBPB, and MYC and upregulated immunoglobulin (Ig) light chain and HSPA5/BIP Furthermore, pathway analysis suggests that enforced FAM46C expression activated the unfolded protein response pathway and induced mitochondrial dysfunction...
August 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28615301/irf4-dependent-cd103-cd11b-dendritic-cells-and-the-intestinal-microbiome-regulate-monocyte-and-macrophage-activation-and-intestinal-peristalsis-in-postoperative-ileus
#18
Judith-Mira Pohl, Sebastian Gutweiler, Stephanie Thiebes, Julia K Volke, Ludger Klein-Hitpass, Denise Zwanziger, Matthias Gunzer, Steffen Jung, William W Agace, Christian Kurts, Daniel Robert Engel
OBJECTIVE: Postoperative ileus (POI), the most frequent complication after intestinal surgery, depends on dendritic cells (DCs) and macrophages. Here, we have investigated the mechanism that activates these cells and the contribution of the intestinal microbiota for POI induction. DESIGN: POI was induced by manipulating the intestine of mice, which selectively lack DCs, monocytes or macrophages. The disease severity in the small and large intestine was analysed by determining the distribution of orally applied fluorescein isothiocyanate-dextran and by measuring the excretion time of a retrogradely inserted glass ball...
June 14, 2017: Gut
https://www.readbyqxmd.com/read/28600336/diagnosis-and-classification-of-hematologic-malignancies-on-the-basis-of-genetics
#19
REVIEW
Justin Taylor, Wenbin Xiao, Omar Abdel-Wahab
Genomic analysis has greatly influenced the diagnosis and clinical management of patients affected by diverse forms of hematologic malignancies. Here, we review how genetic alterations define subclasses of patients with acute leukemias, myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), non-Hodgkin lymphomas, and classical Hodgkin lymphoma. These include new subtypes of acute myeloid leukemia defined by mutations in RUNX1 or BCR-ABL1 translocations as well as a constellation of somatic structural DNA alterations in acute lymphoblastic leukemia...
July 27, 2017: Blood
https://www.readbyqxmd.com/read/28580944/il-17-producing-%C3%AE-%C3%AE-t-cells-switch-migratory-patterns-between-resting-and-activated-states
#20
Duncan R McKenzie, Ervin E Kara, Cameron R Bastow, Timona S Tyllis, Kevin A Fenix, Carly E Gregor, Jasmine J Wilson, Rachelle Babb, James C Paton, Axel Kallies, Stephen L Nutt, Anne Brüstle, Matthias Mack, Iain Comerford, Shaun R McColl
Interleukin 17-producing γδ T (γδT17) cells have unconventional trafficking characteristics, residing in mucocutaneous tissues but also homing into inflamed tissues via circulation. Despite being fundamental to γδT17-driven early protective immunity and exacerbation of autoimmunity and cancer, migratory cues controlling γδT17 cell positioning in barrier tissues and recruitment to inflammatory sites are still unclear. Here we show that γδT17 cells constitutively express chemokine receptors CCR6 and CCR2...
June 5, 2017: Nature Communications
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