scholarly journals Lack of detectable neoantigen depletion in the untreated cancer genome

2018 ◽  
Author(s):  
Jimmy Van den Eynden ◽  
Alejandro Jiménez-Sánchez ◽  
Martin L. Miller ◽  
Erik Larsson
Keyword(s):  
Immune Responses ◽  
Negative Selection ◽  
Somatic Mutations ◽  
Cancer Genomics ◽  
Mutation Rates ◽  
Mutational Signature ◽  
Wide Range ◽  
Hla Binding ◽  
Genomic Regions ◽  
Response Mutant

ABSTRACTSomatic mutations in cancer can result in the presentation of mutated peptides on the cell surface, eliciting an immune response. Mutant peptides are presented via HLA molecules and are known as neoantigens. It has been suggested that selection acts against the underlying mutations, leading to neoantigen depletion. Knowing the extent of this specific form of immunoediting may provide fundamental insights into tumour-immune interactions during tumour evolution. Here, we quantified the extent of neoantigen depletion in a wide range of human cancers by studying somatic mutations in the HLA-binding annotated exome, i.e. genomic regions that can be translated into presented peptides. We initially observed reduced non-synonymous mutation rates in presented regions, suggestive of neoantigen depletion. However, when compared to the expected mutation rates from a trinucleotide-based mutational signature model, depletion signals were negligible. This is explained by correlative relationships between the likelihood of mutagenesis in different nucleotide sequences and predicted HLA affinities for corresponding peptides. Our results suggest that signals of immunogenic negative selection are weak or absent in cancer genomics data and that other mechanisms to escape immune responses early during tumour evolution might be more efficient.

scholarly journals Somatic maintenance impacts the evolution of mutation rate

2017 ◽  
Author(s):  
Andrii Rozhok ◽  
James DeGregori
Keyword(s):  
Population Size ◽  
Negative Selection ◽  
Somatic Mutations ◽  
Elevated Risk ◽  
Mutation Rates ◽  
Reproduction Rate ◽  
Animal Evolution ◽  
Somatic Maintenance ◽  
Somatic Disorders ◽  
The Cost

AbstractThe evolution of multi-cellular animals has produced a conspicuous trend toward increased body size. This trend has introduced at least two novel problems: an elevated risk of somatic disorders, such as cancer, and declining evolvability due to reduced population size, lower reproduction rate and extended generation time. Low population size is widely recognized to explain the high mutation rates in animals by limiting the presumed universally negative selection acting on mutation rates. Here, we present evidence from stochastic modeling that the direction and strength of selection acting on mutation rates is highly dependent on the evolution of somatic maintenance, and thus longevity, which modulates the cost of somatic mutations. We argue that this mechanism may have been critical in facilitating animal evolution.

scholarly journals Effect of Resveratrol Dry Suspension on Immune Function of Piglets

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Qiuting Fu ◽  
Qiankun Cui ◽  
Yi Yang ◽  
Xinghong Zhao ◽  
Xu Song ◽  
...  
Keyword(s):  
Immune Responses ◽  
Immune Function ◽  
Foot And Mouth Disease ◽  
Classical Swine Fever ◽  
Sod Activity ◽  
Humoral And Cellular Immunity ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Mouth Disease Virus ◽  
Wide Range

Resveratrol, a polyphenolic plant antitoxin, has a wide range of pharmacological activities. In this study, we systematically evaluated the effects of resveratrol dry suspension (RDS) on immune function in piglets that were treated with different doses of RDS for 2 weeks. The results showed that the RDS has significant effects on the development, maturation, proliferation, and transformation of T lymphocytes. RDS could regulate humoral immune responses by upregulating the release of IFN-γ and downregulating the release of TNF-α. After piglets were vaccinated against classical swine fever virus and foot-and-mouth disease virus, the antibody titers were significantly increased. RDS treatment showed an excellent resistance to enhance T-SOD activity. Values of blood routine and blood biochemistry showed no toxicity. These results suggested that RDS could be considered as an adjuvant to enhance immune responses to vaccines, as well as dietary additives for animals to enhance humoral and cellular immunity.

scholarly journals The innate immune function of airway epithelial cells in inflammatory lung disease

2015 ◽  
Vol 45 (4) ◽  
pp. 1150-1162 ◽  
Author(s):  
Pieter S. Hiemstra ◽  
Paul B. McCray ◽  
Robert Bals
Keyword(s):  
Immune Responses ◽  
Airway Epithelium ◽  
Cell Function ◽  
Developmental Regulation ◽  
Airway Epithelial Cells ◽  
Chronic Obstructive ◽  
Airway Epithelial ◽  
Tissue Remodelling ◽  
Wide Range ◽  
Differentiation Pathways

The airway epithelium is now considered to be central to the orchestration of pulmonary inflammatory and immune responses, and is also key to tissue remodelling. It acts as the first barrier in the defence against a wide range of inhaled challenges, and is critically involved in the regulation of both innate and adaptive immune responses to these challenges. Recent progress in our understanding of the developmental regulation of this tissue, the differentiation pathways, recognition of pathogens and antimicrobial responses is now exploited to help understand how epithelial cell function and dysfunction contributes to the pathogenesis of a variety of inflammatory lung diseases. Herein, advances in our knowledge of the biology of airway epithelium, as well as its role and (dys)function in asthma, chronic obstructive pulmonary fibrosis and cystic fibrosis will be discussed.

scholarly journals Role of CxxC-finger protein 1 in establishing mouse oocyte epigenetic landscapes

2021 ◽  
Author(s):  
Qian-Qian Sha ◽  
Ye-Zhang Zhu ◽  
Yunlong Xiang ◽  
Jia-Li Yu ◽  
Xiao-Ying Fan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Histone H3 ◽  
Finger Protein ◽  
Maternal Genome ◽  
Wide Range ◽  
Transcriptional Changes ◽  
Nuclear Events ◽  
Genomic Regions ◽  
Cxxc Finger Protein 1

Abstract During oogenesis, oocytes gain competence and subsequently undergo meiotic maturation and prepare for embryonic development; trimethylated histone H3 on lysine-4 (H3K4me3) mediates a wide range of nuclear events during these processes. Oocyte-specific knockout of CxxC-finger protein 1 (CXXC1, also known as CFP1) impairs H3K4me3 accumulation and causes changes in chromatin configurations. This study investigated the changes in genomic H3K4me3 landscapes in oocytes with Cxxc1 knockout and the effects on other epigenetic factors such as the DNA methylation, H3K27me3, H2AK119ub1 and H3K36me3. H3K4me3 is overall decreased after knocking out Cxxc1, including both the promoter region and the gene body. CXXC1 and MLL2, which is another histone H3 methyltransferase, have nonoverlapping roles in mediating H3K4 trimethylation during oogenesis. Cxxc1 deletion caused a decrease in DNA methylation levels and affected H3K27me3 and H2AK119ub1 distributions, particularly at regions with high DNA methylation levels. The changes in epigenetic networks implicated by Cxxc1 deletion were correlated with the transcriptional changes in genes in the corresponding genomic regions. This study elucidates the epigenetic changes underlying the phenotypes and molecular defects in oocytes with deleted Cxxc1 and highlights the role of CXXC1 in orchestrating multiple factors that are involved in establishing the appropriate epigenetic states of maternal genome.

scholarly journals Pioneer: A New Tool for Coding of Multi-Level Finite State Machines Based on Evolution Programming

VLSI Design ◽  
1994 ◽  
Vol 2 (2) ◽  
pp. 105-116
Author(s):  
S. Muddappa ◽  
R. Z. Makki ◽  
Z. Michalewicz ◽  
S. Isukapalli
Keyword(s):  
Finite State Machines ◽  
Mutation Rates ◽  
Natural Phenomenon ◽  
State Machines ◽  
State Assignment ◽  
Wide Range ◽  
Finite State ◽  
Multi Level ◽  
Crossover And Mutation ◽  
Evolution Programs

In this paper we present a new tool for the encoding of multi-level finite state machines based on the concept of evolution programming. Evolution programs are stochastic adaptive algorithms, based on the paradigm of genetic algorithms whose search methods model some natural phenomenon: genetic inheritance and Darwinian strife for survival. Crossover and mutation rates were tailored to the state assignment problem experimentally. We present results over a wide range of MCNC benchmarks which demonstrate the effectiveness of the new tool. The results show that evolution programs can be effectively applied to state assignment.

scholarly journals Recent Advances in Nanovaccines Using Biomimetic Immunomodulatory Materials

Pharmaceutics ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 534 ◽  
Author(s):  
Vijayan ◽  
Mohapatra ◽  
Uthaman ◽  
Park
Keyword(s):  
Immune Responses ◽  
Targeted Delivery ◽  
Vaccine Development ◽  
Polymeric Nanoparticles ◽  
Vital Role ◽  
Effective Control ◽  
Therapeutic Vaccines ◽  
Hiv Therapy ◽  
Recent Advances ◽  
Wide Range

The development of vaccines plays a vital role in the effective control of several fatal diseases. However, effective prophylactic and therapeutic vaccines have yet to be developed for completely curing deadly diseases, such as cancer, malaria, HIV, and serious microbial infections. Thus, suitable vaccine candidates need to be designed to elicit appropriate immune responses. Nanotechnology has been found to play a unique role in the design of vaccines, providing them with enhanced specificity and potency. Nano-scaled materials, such as virus-like particles, liposomes, polymeric nanoparticles (NPs), and protein NPs, have received considerable attention over the past decade as potential carriers for the delivery of vaccine antigens and adjuvants, due to their beneficial advantages, like improved antigen stability, targeted delivery, and long-time release, for which antigens/adjuvants are either encapsulated within, or decorated on, the NP surface. Flexibility in the design of nanomedicine allows for the programming of immune responses, thereby addressing the many challenges encountered in vaccine development. Biomimetic NPs have emerged as innovative natural mimicking biosystems that can be used for a wide range of biomedical applications. In this review, we discuss the recent advances in biomimetic nanovaccines, and their use in anti-bacterial therapy, anti-HIV therapy, anti-malarial therapy, anti-melittin therapy, and anti-tumor immunity.

scholarly journals A Statistical Framework for Evolutionary Analysis of Recurrent Somatic Mutations in Cancers

2020 ◽  
Author(s):  
Xun Gu
Keyword(s):  
Somatic Mutations ◽  
Cancer Genomics ◽  
Computational Procedure ◽  
The Cancer Genome Atlas ◽  
Component Model ◽  
Evolutionary Analysis ◽  
Cancer Genes ◽  
Component Mixture ◽  
Two Component ◽  
Empirical Bayesian Method

AbstractCurrent cancer genomics databases have accumulated millions of somatic mutations that remain to be further explored, faciltating enormous high throuput analyses to explore the underlying mechanisms that may contribute to malignant initiation or progression. In the context of over-dominant passenger mutations (unrelated to cancers), the challenge is to identify somatic mutations that are cancer-driving. Under the notion that carcinogenesis is a form of somatic-cell evolution, we developed a two-component mixture model that enables to accomplish the following analyses. (i) We formulated a quasi-likelihood approach to test whether the two-component model is significantly better than a single-component model, which can be used for new cancer gene predicting. (ii) We implemented an empirical Bayesian method to calculate the posterior probabilities of a site to be cancer-driving for all sites of a gene, which can be used for new driving site predicting. (iii) We developed a computational procedure to calculate the somatic selection intensity at driver sites and passenger sites, respectively, as well as site-specific profiles for all sites. Using these newly-developed methods, we comprehensively analyzed 294 known cancer genes based on The Cancer Genome Atlas (TCGA) database.

scholarly journals Discovering the drivers of clonal hematopoiesis

2020 ◽  
Author(s):  
Oriol Pich ◽  
Iker Reyes-Salazar ◽  
Abel Gonzalez-Perez ◽  
Nuria Lopez-Bigas
Keyword(s):  
Positive Selection ◽  
Molecular Mechanisms ◽  
Somatic Mutations ◽  
Cancer Genomics ◽  
Variant Calling ◽  
Selective Advantage ◽  
Cancer Genes ◽  
Driver Genes ◽  
Hematopoietic Stem ◽  
Clonal Hematopoiesis

AbstractMutations in genes that confer a selective advantage to hematopoietic stem cells (HSCs) in certain conditions drive clonal hematopoiesis (CH). While some CH drivers have been identified experimentally or through epidemiological studies, the compendium of all genes able to drive CH upon mutations in HSCs is far from complete. We propose that identifying signals of positive selection in blood somatic mutations may be an effective way to identify CH driver genes, similarly as done to identify cancer genes. Using a reverse somatic variant calling approach, we repurposed whole-genome and whole-exome blood/tumor paired samples of more than 12,000 donors from two large cancer genomics cohorts to identify blood somatic mutations. The application of IntOGen, a robust driver discovery pipeline, to blood somatic mutations across both cohorts, and more than 24,000 targeted sequenced samples yielded a list of close to 70 genes with signals of positive selection in CH, available at http://www.intogen.org/ch. This approach recovers all known CH genes, and discovers novel candidates. Generating this compendium is an essential step to understand the molecular mechanisms of CH and to accurately detect individuals with CH to ascertain their risk to develop related diseases.

scholarly journals The DBL-1/TGF-β signaling pathway regulates pathogen-specific innate immune responses in C. elegans

2021 ◽  
Author(s):  
Bhoomi Madhu ◽  
Tina L. Gumienny
Keyword(s):  
Innate Immunity ◽  
Immune Responses ◽  
Signaling Pathway ◽  
Defense Responses ◽  
C Elegans ◽  
Host Immune Responses ◽  
Wide Range ◽  
Independent Functions ◽  
Multiple Cell

Innate immunity in animals is orchestrated by multiple cell signaling pathways, including the TGF-β; superfamily pathway. While the role of TGF-β signaling in innate immunity has been clearly identified, the requirement for this pathway in generating specific, robust responses to different bacterial challenges has not been characterized. Here, we address the role of DBL-1/TGF-β in regulating signature host defense responses to a wide range of bacteria in C. elegans. This work reveals a role of DBL-1/TGF-β in animal survival, organismal behaviors, and molecular responses in different environments. Additionally, we identify a novel role for SMA-4/Smad that suggests both DBL-1/TGF-β-dependent and -independent functions in host avoidance responses. RNA-seq analyses and immunity reporter studies indicate DBL-1/TGF-β differentially regulates target gene expression upon exposure to different bacteria. Furthermore, the DBL-1/TGF-β pathway is itself differentially affected by the bacteria exposure. Collectively, these findings demonstrate bacteria-specific host immune responses regulated by the DBL-1/TGF-β signaling pathway.

scholarly journals The RhoA-ROCK pathway in the regulation of T and B cell responses

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2295 ◽  
Author(s):  
Edd Ricker ◽  
Luvana Chowdhury ◽  
Woelsung Yi ◽  
Alessandra B. Pernis
Keyword(s):  
Immune Responses ◽  
Biological Processes ◽  
Dynamic Interactions ◽  
Cell Responses ◽  
Important Mediator ◽  
Downstream Effectors ◽  
Wide Range ◽  
Response To Stress ◽  
The Impact ◽  
Rho Kinases

Effective immune responses require the precise regulation of dynamic interactions between hematopoietic and non-hematopoietic cells. The Rho subfamily of GTPases, which includes RhoA, is rapidly activated downstream of a diverse array of biochemical and biomechanical signals, and is emerging as an important mediator of this cross-talk. Key downstream effectors of RhoA are the Rho kinases, or ROCKs. The ROCKs are two serine-threonine kinases that can act as global coordinators of a tissue’s response to stress and injury because of their ability to regulate a wide range of biological processes. Although the RhoA-ROCK pathway has been extensively investigated in the non-hematopoietic compartment, its role in the immune system is just now becoming appreciated. In this commentary, we provide a brief overview of recent findings that highlight the contribution of this pathway to lymphocyte development and activation, and the impact that dysregulation in the activation of RhoA and/or the ROCKs may exert on a growing list of autoimmune and lymphoproliferative disorders.

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