Toward Personalized Medicine in Bronchiolitis.
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ABSTRACT:
SUBMITTER: Paggi DA
PROVIDER: S-EPMC6580667 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Sickle cell disease (SCD) is a monogenetic disease but has a wide range of phenotypic expressions. Some of these differences in phenotype can be explained by genetic polymorphisms in the human globin gene. These polymorphisms can result in different responses to typical treatment, sometimes leading to inadequate therapeutics. Research is revealing more polymorphisms, and therefore, new targets for intervention to improve outcomes in SCD. This area of pharmacogenomics is continuing to develop. We provide a brief review of the current literature on pharmacogenomics in SCD and possible targets for intervention.
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Project description:Advances in genotype technology in the last decade have put the pharmacogenomics revolution at the forefront of future medicine in clinical practice. Discovery of novel gene variations in drug transporters, drug targets, effector proteins and metabolizing enzymes in the form of single-nucleotide polymorphisms (SNPs) continue to provide insight into the biological phenomena that govern drug efficacy and toxicity. To date, novel gene discoveries extracted from genome-wide association scans and candidate gene studies in at least four antidiabetic drug classes have helped illuminate possible causes of interindividual variability in response. Inadequate protocol guidelines for pharmacogenomics studies often leads to poorly designed studies, making it hard to formulate a definitive conclusion regarding the clinical relevance of the information at hand. These issues, along with the ethical, social, political, legislative, technological, and economic challenges associated with pharmacogenomics have only delayed its entry to mainstream clinical practice. On the other hand, these issues are being actively pursued and rapid progress is being made in each area which assures the possibility of gaining widespread acceptance in clinical practice.
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Project description:Various molecular triggers define heterogeneous subsets of gastrointestinal stromal tumors (GISTs), differing in clinical behavior and drug sensitivity. KIT/PDGFRA-wild-type GISTs, including those succinate dehydrogenase (SDH)-deficient, are overall unresponsive to the tyrosine kinase inhibitors commonly used, fostering the development of specific alternative therapeutic strategies. Epigenetic inactivation of O6-methylguanine-DNA methyltransferase (MGMT) through promoter methylation leads to effectiveness of alkylating agents in several human cancers. SDH-deficient GISTs typically feature widespread DNA methylation. However, the actual occurrence of MGMT methylation in these tumors, potentially predisposing them to respond to alkylating drugs, has not been investigated so far. Here we discuss the recent findings concerning the occurrence of MGMT methylation in different GIST subgroups, including SDH-deficient ones, as a premise for a possible reappraisal of alkylating agents specifically targeting these small, otherwise overall chemorefractory, GIST subgroups.
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Project description:There is wide individual variability in the pharmacokinetics, pharmacodynamics, and tolerance to anticancer drugs within the same ethnic group and even greater variability among different ethnicities. Pharmacogenomics (PG) has the potential to provide personalized therapy based on individual genetic variability in an effort to maximize efficacy and reduce adverse effects. The benefits of PG include improved therapeutic index, improved dose regimen, and selection of optimal types of drug for an individual or set of individuals. Advanced or metastatic breast cancer is typically treated with single or multiple combinations of chemotherapy regimens including anthracyclines, taxanes, antimetabolites, alkylating agents, platinum drugs, vinca alkaloids, and others. In this review, the PG of breast cancer therapeutics, including tamoxifen, which is the most widely used therapeutic for the treatment of hormone-dependent breast cancer, is reviewed. The pharmacological activity of tamoxifen depends on its conversion by cytochrome P450 2D6 (CYP2D6) to its abundant active metabolite, endoxifen. Patients with reduced CYP2D6 activity, as a result of either their genotype or induction by the coadministration of other drugs that inhibit CYP2D6 function, produce little endoxifen and hence derive limited therapeutic benefit from tamoxifen; the same can be said about the different classes of therapeutics in breast cancer. PG studies of breast cancer therapeutics should provide patients with breast cancer with optimal and personalized therapy.
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Project description:Background: Methotrexate (MTX) is one of the most common medications used for rheumatoid arthritis (RA) treatment. Single-nucleotide polymorphisms (SNPs) could potentially predict variability in therapeutic outcomes. Aim: This study aims to assess the impact of SNPs in genes encoding for the MTX pathway for predicting clinical and therapeutic responses to MTX in a cohort of Egyptian patients with RA. Subjects and Methods: Data from 107 Egyptian RA patients (aged 44.4 ± 11.4 years) treated with MTX monotherapy, for a duration of 3.7 ± 3.3 years, were collected. Genotypes of 10 SNPs from four different genes were analyzed using the allelic discrimination PCR technique. Results: The ATIC rs3821353 G/T (p = 0.034) and the C/T and C/C of SLC19A1 rs7279445 (p = 0.0018) were associated with a non-response to MTX, while DHFR rs10072026 C/T and C/C were associated with a good response (p < 0.001). Carriers of the ATIC rs382135 3 G (p = 0.001) and ATIC rs4673990 G (p < 0.001) alleles were more likely to develop RA, while the SLC19A1 rs11702425 T (p < 0.001) and GGH rs12681874 T (p = 0.003) allele carriers were more likely to be protected against RA. Carriers of the ATIC rs4673990 A/G genotype (p < 0.001) were at risk of developing RA, while carriers of the following genotypes were mostly protected against RA: ATIC rs3821353 T/T (p < 0.001), ATIC rs3821353 G/G (p = 0.004), SLC19A1 rs11702425 T/T (p = 0.001), SLC19A1 rs11702425 C/T (p = 0.003), GGH rs12681874 C/T (p = 0.004) and GGH rs12681874 T/T (0.002). Conclusion: The genotyping of genes involved in the MTX pathway may be helpful to predict which RA patients will/will not benefit from MTX, and thus, may help to apply a personalized medicine approach in RA.
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Project description:Leukocytoclastic vasculitis (LCV) is a systemic autoimmune disease characterized by the inflammation of the vascular endothelium. Cutaneous small vessel vasculitis (CSVV) and anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) are two examples of LCV. Advancements in genomic technologies have identified risk haplotypes, genetic variants, susceptibility loci and pathways that are associated with vasculitis immunopathogenesis. The discovery of these genetic factors and their corresponding cellular signaling aberrations have enabled the development and use of novel therapeutic strategies for vasculitis. Personalized medicine aims to provide targeted therapies to individuals who show poor response to conventional interventions. For example, monoclonal antibody therapies have shown remarkable efficacy in achieving disease remission. Here, we discuss pathways involved in disease pathogenesis and the underlying genetic associations in different populations worldwide. Understanding the immunopathogenic pathways in vasculitis and identifying associated genetic variations will facilitate the development of novel and targeted personalized therapies for patients.
| S-EPMC8491767 | biostudies-literature
Project description:Development of a Q-PCR-based assay for the high-performance analysis of circulating cell-free DNA (ccfDNA) requires good knowledge of its structure and size. In this work, we present the first visual determination of ccfDNA by Atomic Force Microscopy (AFM) on plasma samples from colorectal cancer (CRC) patients and healthy donors. In addition to the examination of fragment size distribution profile as performed by Q-PCR, this analysis confirms that ccfDNA is highly fragmented and that more than 80% of ccfDNA fragments in CRC plasma are below 145 bp. We adapted an Allele-Specific Blocker (ASB) Q-PCR to small ccfDNA fragments to determine simultaneously the total ccfDNA concentration, the presence of point mutation, the proportion of mutated allele, and a ccfDNA integrity index. The data validated analytically these four parameters in 124 CRC clinical samples and 71 healthy individuals. The multi-marker method, termed Intplex, enables sensitive and specific non-invasive analysis of tumor ccfDNA, which has great potential in terms of cost, quality control, and easy implementation in every clinical center laboratory.
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Project description:BackgroundThe utilization of pharmacogenomics in everyday practice has shown several notable benefits. Keeping in mind the rising trend of applicability of pharmacogenomics and personalized medicine, we sought to compare the attitudes of future healthcare workers in different branches of the healthcare system.MethodsThe present study was conducted as a questionnaire-based cross-sectional study in October of 2020. Students eligible to participate were all the students of the University of Split School of Medicine enrolled in the academic year 2020/2021.ResultsThe number of students that participated in the study was 503. Students were most interested in clinical examples of pharmacogenomics (31.4%) and the benefits of pharmacogenomics in clinical practice (36.4%). Furthermore, 72.6% of all students agreed that they should be able, in their future practice, to identify patients that could benefit from genetic testing.ConclusionAt the present time, the lack of education and appropriate clinical guidelines appear to be the major barriers to the clinical application of pharmacogenomics, especially in Croatia. Hence, in order to support health care professionals' evidence-based therapeutic recommendations with patients' pharmacogenomic data, universities should offer more pharmacogenomics education in their curricula.
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