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Neoepitopes

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https://www.readbyqxmd.com/read/29092006/novel-tools-to-assist-neoepitope-targeting-in-personalized-cancer-immunotherapy
#1
S K Saini, N Rekers, S R Hadrup
Current cancer immunotherapy approaches utilize the remarkable surveillance capacity of the human immune system, which is capable of recognizing and eliminating cancer cells based on identification of tumor-associated antigens arising as a consequence of the transformation process. Among these, mutational-derived neoepitopes have proved to be powerful targets for tumor elimination and mutational load has been shown to correlate with the clinical response to treatment with checkpoint inhibitors in many different tumor types...
October 30, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28976134/tumor-protein-53-mutations-mapping-to-its-tertiary-structure-with-in-silico-prediction-of-neoepitopic-vaccine-candidates-in-bone-tumors
#2
Hamid Nawaz Tipu, Abdul Rehman Arshad
Mapping of tp 53 mutations in bone cancers present in COSMIC database to its secondary and tertiary structure with in silico prediction of newly formed HLA binding epitopes as candidates for synthetic peptide vaccine. Mutations in bone cancers present in COSMIC database were listed and manually induced in wt p53 FASTA sequence. Wt p53 secondary structure was predicted. Template identified and tertiary structure of wt p53 was modelled in Cn3D followed by individual mutations mapping onto this model. HLA class I binding affinity was determined for mutated sequences to determine any newly binding peptide sequences...
September 2017: Journal of Experimental Therapeutics & Oncology
https://www.readbyqxmd.com/read/28961847/intratumoural-evolutionary-landscape-of-high-risk-prostate-cancer-the-progeny-study-of-genomic-and-immune-parameters
#3
M Linch, G Goh, C Hiley, Y Shanmugabavan, N McGranahan, A Rowan, Y N S Wong, H King, A Furness, A Freeman, J Linares, A Akarca, J Herrero, R Rosenthal, N Harder, G Schmidt, G A Wilson, N J Birkbak, R Mitter, S Dentro, P Cathcart, M Arya, E Johnston, R Scott, M Hung, M Emberton, G Attard, Z Szallasi, S Punwani, S A Quezada, T Marafioti, M Gerlinger, H U Ahmed, C Swanton
Background: Intratumoural heterogeneity (ITH) is well recognised in prostate cancer (PC), but its role in high-risk disease is uncertain. A prospective, single-arm, translational study using targeted multiregion prostate biopsies was carried out to study genomic and T-cell ITH in clinically high-risk PC aiming to identify drivers and potential therapeutic strategies. Patients and methods: Forty-nine men with elevated prostate-specific antigen and multiparametric-magnetic resonance imaging detected PC underwent image-guided multiregion transperineal biopsy...
October 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28959257/the-potential-and-challenges-of-exploiting-the-vast-but-dynamic-neoepitope-landscape-for-immunotherapy
#4
Els M E Verdegaal, Sjoerd H van der Burg
Somatic non-synonymous mutations in the DNA of tumor cells may result in the presentation of tumor-specific peptides to T cells. The recognition of these so-called neoepitopes now has been firmly linked to the clinical success of checkpoint blockade and adoptive T cell therapy. Following proof-of-principle studies in preclinical models there was a surge of strategies to identify and exploit genetically defined clonally expressed neoepitopes. These approaches assume that neoepitope availability remains stable during tumor progression but tumor genetics has taught us otherwise...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28954787/mutational-analysis-of-gene-fusions-predicts-novel-mhc-class-i-restricted-t-cell-epitopes-immune-signatures-in-a-subset-of-prostate-cancer
#5
Jennifer L Kalina, David S Neilson, Yen-Yi Lin, Phineas T Hamilton, Alexandra Paige Comber, Emma M H Loy, S Cenk Sahinalp, Colin C Collins, Faraz Hach, Julian J Lum
PURPOSE: Gene fusions are frequently found in prostate cancer and may result in the formation of unique chimeric amino acid sequences (CASQs) that span the breakpoint of two fused gene products. This study evaluated the potential for fusion-derived CASQs to be a source of tumor neoepitopes, and determined their relationship to patterns of immune signatures in prostate cancer patients Experimental Design: A computational strategy was used to identify CASQs and their corresponding predicted MHC class I epitopes using RNA-Seq data from The Cancer Genome Atlas of prostate tumors...
September 27, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28912897/genomic-analysis-of-tumor-microenvironment-immune-types-across-14-solid-cancer-types-immunotherapeutic-implications
#6
Yu-Pei Chen, Yu Zhang, Jia-Wei Lv, Ying-Qin Li, Ya-Qin Wang, Qing-Mei He, Xiao-Jing Yang, Ying Sun, Yan-Ping Mao, Jing-Ping Yun, Na Liu, Jun Ma
We performed a comprehensive immuno-genomic analysis of tumor microenvironment immune types (TMITs), which is classified into four groups based on PD-L1+CD8A or PD-L1+cytolytic activity (CYT) expression, across a broad spectrum of solid tumors in order to help identify patients who will benefit from anti- PD-1/PD-L1 therapy. The mRNA sequencing data from The Cancer Genome Atlas (TCGA) of 14 solid cancer types representing 6,685 tumor samples was analyzed. TMIT was classified only for those tumor types that both PD-L1 and CD8A/CYT could prefict mutation and/or neoantigen number...
2017: Theranostics
https://www.readbyqxmd.com/read/28880403/natural-igm-initiates-an-inflammatory-response-important-for-both-hepatic-ischemia-reperfusion-injury-and-regeneration
#7
Keely Marshall, Junfei Jin, Carl Atkinson, Ali Alawieh, Fei Qiao, Biao Lei, Kenneth D Chavin, Songqing He, Stephen Tomlinson
RATIONALE: Complement plays a role in both hepatic ischemia reperfusion (IR) injury (IRI) and liver regeneration, but it is not clear how complement is activated in either process. We investigated the role of self-reactive IgM antibodies in activating complement after hepatic IR and liver resection. MAIN RESULTS: Natural IgM antibodies that recognize danger associated molecular patterns (neoepitopes) activate complement following both hepatic IR and liver resection...
September 7, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28863006/intervertebral-disc-degeneration-in-a-percutaneous-mouse-tail-injury-model
#8
Zuozhen Tian, Xiaoyuan Ma, Miersalijiang Yasen, Robert L Mauck, Ling Qin, Frances S Shofer, Lachlan J Smith, Maurizio Pacifici, Motomi Enomoto-Iwamoto, Yejia Zhang
OBJECTIVES: Intervertebral disc (IVD) degenerates progressively with age and after injuries. In this study, we aimed to characterize early molecular events underlying disc degeneration using a mouse tail IVD injury model. DESIGN: We have established a transcutaneous minimally invasive approach to induce mouse tail IVD injury under fluoroscopic guidance. Morphological and molecular changes in the injured IVDs are compared with the baseline features of adjacent intact levels...
August 31, 2017: American Journal of Physical Medicine & Rehabilitation
https://www.readbyqxmd.com/read/28854978/the-neoepitope-landscape-in-pediatric-cancers
#9
Ti-Cheng Chang, Robert A Carter, Yongjin Li, Yuxin Li, Hong Wang, Michael N Edmonson, Xiang Chen, Paula Arnold, Terrence L Geiger, Gang Wu, Junmin Peng, Michael Dyer, James R Downing, Douglas R Green, Paul G Thomas, Jinghui Zhang
BACKGROUND: Neoepitopes derived from tumor-specific somatic mutations are promising targets for immunotherapy in childhood cancers. However, the potential for such therapies in targeting these epitopes remains uncertain due to a lack of knowledge of the neoepitope landscape in childhood cancer. Studies to date have focused primarily on missense mutations without exploring gene fusions, which are a major class of oncogenic drivers in pediatric cancer. METHODS: We developed an analytical workflow for identification of putative neoepitopes based on somatic missense mutations and gene fusions using whole-genome sequencing data...
August 31, 2017: Genome Medicine
https://www.readbyqxmd.com/read/28854952/clinical-implications-of-neoepitope-landscapes-for-adult-and-pediatric-cancers
#10
REVIEW
Yang-Yang Feng, Obi L Griffith, Malachi Griffith
Many immunotherapies rely on the presence of neoepitopes derived from somatic mutations that lead to altered peptide sequences. Several studies have now analyzed the neoepitope landscape of different cancer subtypes, predominantly for adult samples, which tend to feature significantly higher mutational burden. However, a new report publishing the first comprehensive analysis of the pediatric neoepitope landscape suggests that immunotherapies could also hold promise for pediatric cancers.See related research article 10...
August 31, 2017: Genome Medicine
https://www.readbyqxmd.com/read/28842325/c-terminal-processing-of-collagen-xvii-induces-neoepitopes-for-linear-iga-dermatosis-autoantibodies
#11
Ellen Toyonaga, Wataru Nishie, Kentaro Izumi, Ken Natsuga, Hideyuki Ujiie, Hiroaki Iwata, Jun Yamagami, Yoshiaki Hirako, Daisuke Sawamura, Wataru Fujimoto, Hiroshi Shimizu
Transmembrane collagen XVII (COL17) is a hemidesmosomal component of basal keratinocytes that can be targeted by autoantibodies in autoimmune blistering disorders, including linear IgA dermatosis (LAD). COL17 can be physiologically cleaved within the juxtamembranous extracellular NC16A domain, and LAD autoantibodies preferentially react with the processed ectodomains, indicating that the processing induces neoepitopes. However, the details of how neoepitopes develop have not been elucidated. In this study, we show that C-terminal processing of COL17 also plays a role in inducing neoepitopes for LAD autoantibodies...
August 24, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28841418/heterogeneous-tumor-immune-microenvironments-among-differentially-growing-metastases-in-an-ovarian-cancer-patient
#12
Alejandro Jiménez-Sánchez, Danish Memon, Stephane Pourpe, Harini Veeraraghavan, Yanyun Li, Hebert Alberto Vargas, Michael B Gill, Kay J Park, Oliver Zivanovic, Jason Konner, Jacob Ricca, Dmitriy Zamarin, Tyler Walther, Carol Aghajanian, Jedd D Wolchok, Evis Sala, Taha Merghoub, Alexandra Snyder, Martin L Miller
We present an exceptional case of a patient with high-grade serous ovarian cancer, treated with multiple chemotherapy regimens, who exhibited regression of some metastatic lesions with concomitant progression of other lesions during a treatment-free period. Using immunogenomic approaches, we found that progressing metastases were characterized by immune cell exclusion, whereas regressing and stable metastases were infiltrated by CD8(+) and CD4(+) T cells and exhibited oligoclonal expansion of specific T cell subsets...
August 24, 2017: Cell
https://www.readbyqxmd.com/read/28811969/k27m-mutant-histone-3-as-a-novel-target-for-glioma-immunotherapy
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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...
October 2017: Osteoarthritis and Cartilage
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