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https://www.readbyqxmd.com/read/28634284/co-administration-of-rankl-and-ctla4-antibodies-enhances-lymphocyte-mediated-anti-tumor-immunity-in-mice
#1
Elizabeth Ahern, Heidi Harjunpaa, Deborah Barkauskas, Stacey Allen, Kazuyoshi Takeda, Hideo Yagita, David Wyld, William C Dougall, Michele W L Teng, Mark J Smyth
Purpose: Novel partners for established immune checkpoint inhibitors in the treatment of cancer are needed to address the problems of primary and acquired resistance. The efficacy of combination RANKL and CTLA4 blockade in anti-tumor immunity has been suggested by recent case reports in melanoma. Here we provide a rationale for this combination in mouse models of cancer. <br />Experimental Design: The efficacy and mechanism of a combination of RANKL and CTLA4 blockade was examined by tumor infiltrating lymphocyte analysis, tumor growth and metastasis using a variety of neutralizing antibodies and gene-targeted mice...
June 20, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28633489/effects-of-early-pregnancy-on-uterine-lymphocytes-and-endometrial-expression-of-immune-regulatory-molecules-in-dairy-heifers1
#2
Sreelakshmi Vasudevan, Manasi M Kamat, Sadhat S Walusimbi, Joy L Pate, Troy L Ott
Natural killer (NK) cells are essential for establishment of human and rodent pregnancies. The function of these and other cytotoxic T cells (CTL) is controlled by stimulatory and inhibitory signaling. A role for cytotoxic cells during early pregnancy in cattle has not been described, but regulation of their function at the fetal-maternal interface is thought to be critical for conceptus survival. The hypothesis that the relative abundance of CTL and expression of inhibitory signaling molecules is increased by the conceptus during early pregnancy was tested...
June 19, 2017: Biology of Reproduction
https://www.readbyqxmd.com/read/28627735/genetic-alterations-in-adult-t-cell-leukemia-lymphoma
#3
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/28613437/t-cell-subsets-predicting-belatacept-resistant-rejection-finding-the-root-where-the-trouble-starts
#4
EDITORIAL
T Wekerle
The potential of costimulation blockade to revolutionize post-transplant immunosuppression has remained largely unfulfilled to date. Belatacept, the only costimulation blocker approved in organ transplant recipients, has not replaced the 30-plus-year-old CNIs as the mainstay of immunosuppression and is currently used infrequently. Modulating pathogenic immune responses through the interruption of costimulatory signals, which a naïve T cell requires for its full activation, has captivated immunologists since the demonstration that such costimulation blockade leads to antigen-specific immunomodulation (at least in vitro)...
June 14, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28611475/murine-lrba-deficiency-causes-ctla-4-deficiency-in-tregs-without-progression-to-immune-dysregulation
#5
Deborah Burnett, Ian Parish, Etienne Masle-Farquhar, Robert Brink, Christopher Goodnow
Inherited mutations in Lipopolysaccharide Responsive Beige-like Anchor (LRBA) cause a recessive human immune dysregulation syndrome with memory B cell and antibody deficiency (common variable immunodeficiency, CVID), inflammatory bowel disease, enlarged spleen and lymph nodes, accumulation of activated T cells, and multiple autoimmune diseases. To understand the pathogenesis of the syndrome, C57BL/6 mice carrying a homozygous truncating mutation in Lrba were produced using CRISPR/Cas9-mediated gene targeting...
June 14, 2017: Immunology and Cell Biology
https://www.readbyqxmd.com/read/28610825/integrating-next-generation-dendritic-cell-vaccines-into-the-current-cancer-immunotherapy-landscape
#6
REVIEW
Abhishek D Garg, Pierre G Coulie, Benoit J Van den Eynde, Patrizia Agostinis
Cancer immunotherapy is experiencing a renaissance spearheaded by immune checkpoint inhibitors (ICIs). This has spurred interest in 'upgrading' existing immunotherapies that previously experienced only sporadic success, such as dendritic cells (DCs) vaccines. In this review, we discuss the major molecular, immunological, and clinical determinants of existing first- and second-generation DC vaccines. We also outline the future trends for next-generation DC vaccines and describe their major hallmarks and prerequisites necessary for high anticancer efficacy...
June 10, 2017: Trends in Immunology
https://www.readbyqxmd.com/read/28609681/epigenetic-modulation-in-cancer-immunotherapy
#7
REVIEW
Stuart J Gallagher, Elena Shklovskaya, Peter Hersey
The success of immune checkpoint inhibitors in cancer immunotherapy has been widely heralded. However many cancer patients do not respond to immune checkpoint therapy and some relapse due to acquired tumor resistance. Epigenetic targeting may be beneficial in cancer immunotherapy by reversing immune avoidance and escape mechanisms employed by cancer cells, as well as by modulating immune cell differentiation and function. In this manuscript we review recent findings suggesting how epigenetics may be used to improve cancer immunotherapy...
June 10, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28601686/exaggerated-t-follicular-helper-cell-responses-in-lrba-deficiency-due-to-failure-of-ctla4-mediated-regulation
#8
Fayhan J Alroqi, Louis-Marie Charbonnier, Safa Baris, Ayca Kiykim, Janet Chou, Craig D Platt, Abdulrahman Algassim, Sevgi Keles, Bandar K Al Saud, Fowzan S Alkuraya, Michael Jordan, Raif S Geha, Talal A Chatila
PURPOSE: LRBA (lipopolysaccharide-responsive beige like anchor protein) and CTLA4 (cytotoxic T lymphocyte antigen 4) deficiencies give rise to overlapping phenotypes of immune dysregulation and autoimmunity, with dramatically increased frequencies of circulating T Follicular helper (cTFH) cells. We sought to determine the mechanisms of cTFH cell dysregulation in LRBA deficiency and the utility of monitoring cTFH cells as a correlate of clinical response to CTLA4-Ig therapy. METHODS: cTFH cells and other lymphocyte subpopulations were characterized...
June 7, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28600190/understanding-the-checkpoint-blockade-in-lung-cancer-immunotherapy
#9
REVIEW
Maria G Dal Bello, Angela Alama, Simona Coco, Irene Vanni, Francesco Grossi
Immunotherapies have changed the treatment strategy of some types of tumor including melanoma and, more recently, non-small-cell lung cancer (NSCLC). Immune checkpoints are crucial for the maintenance of self-tolerance and it is known that some tumors use checkpoint systems to evade antitumor immune response. The treatment of advanced NSCLC by immune-checkpoint blockade targeting the PD1/PDL1 and CTLA4 pathways has led to significant clinical benefit either as monotherapy or in combination therapy. Moreover, checkpoint receptors such as LAG3, TIM3 and KIRs are also being investigated as potential immunotherapeutic targets...
June 7, 2017: Drug Discovery Today
https://www.readbyqxmd.com/read/28592566/combined-immune-checkpoint-blockade-as-a-therapeutic-strategy-for-brca1-mutated-breast-cancer
#10
Emma Nolan, Peter Savas, Antonia N Policheni, Phillip K Darcy, François Vaillant, Christopher P Mintoff, Sathana Dushyanthen, Mariam Mansour, Jia-Min B Pang, Stephen B Fox, Charles M Perou, Jane E Visvader, Daniel H D Gray, Sherene Loi, Geoffrey J Lindeman
Immune checkpoint inhibitors have emerged as a potent new class of anticancer therapy. They have changed the treatment landscape for a range of tumors, particularly those with a high mutational load. To date, however, modest results have been observed in breast cancer, where tumors are rarely hypermutated. Because BRCA1-associated tumors frequently exhibit a triple-negative phenotype with extensive lymphocyte infiltration, we explored their mutational load, immune profile, and response to checkpoint inhibition in a Brca1-deficient tumor model...
June 7, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28581446/tregs-restrain-dendritic-cell-autophagy-to-ameliorate-autoimmunity
#11
Themis Alissafi, Aggelos Banos, Louis Boon, Tim Sparwasser, Alessandra Ghigo, Kajsa Wing, Dimitrios Vassilopoulos, Dimitrios Boumpas, Triantafyllos Chavakis, Ken Cadwell, Panayotis Verginis
Design of efficacious Treg-based therapies and establishment of clinical tolerance in autoimmune diseases have proven to be challenging. The clinical implementation of Treg immunotherapy has been hampered by various impediments related to the stability and isolation procedures of Tregs as well as the specific in vivo targets of Treg modalities. Herein, we have demonstrated that Foxp3+ Tregs potently suppress autoimmune responses in vivo through inhibition of the autophagic machinery in DCs in a cytotoxic T-lymphocyte-associated protein 4-dependent (CTLA4-dependent) manner...
June 5, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28575876/hdac-inhibitors-enhance-the-immunotherapy-response-of-melanoma-cells
#12
Laurence Booth, Jane L Roberts, Andrew Poklepovic, John Kirkwood, Paul Dent
We focused on the ability of the pan-histone deacetylase (HDAC) inhibitors AR42 and sodium valproate to alter the immunogenicity of melanoma cells. Treatment of melanoma cells with HDAC inhibitors rapidly reduced the expression of multiple HDAC proteins as well as the levels of PD-L1, PD-L2 and ODC, and increased expression of MHCA. In a cell-specific fashion, melanoma isolates released the immunogenic protein HMGB1 into the extracellular environment. Very similar data were obtained in ovarian and H&NSCC PDX isolates, and in established tumor cell lines from the lung and kidney...
May 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/28560327/antibody-mediated-neutralization-of-soluble-mic-significantly-enhances-ctla4-blockade-therapy
#13
Jingyu Zhang, Dai Liu, Guangfu Li, Kevin F Staveley-O'Carroll, Julie N Graff, Zihai Li, Jennifer D Wu
Antibody therapy targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA4) elicited survival benefits in cancer patients; however, the overall response rate is limited. In addition, anti-CTLA4 antibody therapy induces a high rate of immune-related adverse events. The underlying factors that may influence anti-CTLA4 antibody therapy are not well defined. We report the impact of a cancer-derived immune modulator, the human-soluble natural killer group 2D (NKG2D) ligand sMIC (soluble major histocompatibility complex I chain-related molecule), on the therapeutic outcome of anti-CTLA4 antibody using an MIC transgenic spontaneous TRAMP (transgenic adenocarcinoma of the mouse prostate)/MIC tumor model...
May 2017: Science Advances
https://www.readbyqxmd.com/read/28558959/the-transcriptional-landscape-of-p53-signalling-pathway
#14
Chizu Tanikawa, Yao-Zhong Zhang, Ryuta Yamamoto, Yusuke Tsuda, Masami Tanaka, Yuki Funauchi, Jinichi Mori, Seiya Imoto, Rui Yamaguchi, Yusuke Nakamura, Satoru Miyano, Hidewaki Nakagawa, Koichi Matsuda
Although recent cancer genomics studies have identified a large number of genes that were mutated in human cancers, p53 remains as the most frequently mutated gene. To further elucidate the p53-signalling network, we performed transcriptome analysis on 24 tissues in p53(+/+) or p53(-/-) mice after whole-body X-ray irradiation. Here we found transactivation of a total of 3551 genes in one or more of the 24 tissues only in p53(+/+) mice, while 2576 genes were downregulated. p53 mRNA expression level in each tissue was significantly associated with the number of genes upregulated by irradiation...
May 18, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28542175/single-sex-infection-with-female-schistosoma-mansoni-cercariae-mitigates-hepatic-fibrosis-after-secondary-infection
#15
Nicole Koslowski, Martina Sombetzki, Micha Loebermann, Robby Engelmann, Niels Grabow, Christoph H Österreicher, Michael Trauner, Brigitte Mueller-Hilke, Emil C Reisinger
BACKGROUND: Infection with Schistosoma spp. affects more than 258 million people worldwide. Current treatment strategies are mainly based on the anthelmintic Praziquantel, which is effective against adult worms but neither prevents re-infection nor cures severe liver damage. The best long-term strategy to control schistosomiasis may be to develop an immunization. Therefore, we designed a two-step Schistosoma mansoni infection model to study the immune-stimulating effect of a primary infection with either male or female cercariae, measured on the basis of TH1/TH2-response, granuloma size and hepatic fibrosis after a secondary bisexual S...
May 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28538872/melanoma-tumor-microenvironment-and-new-treatments
#16
Mara Huffenbaecher Giavina-Bianchi, Pedro Francisco Giavina-Bianchi, Cyro Festa
In the recent past years, many discoveries in the tumor microenvironment have led to changes in the management of melanoma and it is rising up hopes, specially, to those in advanced stages. FDA approved seven new drugs from 2011 to 2014. They are: Vemurafenib, Dabrafenib and Trametinib, kinases inhibitors used for patients that have BRAFV600E mutation; Ipilimumab (anti-CTLA4), Pembrolizumab (anti-PD-1) and Nivolumab (anti-PD-1), monoclonal antibodies that stimulate the immune system; and Peginterferon alfa-2b, an anti-proliferative cytokine used as adjuvant therapy...
March 2017: Anais Brasileiros de Dermatologia
https://www.readbyqxmd.com/read/28529997/pd-1-and-ctla4-two-checkpoints-one-pathway
#17
Lucy S K Walker
No abstract text is available yet for this article.
May 12, 2017: Science Immunology
https://www.readbyqxmd.com/read/28527946/the-microbiome-and-hepatobiliary-pancreatic-cancers
#18
Kosuke Mima, Shigeki Nakagawa, Hiroshi Sawayama, Takatsugu Ishimoto, Katsunori Imai, Masaaki Iwatsuki, Daisuke Hashimoto, Yoshifumi Baba, Yo-Ichi Yamashita, Naoya Yoshida, Akira Chikamoto, Hideo Baba
The human intestinal microbiome encompasses at least 100 trillion microorganisms that can influence host immunity and disease conditions, including cancer. Hepatobiliary and pancreatic cancers have been associated with poor prognosis owing to their high level of tumor invasiveness, distant metastasis, and resistance to conventional treatment options, such as chemotherapy. Accumulating evidence from animal models suggests that specific microbes and microbial dysbiosis can potentiate hepatobiliary-pancreatic tumor development by damaging DNA, activating oncogenic signaling pathways, and producing tumor-promoting metabolites...
May 17, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28520980/can-non-hla-single-nucleotide-polymorphisms-help-stratify-risk-in-trialnet-relatives-at-risk-for-type-1-diabetes
#19
Andrea K Steck, Ping Xu, Susan Geyer, Maria J Redondo, Peter Antinozzi, John M Wentworth, Jay Sosenko, Suna Onengut-Gumuscu, Wei-Min Chen, Stephen S Rich, Alberto Pugliese
Context: Genome-wide association studies identified >50 type 1 diabetes (T1D) associated non-HLA loci. Objective: The purpose of this study was to assess the contribution of non-HLA single nucleotide polymorphisms (SNPs) to risk of disease progression. Design and Setting: The TrialNet Pathway to Prevention Study follows relatives of T1D patients for development of autoantibodies (Ab) and T1D. Participants: Using the Immunochip, we analyzed 53 diabetes-associated, non-HLA SNPs in 1,016 Ab positive at risk non-Hispanic White relatives...
May 17, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28513269/immune-surveillance-in-melanoma-from-immune-attack-to-melanoma-escape-and-even-counterattack
#20
Fade Mahmoud, Bradley Shields, Issam Makhoul, Nathan Avaritt, Henry K Wong, Laura F Hutchins, Sara Shalin, Alan J Tackett
Pharmacologic inhibition of the cytotoxic T lymphocyte antigen 4 (CTLA4) and the programmed death receptor-1 (PD1) has resulted in unprecedented durable responses in metastatic melanoma. However, resistance to immunotherapy remains a major challenge. Effective immune surveillance against melanoma requires 4 essential steps: activation of the T lymphocytes, homing of the activated T lymphocytes to the melanoma microenvironment, identification and episode of melanoma cells by activated T lymphocytes, and the sensitivity of melanoma cells to apoptosis...
May 17, 2017: Cancer Biology & Therapy
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