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Neoepitopes

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https://www.readbyqxmd.com/read/28811969/k27m-mutant-histone-3-as-a-novel-target-for-glioma-immunotherapy
#1
Katharina Ochs, Martina Ott, Theresa Bunse, Felix Sahm, Lukas Bunse, Katrin Deumelandt, Jana K Sonner, Melanie Keil, Andreas von Deimling, Wolfgang Wick, Michael Platten
Mutation-specific vaccines have become increasingly important in glioma immunotherapy; however, shared neoepitopes are rare. For diffuse gliomas, a driver mutation in the gene for isocitrate dehydrogenase type-1 has been shown to produce an immunogenic epitope currently targeted in clinical trials. For highly aggressive midline gliomas, a recurrent point mutation in the histone-3 gene (H3F3A) causes an amino acid change from lysine to methionine at position 27 (K27M). Here, we demonstrate that a peptide vaccine against K27M-mutant histone-3 is capable of inducing effective, mutation-specific, cytotoxic T-cell- and T-helper-1-cell-mediated immune responses in a major histocompatibility complex (MHC)-humanized mouse model...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28769925/pharmacodynamic-monitoring-of-ro5459072-a-small-molecule-inhibitor-of-cathepsin-s
#2
Michel Theron, Darren Bentley, Sandra Nagel, Marianne Manchester, Michael Gerg, Thomas Schindler, Ana Silva, Barbara Ecabert, Priscila Teixeira, Camille Perret, Bernhard Reis
Major histocompatibility complex class II (MHCII)-restricted antigen priming of CD4(+) T cells is both involved in adaptive immune responses and the pathogenesis of autoimmune diseases. Degradation of invariant chain Ii, a protein that prevents premature peptide loading, is a prerequisite for nascent MHCII-peptide complex formation. A key proteolytic step in this process is mediated by cathepsin S. Inhibition of this cysteine protease is known to result in the intracellular accumulation of Lip10 in B cells...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28762987/autoreactive-t-cells-in-type-1-diabetes
#3
REVIEW
Alberto Pugliese
Type 1 diabetes (T1D) is a chronic autoimmune disease that causes severe loss of pancreatic β cells. Autoreactive T cells are key mediators of β cell destruction. Studies of organ donors with T1D that have examined T cells in pancreas, the diabetogenic insulitis lesion, and lymphoid tissues have revealed a broad repertoire of target antigens and T cell receptor (TCR) usage, with initial evidence of public TCR sequences that are shared by individuals with T1D. Neoepitopes derived from post-translational modifications of native antigens are emerging as novel targets that are more likely to evade self-tolerance...
August 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28751823/global-autorecognition-and-activation-of-complement-by-mannan-binding-lectin-in-a-mouse-model-of-type-1-diabetes
#4
Esben Axelgaard, Jakob Appel Østergaard, Saranda Haxha, Steffen Thiel, Troels Krarup Hansen
Increasing evidence links mannan-binding lectin (MBL) to late vascular complications of diabetes. MBL is a complement-activating pattern recognition molecule of the innate immune system that can mediate an inflammation response through activation of the lectin pathway. In two recent animal studies, we have shown that autoreactivity of MBL is increased in the kidney in diabetic nephropathy. We hypothesize that long-term exposure to uncontrolled high blood glucose in diabetes may mediate formation of neoepitopes in several tissues and that MBL is able to recognize these structures and thus activate the lectin pathway...
2017: Mediators of Inflammation
https://www.readbyqxmd.com/read/28737980/nitration-of-h2b-histone-elicits-an-immune-response-in-experimental-animals
#5
Md Asad Khan, Khursheed Alam, Syed Mehdi Hassan, M Moshahid A Rizvi
Histone H2B is an autoantigen that appears in circulation due to altered apoptosis/or insufficient clearance and is likely to be involved in the induction and progression of autoimmune diseases since modified-H2B is immunogenic. Our studies demonstrate that tyrosines of H2B histone spontaneously converts to free and nitrotyrosine bound protein in vivo. Commercially available H2B histone was modified with peroxynitrite in vitro. Modified H2B was found to be more immunogenic than native form in experimental animals...
July 24, 2017: Autoimmunity
https://www.readbyqxmd.com/read/28735021/wisp1-ccn4-aggravates-cartilage-degeneration-in-experimental-osteoarthritis
#6
M H van den Bosch, A B Blom, V Kram, A Maeda, S Sikka, Y Gabet, T M Kilts, W B van den Berg, P L van Lent, P M van der Kraan, M F Young
OBJECTIVE: Increased Wisp1 expression was previously reported in experimental and human osteoarthritis (OA). Moreover, adenoviral overexpression of Wisp1 in naïve mouse knee joints resulted in early OA-like cartilage lesions. Here, we determined how the matricellular protein WISP1 is involved in the pathology that occurs in the complex osteoarthritic environment with aging and experimental OA in wild type (WT) and Wisp1(-/-) mice. METHODS: WT and Wisp1(-/-) mice were aged or experimental OA was induced with intraarticular collagenase injection, destabilization of the medial meniscus (DMM) or anterior cruciate ligament transection (ACLT)...
July 19, 2017: Osteoarthritis and Cartilage
https://www.readbyqxmd.com/read/28698575/dual-non-contiguous-peptide-occupancy-of-hla-class-i-evoke-antiviral-human-cd8-t-cell-response-and-form-neo-epitopes-with-self-antigens
#7
Ziwei Xiao, Zhiyong Ye, Vikeramjeet Singh Tadwal, Meixin Shen, Ee Chee Ren
Host CD8 T cell response to viral infections involves recognition of 8-10-mer peptides presented by MHC-I molecules. However, proteasomes generate predominantly 2-7-mer peptides, but the role of these peptides is largely unknown. Here, we show that single short peptides of <8-mer from Latent Membrane Protein 2 (LMP2) of Epstein Barr Virus (EBV) can bind HLA-A*11:01 and stimulate CD8(+) cells. Surprisingly, two peptide fragments between 4-7-mer derived from LMP2(340-349) were able to complement each other, forming combination epitopes that can stimulate specific CD8(+) T cell responses...
July 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28689920/relationship-between-weight-loss-in-obese-knee-osteoarthritis-patients-and-serum-biomarkers-of-cartilage-breakdown-secondary-analyses-of-a-randomised-trial
#8
E M Bartels, Y Henrotin, H Bliddal, P Centonze, M Henriksen
OBJECTIVE: To explore effects of weight loss and maintenance on serum cartilage biomarkers denaturation neoepitope for Collagen2 (Coll2-1) and Fibulin3 fragment (Fib3-2), as well as correlations between Coll2-1 and Fib3-2 and symptomatic improvement, in a knee osteoarthritis (KOA) population. DESIGN: 192 obese KOA patients followed a 16 week weight loss intervention and 52 weeks weight maintenance (ClinicalTrials.gov identifier: NCT00655941). Assessments were at 0, 8, 16 and 68 weeks...
July 6, 2017: Osteoarthritis and Cartilage
https://www.readbyqxmd.com/read/28642243/anti-inflammatory-and-anti-osteoarthritis-effects-of-tectorigenin
#9
Cheng-Long Wang, De Li, Chuan-Dong Wang, Fei Xiao, Jun-Feng Zhu, Chao Shen, Bin Zuo, Yi-Min Cui, Hui Wang, Yuan Gao, Guo-Li Hu, Xiao-Ling Zhang, Xiao-Dong Chen
Osteoarthritis (OA) is a common and dynamic disease of the joints, including the articular cartilage, underlying bones and synovium. In particular, OA is considered as the degeneration of the cartilage. Tectorigenin (Tec) is known to affect many biological processes; however, its effects on articular chondrocytes remain unclear. This study aimed to assess the effects of Tec on articular cartilage. In vitro, Tec inhibited the expression levels of type X collagen, cyclooxigenase-2, matrix metalloproteinase (MMP)-3 and MMP-13, but enhanced the expression of Runx1, type II collagen and aggrecan in the presence of IL-1β...
August 15, 2017: Biology Open
https://www.readbyqxmd.com/read/28637898/activation-of-complement-by-pigment-epithelium-derived-factor-in-rheumatoid-arthritis
#10
Leonie M Vogt, Simone Talens, Ewa Kwasniewicz, Carsten Scavenius, André Struglics, Jan J Enghild, Tore Saxne, Anna M Blom
The aim of this study was to identify molecules that trigger complement activation in rheumatic joints. C4d, the final cleavage product of C4 activation, is found in the diseased joint and can bind covalently to complement-activating molecules. By using a highly specific Ab against a cleavage neoepitope in C4d, several molecules that were specifically bound to C4d were identified from pooled synovial fluid (SF) from four rheumatoid arthritis (RA) patients. One of these molecules, pigment epithelium-derived factor (PEDF), is a broadly expressed multifunctional member of the serine proteinase inhibitor family...
June 21, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28629465/natural-igm-antibodies-that-bind-neoepitopes-exposed-as-a-result-of-spinal-cord-injury-drive-secondary-injury-by-activating-complement
#11
Aarti Narang, Fei Qiao, Carl Atkinson, Hong Zhu, Xiaofeng Yang, Liudmila Kulik, V Michael Holers, Stephen Tomlinson
BACKGROUND: Natural IgM antibodies (Abs) function as innate immune sensors of injury via recognition of neoepitopes expressed on damaged cells, although how this recognition systems function following spinal cord injury (SCI) exposes various neoepitopes and their precise nature remains largely unknown. Here, we investigated the role of two natural IgM monoclonal Abs (mAbs), B4 and C2, that recognize post-ischemic neoepitopes following ischemia and reperfusion in other tissues. METHODS: Identification of post-SCI expressed neoepitopes was examined using previously characterized monoclonal Abs (B4 and C2 mAbs)...
June 19, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28610663/eculizumab-c5-complexes-express-a-c5a-neoepitope-in-vivo-consequences-for-interpretation-of-patient-complement-analyses
#12
Per H Nilsson, Anub Mathew Thomas, Grethe Bergseth, Alice Gustavsen, Elena B Volokhina, Lambertus P van den Heuvel, Andreas Barratt-Due, Tom E Mollnes
The complement system has obtained renewed clinical focus due to increasing number of patients treated with eculizumab, a monoclonal antibody inhibiting cleavage of C5 into C5a and C5b. The FDA approved indications are paroxysmal nocturnal haemoglobinuria and atypical haemolytic uremic syndrome, but many other diseases are candidates for complement inhibition. It has been postulated that eculizumab does not inhibit C5a formation in vivo, in contrast to what would be expected since it blocks C5 cleavage. We recently revealed that this finding was due to a false positive reaction in a C5a assay...
June 10, 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28601068/prevalence-of-autoantibodies-against-3-dg-glycated-h2a-protein-in-type-2-diabetes
#13
J M Ashraf, S M S Abdullah, S Ahmad, S Fatma, M H Baig, J Iqbal, A M Madkhali, A B A Jerah
Advanced glycation end-products (AGEs) have been found to be critically involved in initiation or progression of diabetes secondary complications (nephropathy, retinopathy, neuropathy, and angiopathy). Various hyper-glycating carbonyl compounds such as 3-deoxyglucosone (3-DG) are produced in pathophysiological conditions that form AGEs in high quantity both in vivo and in vitro. In the first stage of this study, we glycated histone H2A protein by 3-DG, and the results showed the formation of various intermediates and AGEs as well as structural changes in the protein...
May 2017: Biochemistry. Biokhimii︠a︡
https://www.readbyqxmd.com/read/28572258/immunotherapy-for-breast-cancer-what-are-we-missing
#14
EDITORIAL
Robert H Vonderheide, Susan M Domchek, Amy S Clark
The recent demonstration of modest single-agent activity of programmed death-ligand 1 (PD-L1) and programmed death receptor-1 (PD-1) antibodies in patients with breast cancer has generated hope that breast cancer can be made amenable to immunotherapy. Depending on the subtype of breast cancer, it is now clear in both primary and metastatic disease that the extent of tumor-infiltrating T cells is not only prognostic for survival but predictive of response to nonimmune, standard therapies. Despite these findings, immune cytolytic activity in spontaneous breast tumors, the burden of nonsynonymous tumor mutations, and the predicted load of neoepitopes-factors linked to response to checkpoint blockade in other malignancies-are all relatively modest in breast cancer compared with melanoma or lung cancer...
June 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28536262/in-silico-and-cell-based-analyses-reveal-strong-divergence-between-prediction-and-observation-of-t-cell-recognized-tumor-antigen-t-cell-epitopes
#15
COMPARATIVE STUDY
Julien Schmidt, Philippe Guillaume, Danijel Dojcinovic, Julia Karbach, George Coukos, Immanuel Luescher
Tumor exomes provide comprehensive information on mutated, overexpressed genes and aberrant splicing, which can be exploited for personalized cancer immunotherapy. Of particular interest are mutated tumor antigen T-cell epitopes, because neoepitope-specific T cells often are tumoricidal. However, identifying tumor-specific T-cell epitopes is a major challenge. A widely used strategy relies on initial prediction of human leukocyte antigen-binding peptides by in silico algorithms, but the predictive power of this approach is unclear...
July 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28533942/hla-a24-ligandome-analysis-of-colon-and-lung-cancer-cells-identifies-a-novel-cancer-testis-antigen-and-a-neoantigen-that-elicits-specific-and-strong-ctl-responses
#16
Vitaly Kochin, Takayuki Kanaseki, Serina Tokita, Sho Miyamoto, Yosuke Shionoya, Yasuhiro Kikuchi, Daichi Morooka, Yoshihiko Hirohashi, Tomohide Tsukahara, Kazue Watanabe, Shingo Toji, Yasuo Kokai, Noriyuki Sato, Toshihiko Torigoe
This study focused on HLA-A24 and comprehensively analyzed the ligandome of colon and lung cancer cells without the use of MHC-binding in silico prediction algorithms. Affinity purification using the antibody specific to HLA-A24 followed by LC-MS/MS sequencing was used to detect peptides, which harbored the known characteristics of HLA-A24 peptides in terms of length and anchor motifs. Ligandome analysis demonstrated the natural presentation of two different types of novel tumor-associated antigens. The ligandome contained a peptide derived from SUV39H2, a gene found to be expressed in a variety of cancers but not in normal tissues (except for the testis)...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28526919/antibodies-to-post-translationally-modified-insulin-as-a-novel-biomarker-for-prediction-of-type-1-diabetes-in-children
#17
Rocky Strollo, Chiara Vinci, Nicola Napoli, Paolo Pozzilli, Johnny Ludvigsson, Ahuva Nissim
AIMS/HYPOTHESIS: We have shown that autoimmunity to insulin in type 1 diabetes may result from neoepitopes induced by oxidative post-translational modifications (oxPTM). Antibodies specific to oxPTM-insulin (oxPTM-INS-Ab) are present in most newly diagnosed individuals with type 1 diabetes and are more common than autoantibodies to native insulin. In this study, we investigated whether oxPTM-INS-Ab are present before clinical onset of type 1 diabetes, and evaluated the ability of oxPTM-INS-Ab to identify children progressing to type 1 diabetes...
August 2017: Diabetologia
https://www.readbyqxmd.com/read/28511649/il-10-ameliorates-tnf-%C3%AE-induced-meniscus-degeneration-in-mature-meniscal-tissue-in-vitro
#18
P Behrendt, K Häfelein, A Preusse-Prange, A Bayer, A Seekamp, B Kurz
BACKGROUND: Joint inflammation causes meniscus degeneration and can exacerbate post-traumatic meniscus injuries by extracellular matrix degradation, cellular de-differentiation and cell death. The aim of this study was to examine whether anti-inflammatory interleukin-10 exerts protective effects in an in vitro model of TNF-α-induced meniscus degeneration. METHODS: Meniscus tissue was harvested from the knees of adult cows. After 24 h of equilibrium explants were simultaneously treated with bovine TNF-α and IL-10...
May 16, 2017: BMC Musculoskeletal Disorders
https://www.readbyqxmd.com/read/28473443/relationship-of-autoantibodies-to-mda-ldl-and-apob-immune-complexes-to-sex-ethnicity-subclinical-atherosclerosis-and-cardiovascular-events
#19
COMPARATIVE STUDY
Anand Prasad, Paul Clopton, Colby Ayers, Amit Khera, James A de Lemos, Joseph L Witztum, Sotirios Tsimikas
OBJECTIVE: Modifications of lipid constituents within atherosclerotic lesions generate neoepitopes that activate innate and adaptive immune responses. We aimed to define the prevalence, distribution, and relationship of autoantibody titers of oxidized lipoproteins to subclinical atherosclerosis and major adverse cardiovascular events (MACE) in different ethnic groups. APPROACH AND RESULTS: IgG and IgM autoantibodies to malondialdehyde-modified low-density lipoprotein (MDA-LDL) and apolipoprotein B-100-immune complexes were measured in 3509 individuals (1814 blacks, 1031 whites, 589 Hispanics, and 85 no race identifier) from the Dallas Heart Study with median 10...
June 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28473207/quantification-of-cartilage-oligomeric-matrix-protein-comp-and-a-comp-neoepitope-in-synovial-fluid-of-patients-with-different-joint-disorders-by-novel-automated-assays
#20
P Lorenzo, A Aspberg, T Saxne, P Önnerfjord
OBJECTIVE: To develop automated immunoassays for the quantification of Cartilage Oligomeric Matrix Protein (COMP) and a COMP neoepitope in synovial fluid and to investigate their diagnostic potential in different joint conditions. METHODS: Two sandwich immunoassays were developed for the quantification of COMP and a COMP neoepitope, using an automated analyser (IDS-iSYS, Immunodiagnostic Systems, Boldon, UK). Assay performance was evaluated in terms of sensitivity, recovery, linearity, and intra- and inter-assay precision...
May 2, 2017: Osteoarthritis and Cartilage
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