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JACC. Advances Sep 2023
PubMed: 38939475
DOI: 10.1016/j.jacadv.2023.100572 -
Cells Aug 2023RECQ5, a member of the conserved RECQ helicase family, is the sole human RECQ homolog that has not been linked to a hereditary developmental syndrome. Nonetheless,... (Review)
Review
RECQ5, a member of the conserved RECQ helicase family, is the sole human RECQ homolog that has not been linked to a hereditary developmental syndrome. Nonetheless, dysregulation of RECQ5 has emerged as a significant clinical concern, being linked to cancer predisposition, cardiovascular disease, and inflammation. In cells, RECQ5 assumes a crucial role in the regulation of DNA repair pathways, particularly in the repair of DNA double-strand breaks and inter-strand DNA crosslinks. Moreover, RECQ5 exhibits a capacity to modulate gene expression by interacting with transcription machineries and their co-regulatory proteins, thus safeguarding against transcription-induced DNA damage. This review aims to provide an overview of the multifaceted functions of RECQ5 and its implications in maintaining genomic stability. We will discuss the potential effects of clinical variants of RECQ5 on its cellular functions and their underlying mechanisms in the pathogenesis of cancer and cardiovascular disease. We will review the impact of RECQ5 variants in the field of pharmacogenomics, specifically their influence on drug responses, which may pave the way for novel therapeutic interventions targeting RECQ5 in human diseases.
Topics: Humans; Cardiovascular Diseases; DNA; RecQ Helicases; DNA Breaks, Double-Stranded; DNA Damage
PubMed: 37626846
DOI: 10.3390/cells12162037 -
Frontiers in Genetics 2023
PubMed: 37964778
DOI: 10.3389/fgene.2023.1308169 -
EBioMedicine Mar 2024Pharmacogenomics (PGx) holds promise to revolutionize modern healthcare. Although there are several prospective clinical studies in oncology and cardiology,...
BACKGROUND
Pharmacogenomics (PGx) holds promise to revolutionize modern healthcare. Although there are several prospective clinical studies in oncology and cardiology, demonstrating a beneficial effect of PGx-guided treatment in reducing adverse drug reactions, there are very few such studies in psychiatry, none of which spans across all main psychiatric indications, namely schizophrenia, major depressive disorder and bipolar disorder. In this study we aim to investigate the clinical effectiveness of PGx-guided treatment (occurrence of adverse drug reactions, hospitalisations and re-admissions, polypharmacy) and perform a cost analysis of the intervention.
METHODS
We report our findings from a multicenter, large-scale, prospective study of pre-emptive genome-guided treatment named as PREemptive Pharmacogenomic testing for preventing Adverse drug REactions (PREPARE) in a large cohort of psychiatric patients (n = 1076) suffering from schizophrenia, major depressive disorder and bipolar disorder.
FINDINGS
We show that patients with an actionable phenotype belonging to the PGx-guided arm (n = 25) present with 34.1% less adverse drug reactions compared to patients belonging to the control arm (n = 36), 41.2% less hospitalisations (n = 110 in the PGx-guided arm versus n = 187 in the control arm) and 40.5% less re-admissions (n = 19 in the PGx-guided arm versus n = 32 in the control arm), less duration of initial hospitalisations (n = 3305 total days of hospitalisation in the PGx-guided arm from 110 patients, versus n = 6517 in the control arm from 187 patients) and duration of hospitalisation upon readmission (n = 579 total days of hospitalisation upon readmission in the PGx-guided arm, derived from 19 patients, versus n = 928 in the control arm, from 32 patients respectively). It was also shown that in the vast majority of the cases, there was less drug dose administrated per drug in the PGx-guided arm compared to the control arm and less polypharmacy (n = 124 patients prescribed with at least 4 psychiatric drugs in the PGx-guided arm versus n = 143 in the control arm) and smaller average number of co-administered psychiatric drugs (2.19 in the PGx-guided arm versus 2.48 in the control arm. Furthermore, less deaths were reported in the PGx-guided arm (n = 1) compared with the control arm (n = 9). Most importantly, we observed a 48.5% reduction of treatment costs in the PGx-guided arm with a reciprocal slight increase of the quality of life of patients suffering from major depressive disorder (0.935 versus 0.925 QALYs in the PGx-guided and control arm, respectively).
INTERPRETATION
While only a small proportion (∼25%) of the entire study sample had an actionable genotype, PGx-guided treatment can have a beneficial effect in psychiatric patients with a reciprocal reduction of treatment costs. Although some of these findings did not remain significant when all patients were considered, our data indicate that genome-guided psychiatric treatment may be successfully integrated in mainstream healthcare.
FUNDING
European Union Horizon 2020.
Topics: Humans; Pharmacogenetics; Prospective Studies; Depressive Disorder, Major; Quality of Life; Psychiatry; Drug-Related Side Effects and Adverse Reactions
PubMed: 38364700
DOI: 10.1016/j.ebiom.2024.105009 -
Journal of Personalized Medicine Nov 2023Rheumatoid arthritis (RA) is a chronic autoimmune disorder that has a significant impact on quality of life and work capacity. Treatment of RA aims to control... (Review)
Review
Rheumatoid arthritis (RA) is a chronic autoimmune disorder that has a significant impact on quality of life and work capacity. Treatment of RA aims to control inflammation and alleviate pain; however, achieving remission with minimal toxicity is frequently not possible with the current suite of drugs. This review aims to summarise current treatment practices and highlight the urgent need for alternative pharmacogenomic approaches for novel drug discovery. These approaches can elucidate new relationships between drugs, genes, and diseases to identify additional effective and safe therapeutic options. This review discusses how computational approaches such as connectivity mapping offer the ability to repurpose FDA-approved drugs beyond their original treatment indication. This review also explores the concept of drug sensitisation to predict co-prescribed drugs with synergistic effects that produce enhanced anti-disease efficacy by involving multiple disease pathways. Challenges of this computational approach are discussed, including the availability of suitable high-quality datasets for comprehensive analysis and other data curation issues. The potential benefits include accelerated identification of novel drug combinations and the ability to trial and implement established treatments in a new index disease. This review underlines the huge opportunity to incorporate disease-related data and drug-related data to develop methods and algorithms that have strong potential to determine novel and effective treatment regimens.
PubMed: 38138860
DOI: 10.3390/jpm13121633 -
Asian Biomedicine : Research, Reviews... Jun 2023Statins are the most widely used lipid-lowering agents for patients with hyperlipidemia. However, interindividual variations in efficacy and risk of adverse drug... (Review)
Review
BACKGROUND
Statins are the most widely used lipid-lowering agents for patients with hyperlipidemia. However, interindividual variations in efficacy and risk of adverse drug reactions to statin treatment have been widely reported. Ethnicity is well known to be one of the contributing factors to this variation, particularly among Asians.
OBJECTIVES
To identify genetic variants associated with statin treatment responses among Asian populations with a focus on four commonly prescribed statins: atorvastatin, rosuvastatin, simvastatin, and pravastatin.
METHODS
A literature search was conducted in Medline and Embase databases. Studies published from 2008 to 2021 were included. The title and abstract of each article were screened by two reviewers and verified by another two reviewers. Data charted include information on authors, year of study, study population, statin studied, gene studied, study findings, and data of significant statistical value.
RESULTS
A total of 35 articles were included from the 1,939 original studies related to treatment efficacy and 5 articles out of the 284 original studies related to adverse effects. Genetic variants in transmembrane transporters, cytochrome P450 isoenzymes, and apolipoproteins are the most extensively studied among Asian populations, with a main focus on ethnic Chinese. However, Asia consists of genetically different populations, and the results of this review indicated that there is a paucity of studies on other ethnic groups within Asia.
CONCLUSIONS
Considering the ethnicity of patients could provide a potential value to personalized medicine in statin therapy.
PubMed: 37818163
DOI: 10.2478/abm-2023-0050 -
Cancer Research Nov 2023Proteomics is a powerful approach that can rapidly enhance our understanding of cancer development. Detailed characterization of the genetic, pharmacogenomic, and immune...
UNLABELLED
Proteomics is a powerful approach that can rapidly enhance our understanding of cancer development. Detailed characterization of the genetic, pharmacogenomic, and immune landscape in relation to protein expression in patients with cancer could provide new insights into the functional roles of proteins in cancer. By taking advantage of the genotype data from The Cancer Genome Atlas and protein expression data from The Cancer Proteome Atlas, we characterized the effects of genetic variants on protein expression across 31 cancer types and identified approximately 100,000 protein quantitative trait loci (pQTL). Among these, over 8000 pQTLs were associated with patient overall survival. Furthermore, characterization of the impact of protein expression on more than 350 imputed anticancer drug responses in patients revealed nearly 230,000 significant associations. In addition, approximately 21,000 significant associations were identified between protein expression and immune cell abundance. Finally, a user-friendly data portal, GPIP (https://hanlaboratory.com/GPIP), was developed featuring multiple modules that enable researchers to explore, visualize, and browse multidimensional data. This detailed analysis reveals the associations between the proteomic landscape and genetic variation, patient outcome, the immune microenvironment, and drug response across cancer types, providing a resource that may offer valuable clinical insights and encourage further functional investigations of proteins in cancer.
SIGNIFICANCE
Comprehensive characterization of the relationship between protein expression and the genetic, pharmacogenomic, and immune landscape of tumors across cancer types provides a foundation for investigating the role of protein expression in cancer development and treatment.
Topics: Humans; Proteomics; Pharmacogenetics; Proteome; Genotype; Neoplasms; Tumor Microenvironment
PubMed: 37548539
DOI: 10.1158/0008-5472.CAN-23-0758 -
Pharmacology Research & Perspectives Dec 2023
Topics: Precision Medicine; Pharmacogenetics; Drug Discovery
PubMed: 37885364
DOI: 10.1002/prp2.1147 -
Journal of Cardiovascular Development... Dec 2023Ischemic stroke is a heterogeneous condition influenced by a combination of genetic and environmental factors. Recent advancements have explored genetics in relation to... (Review)
Review
Ischemic stroke is a heterogeneous condition influenced by a combination of genetic and environmental factors. Recent advancements have explored genetics in relation to various aspects of ischemic stroke, including the alteration of individual stroke occurrence risk, modulation of treatment response, and effectiveness of post-stroke functional recovery. This article aims to review the recent findings from genetic studies related to various clinical and molecular aspects of ischemic stroke. The potential clinical applications of these genetic insights in stratifying stroke risk, guiding personalized therapy, and identifying new therapeutic targets are discussed herein.
PubMed: 38132662
DOI: 10.3390/jcdd10120495 -
Scientific Reports Aug 2023Circadian rhythms (CRs) are fundamental biological processes that significantly impact human well-being. Disruption of these rhythms can trigger insufficient...
Circadian rhythms (CRs) are fundamental biological processes that significantly impact human well-being. Disruption of these rhythms can trigger insufficient neurocognitive development, insomnia, mental disorders, cardiovascular diseases, metabolic dysfunctions, and cancer. The field of chronobiology has increased our understanding of how rhythm disturbances contribute to cancer pathogenesis, and how circadian timing influences the efficacy of cancer treatments. As the circadian clock steadily gains recognition as an emerging factor in tumorigenesis, a thorough and comprehensive multi-omics analysis of CR genes/proteins has never been performed. To shed light on this, we performed, for the first time, an integrated data analysis encompassing genomic/transcriptomic alterations across 32 cancer types (n = 10,918 tumors) taken from the PanCancer Atlas, unfavorable prognostic protein analysis, protein-protein interactomics, and shortest distance score pathways to cancer hallmark phenotypes. This data mining strategy allowed us to unravel 31 essential CR-related proteins involved in the signaling crossroad between circadian rhythms and cancer. In the context of drugging the clock, we identified pharmacogenomic clinical annotations and drugs currently in late phase clinical trials that could be considered as potential cancer therapeutic strategies. These findings highlight the diverse roles of CR-related genes/proteins in the realm of cancer research and therapy.
Topics: Humans; Circadian Clocks; Multiomics; Neoplasms; Circadian Rhythm; Carcinogenesis
PubMed: 37648722
DOI: 10.1038/s41598-023-39401-1