scholarly journals Mutational patterns in oncogenes and tumour suppressors

2016 ◽  
Vol 44 (3) ◽  
pp. 925-931 ◽  
Author(s):  
Hanadi M. Baeissa ◽  
Graeme Benstead-Hume ◽  
Christopher J. Richardson ◽  
Frances M.G. Pearl
Keyword(s):  
Tumour Cell ◽  
Selective Advantage ◽  
Therapeutic Strategies ◽  
Human Proteome ◽  
Driver Mutations ◽  
Disease Progress ◽  
Tumour Suppressors ◽  
Cancer Initiation ◽  
The Impact ◽  
Automatic Pipeline

All cancers depend upon mutations in critical genes, which confer a selective advantage to the tumour cell. Knowledge of these mutations is crucial to understanding the biology of cancer initiation and progression, and to the development of targeted therapeutic strategies. The key to understanding the contribution of a disease-associated mutation to the development and progression of cancer, comes from an understanding of the consequences of that mutation on the function of the affected protein, and the impact on the pathways in which that protein is involved. In this paper we examine the mutation patterns observed in oncogenes and tumour suppressors, and discuss different approaches that have been developed to identify driver mutations within cancers that contribute to the disease progress. We also discuss the MOKCa database where we have developed an automatic pipeline that structurally and functionally annotates all proteins from the human proteome that are mutated in cancer.

Aberrant protein glycosylation in cancer: implications in targeted therapy

2021 ◽  
Author(s):  
Joana G. Rodrigues ◽  
Henrique O. Duarte ◽  
Celso A. Reis ◽  
Joana Gomes
Keyword(s):  
Targeted Therapy ◽  
Tumour Cell ◽  
Rational Design ◽  
Molecular Mechanisms ◽  
Clinical Performance ◽  
Therapeutic Strategies ◽  
Protein Glycosylation ◽  
Immune Checkpoints ◽  
Immunosuppressive Microenvironment ◽  
The Impact

Aberrant cell surface glycosylation signatures are currently known to actively drive the neoplastic transformation of healthy cells. By disrupting the homeostatic functions of their protein carriers, cancer-associated glycans mechanistically underpin several molecular hallmarks of human malignancy. Furthermore, such aberrant glycan structures play key roles in the acquisition of molecular resistance to targeted therapeutic agents, which compromises their clinical efficacy, by modulating tumour cell aggressiveness and supporting the establishment of an immunosuppressive microenvironment. Recent advances in the study of the tumour cell glycoproteome have unravelled previously elusive molecular mechanisms of therapeutic resistance, guided the rational design of novel personalized therapeutic strategies, and may further improve the clinical performance of currently approved anti-cancer targeted agents. In this review, we highlight the impact of glycosylation in cancer targeted therapy, with particular focus on receptor tyrosine kinase-targeted therapy, immune checkpoints blockade therapy, and current developments on therapeutic strategies directed to glycan-binding proteins and other innovative glycan therapeutic strategies.

Molecular Processes Involved in Pancreatic Cancer and Therapeutics

2020 ◽  
Vol 14 ◽  
Author(s):  
Subhajit Makar ◽  
Abhrajyoti Ghosh ◽  
Divya ◽  
Shalini Shivhare ◽  
Ashok Kumar ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Locally Advanced ◽  
Therapeutic Strategies ◽  
Screening Methods ◽  
Pancreatic Cancer Cells ◽  
Systemic Treatments ◽  
Cancer Initiation ◽  
Novel Therapeutic Strategies

: Despite advances in the development of cytotoxic and targeted therapies, pancreatic adenocarcinoma (PAC) remains a significant cause of cancer mortality worldwide. It is also difficult to detect it at an early stage due to numbers of factors. Most of the patients are present with locally advanced or metastatic disease, which precludes curative resection. In the absence of effective screening methods, considerable efforts have been made to identify better systemic treatments during the past decade. This review describes the recent advances in molecular mechanisms involved in pancreatic cancer initiation, progression, and metastasis. Additionally, the importance of deregulated cellular signalling pathways and various cellular proteins as potential targets for developing novel therapeutic strategies against incurable forms of pancreatic cancer is reported. The emphasis is on the critical functions associated with growth factors and their receptors viz. c-MET/HGF, CTHRC1, TGF-β, JAK-STAT, cyclooxygenase pathway, WNT, CCK, MAPK-RAS-RAF, PI3K-AKT, Notch, src, IGF-1R, CDK2NA and chromatin regulation for the sustained growth, survival, and metastasis of pancreatic cancer cells. It also includes various therapeutic strategies viz. immunotherapy, surgical therapy, radiation therapy and chemotherapy.

scholarly journals Clonal approaches to understanding the impact of mutations on hematologic disease development

Blood ◽  
2019 ◽  
Vol 133 (13) ◽  
pp. 1436-1445 ◽  
Author(s):  
Jyoti Nangalia ◽  
Emily Mitchell ◽  
Anthony R. Green
Keyword(s):  
Somatic Mutations ◽  
Clonal Selection ◽  
Single Cells ◽  
Driver Mutations ◽  
Great Promise ◽  
Tumor Evolution ◽  
Disease Development ◽  
Hematopoietic Tissue ◽  
The Impact

Abstract Interrogation of hematopoietic tissue at the clonal level has a rich history spanning over 50 years, and has provided critical insights into both normal and malignant hematopoiesis. Characterization of chromosomes identified some of the first genetic links to cancer with the discovery of chromosomal translocations in association with many hematological neoplasms. The unique accessibility of hematopoietic tissue and the ability to clonally expand hematopoietic progenitors in vitro has provided fundamental insights into the cellular hierarchy of normal hematopoiesis, as well as the functional impact of driver mutations in disease. Transplantation assays in murine models have enabled cellular assessment of the functional consequences of somatic mutations in vivo. Most recently, next-generation sequencing–based assays have shown great promise in allowing multi-“omic” characterization of single cells. Here, we review how clonal approaches have advanced our understanding of disease development, focusing on the acquisition of somatic mutations, clonal selection, driver mutation cooperation, and tumor evolution.

scholarly journals Consumption of Select Dietary Emulsifiers Exacerbates the Development of Spontaneous Intestinal Adenoma

2021 ◽  
Vol 22 (5) ◽  
pp. 2602
Author(s):  
Emilie Viennois ◽  
Benoit Chassaing
Keyword(s):  
Intestinal Inflammation ◽  
Tumor Development ◽  
Low Grade ◽  
Gastrointestinal Cancers ◽  
Cancer Initiation ◽  
And Function ◽  
The Impact ◽  
Chronic Intestinal Inflammation ◽  
Low Grade Inflammation ◽  
Intestinal Adenoma

Inflammation is a well-characterized critical driver of gastrointestinal cancers. Previous findings have shown that intestinal low-grade inflammation can be promoted by the consumption of select dietary emulsifiers, ubiquitous component of processed foods which alter the composition and function of the gut microbiota. Using a model of colitis-associated cancer, we previously reported that consumption of the dietary emulsifiers carboxymethylcellulose or polysorbate-80 exacerbated colonic tumor development. Here, we investigate the impact of dietary emulsifiers consumption on cancer initiation and progression in a genetical model of intestinal adenomas. In APCmin mice, we observed that dietary emulsifiers consumption enhanced small-intestine tumor development in a way that appeared to be independent of chronic intestinal inflammation but rather associated with emulsifiers’ impact on the proliferative status of the intestinal epithelium as well as on intestinal microbiota composition in both male and female mice. Overall, our findings further support the hypothesis that emulsifier consumption may be a new modifiable risk factor for colorectal cancer (CRC) and that alterations in host–microbiota interactions can favor gastrointestinal carcinogenesis in individuals with a genetical predisposition to such disorders.

The Impact of New Immunological Therapeutic Strategies on Recurrent Miscarriage and Recurrent Implantation Failure

2021 ◽  
Author(s):  
Forough Parhizkar ◽  
Roza Motavalli-Khiavi ◽  
Leili Aghebati-Maleki ◽  
Zahra Parhizkar ◽  
Ramin Pourakbari ◽  
...  
Keyword(s):  
Recurrent Miscarriage ◽  
Therapeutic Strategies ◽  
Implantation Failure ◽  
Recurrent Implantation Failure ◽  
The Impact

SARS-Coronavirus 2, A Metabolic Reprogrammer: A Review in the Context of the Possible Therapeutic Strategies

2021 ◽  
Vol 22 ◽  
Author(s):  
Poornima Gopi ◽  
TR Anju ◽  
Vinod Soman Pillai ◽  
Mohanan Veettil
Keyword(s):  
Virus Infection ◽  
Host Cell ◽  
Metabolic Pathways ◽  
Inflammatory Responses ◽  
Membrane Lipid ◽  
Therapeutic Strategies ◽  
Metabolic Reprogramming ◽  
Multiple Organs ◽  
The Cross ◽  
The Impact

: Novel coronavirus, SARS-CoV-2 is advancing at a staggering pace to devastate the health care system and foster the concerns over public health. In contrast to the past outbreaks, coronaviruses aren’t clinging themselves as a strict respiratory virus. Rather, becoming a multifaceted virus, it affects multiple organs by interrupting a number of metabolic pathways leading to significant rates of morbidity and mortality. Following infection they rigorously reprogram multiple metabolic pathways of glucose, lipid, protein, nucleic acid and their metabolites to extract adequate energy and carbon skeletons required for their existence and further molecular constructions inside a host cell. Although the mechanism of these alterations are yet to be known, the impact of these reprogramming is reflected in the hyper inflammatory responses, so called cytokine storm and the hindrance of host immune defence system. The metabolic reprogramming during SARS-CoV-2 infection needs to be considered while devising therapeutic strategies to combat the disease and its further complication. The inhibitors of cholesterol and phospholipids synthesis and cell membrane lipid raft of the host cell can, to a great extent, control the viral load and further infection. Depletion of energy source by inhibiting the activation of glycolytic and hexoseamine biosynthetic pathway can also augment the antiviral therapy. The cross talk between these pathways also necessitates the inhibition of amino acid catabolism and tryptophan metabolism. A combinatorial strategy which can address the cross talks between the metabolic pathways might be more effective than a single approach and the infection stage and timing of therapy will also influence the effectiveness of the antiviral approach. We herein focus on the different metabolic alterations during the course of virus infection that help to exploit the cellular machinery and devise a therapeutic strategy which promotes resistance to viral infection and can augment body’s antivirulence mechanisms. This review may cast the light into the possibilities of targeting altered metabolic pathways to defend virus infection in a new perspective.

scholarly journals Algorithmic Methods to Infer the Evolutionary Trajectories in Cancer Progression

2015 ◽  
Author(s):  
Giulio Caravagna ◽  
Alex Graudenzi ◽  
DANIELE RAMAZZOTTI ◽  
Rebeca Sanz-Pamplona ◽  
Luca De Sano ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Current Knowledge ◽  
Population Level ◽  
Selective Advantage ◽  
Explanatory Models ◽  
Driver Mutations ◽  
Cross Sectional ◽  
Progression Model ◽  
Colorectal Cancer Progression ◽  
Ngs Data

The genomic evolution inherent to cancer relates directly to a renewed focus on the voluminous next generation sequencing (NGS) data, and machine learning for the inference of explanatory models of how the (epi)genomic events are choreographed in cancer initiation and development. However, despite the increasing availability of multiple additional -omics data, this quest has been frustrated by various theoretical and technical hurdles, mostly stemming from the dramatic heterogeneity of the disease. In this paper, we build on our recent works on "selective advantage" relation among driver mutations in cancer progression and investigate its applicability to the modeling problem at the population level. Here, we introduce PiCnIc (Pipeline for Cancer Inference), a versatile, modular and customizable pipeline to extract ensemble-level progression models from cross-sectional sequenced cancer genomes. The pipeline has many translational implications as it combines state-of-the-art techniques for sample stratification, driver selection, identification of fitness-equivalent exclusive alterations and progression model inference. We demonstrate PiCnIc's ability to reproduce much of the current knowledge on colorectal cancer progression, as well as to suggest novel experimentally verifiable hypotheses.

scholarly journals Genetic polymorphisms mediating behavioural and immune response to pathogens may moderate the impact of the COVID-19 pandemic: a pilot study

2020 ◽  
Author(s):  
Ravi Philip Rajkumar
Keyword(s):  
Immune Response ◽  
Pilot Study ◽  
Immune Responses ◽  
Genetic Variants ◽  
Mortality Rates ◽  
Therapeutic Strategies ◽  
Published Data ◽  
Entire World ◽  
S Allele ◽  
The Impact

AbstractBackgroundThe COVID-19 pandemic has affected the entire world, but there are wide variations in prevalence and mortality across nations. Genetic variants which influence behavioural or immune responses to pathogens, selected for by pathogen pressure, may influence this variability. Two relevant polymorphisms in this context are the s allele of the serotonin transporter promoter (5-HTTLPR) and the G allele of the interleukin-6 gene (IL-6 rs1800795).MethodsThe frequencies of the 5-HTTLPR s allele and IL-6 rs1800795 G allele were obtained from published data. The correlations between these allele frequencies and the prevalence and mortality rates of COVID-19 were examined across 44 nations.ResultsThe IL-6 rs1800795 G allele was negatively correlated with COVID-19 prevalence (ρ = −0.466, p < 0.01) and mortality (ρ = −0.591, p<0.001) across nations. The 5-HTTLPR s allele was negatively correlated with COVID-19 mortality rates (ρ = −0.437, p = 0.023).ConclusionsThese results suggest that a significant relationship exists between genetic variants that influence behavioural and immune responses to pathogens and indices of the impact of COVID-19 across nations. Further investigation of these variants and their correlates may permit the development of better preventive or therapeutic strategies in the management of the COVID-19 pandemic.

scholarly journals Targeting Dietary and Microbial Tryptophan-Indole Metabolism as Therapeutic Approaches to Colon Cancer

2021 ◽  
Author(s):  
K. Leigh Greathouse ◽  
Madhur Wyatt
Keyword(s):  
Immune Surveillance ◽  
Microbial Transformation ◽  
Colon Carcinogenesis ◽  
Tryptophan Metabolism ◽  
Host Cells ◽  
Therapeutic Approaches ◽  
Therapeutic Modalities ◽  
Indolic Compounds ◽  
Cancer Initiation ◽  
The Impact

Tryptophan metabolism, via the kynurenine (Kyn) pathway, and microbial transformation of tryptophan to indolic compounds, are fundamental for host health; both of which are altered in colon carcinogenesis. Alterations in tryptophan metabolism begin early in colon carcinogenesis as an adaptive mechanism for the tumor to escape immune surveillance and metastasize. The microbial community is a key part of the tumor microenvironment and influences cancer initiation, promotion and treatment response. A growing awareness of the impact of the microbiome on tryptophan (Trp) metabolism in the context of carcinogenesis has prompted this review. We first compare the different metabolic pathways of Trp under normal cellular physiology to colon carcinogenesis, in both the host cells and the microbiome. Second, we review how the microbiome, specifically indoles, influence host tryptophan pathways under normal and oncogenic metabolism. We conclude by proposing several dietary, microbial and drug therapeutic modalities that can be utilized in combination to abrogate tumorigenesis.

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