Clin Pharmacol Ther. 2025 Jan 9. doi: 10.1002/cpt.3545. Online ahead of print.

ABSTRACT

Pharmacogenetic testing can prevent severe toxicities from several oncology drug therapies; it also has the potential to improve the outcomes from supportive care drugs. Paired tumor and germline sequencing is increasingly common in oncology practice; these include sequencing of pharmacogenes, but the germline pharmacogenetic variants are rarely included in the clinical reports, despite many being clinically actionable. We established an informatics workflow to evaluate the clinical sequencing results for pharmacogenetic variants. We used the Aldy computational tool, which we have previously shown to determine the variant alleles in 14 pharmacogenes in clinical sequencing data with >99% accuracy, to identify pharmacogenetic variants in the clinical whole exome sequencing from our molecular tumor board. Patients with genetic variants that are clinically actionable for their individual therapy programs, including both treatment and supportive care, are referred to a clinical pharmacogenetics testing laboratory for confirmation. Through an evaluation of our weekly informatics workflow, we determined it took approximately 3.25 hours to complete the analysis of the sequencing data from approximately 20 patients. Using a United States pharmacist's median salary, we estimated the incremental added cost of the process to be only ~$15 per patient. This adds only a minor increase to the patient's cost of testing and has the potential to improve the safety and efficacy of their treatment.

PMID:39789831 | DOI:10.1002/cpt.3545

Sci Rep. 2025 Jan 9;15(1):1521. doi: 10.1038/s41598-024-84192-8.

ABSTRACT

Aripiprazole (ARI) is an atypical antipsychotic which is a substrate of P-glycoprotein (P-gp), a transmembrane glycoprotein that plays a crucial role in eliminating potentially harmful compounds from the organism. ARI once-monthly (AOM) is a long-acting injectable form which improves treatment compliance. Genetic polymorphisms in ABCB1 may lead to changes in P-gp function, leading to individual differences in drug disposition. The present study aims to determine how the different variants of the three most prevalent SNPs of the ABCB1 gene affect plasma concentrations of ARI, of its active metabolite dehydroaripiprazole (DHA) and ARI/DHA ratio in patients under AOM treatment. The metabolizing state of the two main aripiprazole metabolizing enzymes (CYP2D6 and CYP3A4) were considered to specifically study the effect of P-gp on plasma concentrations of the parent compound and its active metabolite. The study found a clear relationship between the genotypes found for the different ABCB1 SNPs and the ARI/DHA ratio. Specifically, patients with GG genotype in G2677T have almost twice the ratio compared to TT genotype. Similarly, this increase is also found in C3435T with 1.4-fold and in C1236T with 1.6-fold for the same genotypes. Regarding haplotypes, significant differences were obtained between CC-GG-CC and TT-TT-TT patients, with an 87.9% higher ratio in patients with the CC-GG-CC haplotype. There was a clear trend towards lower ARI concentrations and higher DHA concentrations when the presence of mutated T alleles increases. The ABCB1 gene could be a good partner along with CYP2D6 and CYP3A4 genotyping in conjunction with monitoring ARI plasma concentrations.

PMID:39789135 | DOI:10.1038/s41598-024-84192-8

Nat Commun. 2025 Jan 9;16(1):538. doi: 10.1038/s41467-025-55864-4.

NO ABSTRACT

PMID:39788999 | DOI:10.1038/s41467-025-55864-4

Eur Psychiatry. 2025 Jan 10:1-13. doi: 10.1192/j.eurpsy.2024.1816. Online ahead of print.

NO ABSTRACT

PMID:39788917 | DOI:10.1192/j.eurpsy.2024.1816

Therapie. 2024 Dec 20:S0040-5957(24)00215-4. doi: 10.1016/j.therap.2024.11.010. Online ahead of print.

ABSTRACT

4P medicine (personalized, preventive, predictive, and participatory) is experiencing a remarkable rise, and pharmacogenetics is an essential part of it. However, several obstacles are hindering its deployment. This round table brought together a group of experts to take stock of the situation, reflecting on ways to facilitate the prescription of these tests and the dissemination of the results on a national scale. The experts looked at the methods of prescribing and communicating pharmacogenetic data in the current situation as well as in the coming years, with the arrival of artificial intelligence software. The questions relating to the reimbursement of tests - as topical as ever - were also discussed, as this is a way to allow all patients to access these tests. Numerous recommendations have been formulated on these various points, aimed at facilitating prescription management for healthcare professionals, and ensuring the retention and use of the results throughout the patient's life. Finally, better patient information was recommended, as well as strengthening the involvement of healthcare professionals and industry stakeholders in this process, with insistence on the necessary training and commitment to ensure its success.

PMID:39788802 | DOI:10.1016/j.therap.2024.11.010

Nature. 2025 Jan 8. doi: 10.1038/s41586-024-08391-z. Online ahead of print.

ABSTRACT

Transcriptional regulation, which involves a complex interplay between regulatory sequences and proteins, directs all biological processes. Computational models of transcription lack generalizability to accurately extrapolate to unseen cell types and conditions. Here we introduce GET (general expression transformer), an interpretable foundation model designed to uncover regulatory grammars across 213 human fetal and adult cell types1,2. Relying exclusively on chromatin accessibility data and sequence information, GET achieves experimental-level accuracy in predicting gene expression even in previously unseen cell types3. GET also shows remarkable adaptability across new sequencing platforms and assays, enabling regulatory inference across a broad range of cell types and conditions, and uncovers universal and cell-type-specific transcription factor interaction networks. We evaluated its performance in prediction of regulatory activity, inference of regulatory elements and regulators, and identification of physical interactions between transcription factors and found that it outperforms current models4 in predicting lentivirus-based massively parallel reporter assay readout5,6. In fetal erythroblasts7, we identified distal (greater than 1 Mbp) regulatory regions that were missed by previous models, and, in B cells, we identified a lymphocyte-specific transcription factor-transcription factor interaction that explains the functional significance of a leukaemia risk predisposing germline mutation8-10. In sum, we provide a generalizable and accurate model for transcription together with catalogues of gene regulation and transcription factor interactions, all with cell type specificity.

PMID:39779852 | DOI:10.1038/s41586-024-08391-z

Osteoporos Int. 2025 Jan 8. doi: 10.1007/s00198-024-07352-6. Online ahead of print.

ABSTRACT

BACKGROUD: Hypoparathyroidism (hypoPT) is characterized by acute and chronic complications due to insufficient parathyroid hormone (PTH) production or action. Several management guidelines have been developed, but mostly based on evidence from Western countries. Data from Eastern countries have not been systematically compared with those from Western countries.

METHODS: Literatures regarding to the epidemiology, genetics, risk factors, clinical manifestations and therapies for hypoPT in Easten and Western countries, including China, South Korea, Japan, India, and USA, Canada, Italy, and etc., were searched through PubMed and CNKI. This review was officially endorsed by European Calcified Tissue Society (ECTS) board.

RESULTS: Postoperative hypoPT is the major form of hypoPT in both Western and Eastern countries. The genetic profiles and clinical features of hypoPT are similar in Eastern and Western countries. The most commonly used medications in Eastern countries are calcium and native vitamin D or active vitamin D analogues, similar to their Western counterparts. While PTH replacement therapy is not available and approved to use in most Eastern countries.

CONCLUSION: Physicians and surgeons should follow the guidelines on the management of thyroid nodules, taking more care of protecting parathyroid glands during surgery. The cross-talk between East and West in the management of hypoPT should be continued. Direct comparisons of the management strategies in patients with hypoPT between Eastern and Wester countries regarding to the morbidity, mortality, quality of life, optimal dosage, efficacies and side-effects of conventional therapies or newer medications, as well as pharmacogenetics and pharmacoeconomics, would be valuable.

PMID:39777494 | DOI:10.1007/s00198-024-07352-6

Eur J Clin Pharmacol. 2025 Jan 7. doi: 10.1007/s00228-024-03798-z. Online ahead of print.

ABSTRACT

OBJECTIVE: Several studies have attempted to identify genetic determinants of clinical response to opioids administered during labor or after cesarean section. However, their results were often contrasting. A systematic review and meta-analysis was conducted to quantitatively assess the association between gene polymorphisms and clinical outcomes of opioid administration in the treatment of labor pain and post-cesarean pain.

METHODS: A comprehensive search was performed up to December 2023 using PubMed, Web of Knowledge, Cochrane Library, and OpenGrey databases. The clinical endpoints of interest were pain score after opioid treatment, total opioid consumption, patient's analgesic satisfaction, and incidence of opioid side effects. Random-effects meta-analyses were conducted when data were available in at least three studies.

RESULTS: Twenty-six studies enrolling 7765 patients were included in the systematic review. Overall, a total of 12 candidate polymorphic genes (OPRM1, COMT, CYP2D6, CYP3A4, ABCB1, ABCC3, UGT2B7, CGRP, OPRK1, OPRD1, KCNJ6, KCNJ9) were considered by the included studies, among which the most investigated variant was OPRM1 rs1799971. Overall pooled results indicated that individuals carrying the G allele of OPRM1 rs1799971 required higher opioid doses for pain management in comparison to rs1799971 AA subjects (standardized mean difference: 0.26; 95% CI: 0.09-0.44; P = 0.003). Such an association was confirmed in the subgroups of patients with labor pain and post-cesarean pain.

CONCLUSION: The present meta-analysis provides strong evidence of an association between OPRM1 rs1799971 and opioid dose requirement for relief of labor pain or post-cesarean pain. However, given the insufficient evidence for other polymorphic gene variants, large studies are still needed to investigate the impact of genetic variability on the efficacy and safety of opioid medications for relief of labor pain and post-cesarean pain (INPLASY Registration No. 202410040).

PMID:39774699 | DOI:10.1007/s00228-024-03798-z

Ther Drug Monit. 2025 Feb 1;47(1):141-151. doi: 10.1097/FTD.0000000000001289. Epub 2024 Dec 10.

ABSTRACT

Different polymorphisms in genes encoding metabolizing enzymes and drug transporters have been associated with tacrolimus pharmacokinetics. In particular, studies on CYP3A4 and CYP3A5, and their combined cluster have demonstrated their significance in adjusting tacrolimus dosing to minimize under- and overexposure thereby increasing the proportion of patients who achieve tacrolimus therapeutic target. Many factors influence the pharmacokinetics of tacrolimus, contributing to inter-patient variability affecting individual dosing requirements. On the other hand, the growing use of population pharmacokinetic models in solid organ transplantation, including different tacrolimus formulations, has facilitated the integration of pharmacogenetic data and other variables into algorithms to easier implement the personalized dose adjustment in transplant centers. The future of personalized medicine in transplantation lies in implementing these models in clinical practice, with pharmacogenetics as a key factor to account for the high inter-patient variability in tacrolimus exposure. To date, three clinical trials have validated the clinical application of these approaches. The aim of this review is to provide an overview of the current studies regarding the different population pharmacokinetic including pharmacogenetics and those translated to the clinical practice for individualizing tacrolimus dose adjustment in kidney transplantation.

PMID:39774592 | DOI:10.1097/FTD.0000000000001289

Postepy Biochem. 2024 Dec 2;70(4):462-473. doi: 10.18388/pb.2021_568.

ABSTRACT

Farmakogenomika to dziedzina z pogranicza farmacji i genomiki. Zajmuje się ona badaniem wpływu występujących u pacjenta wariantów genów związanych z metabolizmem leków na jego reakcję na konkretny lek. Rolą testów farmakogenomicznych jest określenie tempa metabolizmu leków i wykorzystanie tej informacji w praktyce klinicznej. Takie podejście otwiera nowe możliwości w optymalizacji terapii, poprzez dobranie właściwego leku i dostosowanie dawki tak, aby zminimalizować działania niepożądane, jednocześnie maksymalizując skuteczność podawanego preparatu. Dzięki temu zwiększona jest szansa na przypisanie pacjentowi odpowiedniego leku, co przyspiesza wprowadzenie skutecznej terapii. Perspektywy zastosowania farmakogenomiki w psychiatrii są obiecujące, choć podobnie jak w przypadku schorzeń innych układów, stworzenie jednolitych rekomendacji jest utrudnione przez złożoność wielu zaburzeń psychicznych oraz wpływ innych czynników, takich jak interakcje pomiędzy przyjmowanymi lekami. Z tego powodu rekomendacje tworzone przez różne instytucje różnią się między sobą. Celem niniejszego artykułu jest omówienie aktualnych możliwości zastosowania farmakogenomiki w psychiatrii oraz trudności jej wprowadzenia jako standardu leczenia psychiatrycznego.

PMID:39772325 | DOI:10.18388/pb.2021_568

Pharmaceutics. 2024 Dec 12;16(12):1585. doi: 10.3390/pharmaceutics16121585.

ABSTRACT

Background: Osteosarcoma is a rare disease, but it is the most frequent malignant bone tumor. Primary treatment consists of preoperative MAP (methotrexate (MTX), doxorubicin and cisplatin) chemotherapy followed by surgery and adjuvant chemotherapy. Pathological response to preoperative chemotherapy is one of the most important prognostic factors, but molecular biomarkers are lacking. Additionally, chemotherapy-induced toxicity might jeopardize treatment completion. We evaluated variants in genes involved in DNA repair and drug metabolism pathways as predictors of response to MAP-based treatment. Material and Methods: Germline polymorphisms in MTHFR, SLC19A1, ABCB1, ABCC2, ABCC3, ERCC1, ERCC2 and GSTP1 genes were determined for association studies in 69 patients diagnosed with localized osteosarcoma who enrolled in the prospective GEIS-33 trial. P-glycoprotein expression in tumor tissue was also analyzed. Results: In the multivariate analysis, the ABCC2 rs2273697 (odds ratio [OR] 12.3, 95% CI 2.3-66.2; p = 0.003) and ERCC2 rs1799793 (OR 9.6, 95% CI 2.1-43.2; p = 0.003) variants were associated with poor pathological response. P-glycoprotein expression did not correlate with pathological response. The ABCB1 rs1128503 (OR 11.4, 95% CI 2.2-58.0; p = 0.003) and ABCC3 rs4793665 (OR 12.0, 95% CI 2.1-70.2; p = 0.006) variants were associated with MTX grade 3-4 hepatotoxicity. Conclusions: Our findings add to the evidence that genetic variants in the ABC transporters and DNA-repair genes may serve as predictive biomarkers for MAP chemotherapy and contribute to treatment personalization.

PMID:39771563 | DOI:10.3390/pharmaceutics16121585

Molecules. 2024 Dec 16;29(24):5934. doi: 10.3390/molecules29245934.

ABSTRACT

Targeted metabolomics and lipidomics are increasingly utilized in clinical research, providing quantitative and comprehensive assessments of metabolic profiles that underlie physiological and pathological mechanisms. These approaches enable the identification of critical metabolites and metabolic alterations essential for accurate diagnosis and precision treatment. Mass spectrometry, in combination with various separation techniques, offers a highly sensitive and specific platform for implementing targeted metabolomics and lipidomics in clinical settings. Nevertheless, challenges persist in areas such as sample collection, quantification, quality control, and data interpretation. This review summarizes recent advances in targeted metabolomics and lipidomics, emphasizing their applications in clinical research. Advancements, including microsampling, dynamic multiple reaction monitoring, and integration of ion mobility mass spectrometry, are highlighted. Additionally, the review discusses the critical importance of data standardization and harmonization for successful clinical implementation.

PMID:39770023 | DOI:10.3390/molecules29245934

Int J Mol Sci. 2024 Dec 16;25(24):13464. doi: 10.3390/ijms252413464.

ABSTRACT

In open-angle glaucoma, the increase in intraocular pressure (IOP) is caused by an increased resistance to aqueous humour outflow in the trabecular meshwork. Since genetic variability of matrix metalloproteinase (MMP) genes may influence extracellular matrix remodelling, we investigated their association with glaucoma risk and/or response to treatment. The retrospective part of the study included patients with primary open-angle glaucoma and ocular hypertension (OHT); in the prospective part of the study, newly diagnosed patients with POAG or OHT were randomised to receive either latanoprost or selective laser trabeculoplasty (SLT) as the initial treatment. The reduction in IOP was measured 6 weeks after treatment. The following MMP single nucleotide polymorphisms were genotyped: MMP2 rs243865, rs243849, and rs7201; MMP3 rs3025058; MMP9 rs17576, rs17577, rs20544, and rs2250889; MMP14 rs1042704, rs1042704, and rs743257. Logistic regression was used to calculate odds ratios to assess the association between MMP polymorphism and risk of POAG or OHT, glaucoma phenotypes and response to treatment. Only carriers of the MMP3 rs3025058 TT genotype had a significantly higher risk of OHT, more advanced glaucoma, and a higher C/D ratio in the additive and dominant models. None of the investigated MMP polymorphisms were associated with response to treatment with latanoprost and SLT in our study population.

PMID:39769228 | DOI:10.3390/ijms252413464

Life (Basel). 2024 Nov 26;14(12):1555. doi: 10.3390/life14121555.

ABSTRACT

Alzheimer's disease (AD) is a complex/multifactorial brain disorder involving hundreds of defective genes, epigenetic aberrations, cerebrovascular alterations, and environmental risk factors. The onset of the neurodegenerative process is triggered decades before the first symptoms appear, probably due to a combination of genomic and epigenetic phenomena. Therefore, the primary objective of any effective treatment is to intercept the disease process in its presymptomatic phases. Since the approval of acetylcholinesterase inhibitors (Tacrine, Donepezil, Rivastigmine, Galantamine) and Memantine, between 1993 and 2003, no new drug was approved by the FDA until the advent of immunotherapy with Aducanumab in 2021 and Lecanemab in 2023. Over the past decade, more than 10,000 new compounds with potential action on some pathogenic components of AD have been tested. The limitations of these anti-AD treatments have stimulated the search for multi-target (MT) drugs. In recent years, more than 1000 drugs with potential MT function have been studied in AD models. MT drugs aim to address the complex and multifactorial nature of the disease. This approach has the potential to offer more comprehensive benefits than single-target therapies, which may be limited in their effectiveness due to the intricate pathology of AD. A strategy still unexplored is the combination of epigenetic drugs with MT agents. Another option could be biotechnological products with pleiotropic action, among which nosustrophine-like compounds could represent an attractive, although not definitive, example.

PMID:39768263 | DOI:10.3390/life14121555

Res Sq [Preprint]. 2024 Dec 23:rs.3.rs-5418279. doi: 10.21203/rs.3.rs-5418279/v1.

ABSTRACT

Antidepressants exhibit a considerable variation in efficacy, and increasing evidence suggests that individual genetics contribute to antidepressant treatment response. Here, we combined data on antidepressant non-response measured using rating scales for depressive symptoms, questionnaires of treatment effect, and data from electronic health records, to increase statistical power to detect genomic loci associated with non-response to antidepressants in a total sample of 135,471 individuals prescribed antidepressants (25,255 non-responders and 110,216 responders). We performed genome-wide association meta-analyses, genetic correlation analyses, leave-one-out polygenic prediction, and bioinformatics analyses for genetically informed drug prioritization. We identified two novel loci (rs1106260 and rs60847828) associated with non-response to antidepressants and showed significant polygenic prediction in independent samples. Genetic correlation analyses show positive associations between non-response to antidepressants and most psychiatric traits, and negative associations with cognitive traits and subjective well-being. In addition, we investigated drugs that target proteins likely involved in mechanisms underlying antidepressant non-response, and shortlisted drugs that warrant further replication and validation of their potential to reduce depressive symptoms in individuals who do not respond to first-line antidepressant medications. These results suggest that meta-analyses of GWAS utilizing real-world measures of treatment outcomes can increase sample sizes to improve the discovery of variants associated with non-response to antidepressants.

PMID:39764137 | PMC:PMC11703334 | DOI:10.21203/rs.3.rs-5418279/v1

Phytomedicine. 2024 Dec 21;136:156343. doi: 10.1016/j.phymed.2024.156343. Online ahead of print.

ABSTRACT

BACKGROUND: Among all gynecological cancers, ovarian cancer is the leading cause of death. Epithelial ovarian cancer (EOC) accounts for over 85 % of ovarian cancer cases and is characterized by insidious onset, early metastasis, and a high recurrence rate. Alterations in gut microbiota, often as a consequence of chemotherapy, can promote cancer development and exacerbate the disease. The m6A reader IGF2BP3 is a regulator in the occurrence and progression of various tumors and is associated with angiogenesis. Enterolactone (ENL) has demonstrated significant anti-tumor activity against various human cancers, including EOC. However, whether ENL could interact with IGF2BP3 to suppress EOC remains unclear.

PURPOSE: This study aims to investigate suppressive effects of ENL upon combining with IGF2BP3 on EOC and elucidates the underlying mechanism.

METHODS: The Cell Counting Kit-8 and crystal violet assays were used to assess tumor cell proliferation. Scratch and Transwell assays were employed to evaluate tumor cell migration, while tube formation assays were utilized to examine angiogenesis. Western blotting was used to measure the expression levels of IGF2BP3, VEGF, PI3K, AKT1, p-PI3K, and p-AKT1. An in vivo xenograft nude mouse model was established, fecal samples were collected, and 16S rDNA sequencing was performed to analyze gut microbiota in association with the suppressive effects of ENL and its interactions with IGF2BP3.

RESULTS: IGF2BP3 is highly expressed in EOC and is positively correlated with poor survival in EOC patients. ENL reduces IGF2BP3 expression in EOC, thereby inhibiting the IGF2BP3-mediated VEGF/PI3K/AKT signaling pathway and suppressing the proliferation, migration, invasion, and angiogenesis of EOC. Additionally, ENL ameliorates gut microbiome, especially in conjunction with shIGF2BP3.

CONCLUSION: ENL interacts with IGF2BP3 and suppresses its expression in EOC, leading to the deactivation of the IGF2BP3-mediated VEGF/PI3K/AKT signaling pathway and the subsequent inhibition of angiogenesis. The combination of ENL and shIGF2BP3 demonstrates a synergistic effect on EOC. ENL also ameliorates the gut microbiome, especially in conjunction with shIGF2BP3, to suppress EOC.

PMID:39765033 | DOI:10.1016/j.phymed.2024.156343

Res Sq [Preprint]. 2024 Dec 16:rs.3.rs-5418156. doi: 10.21203/rs.3.rs-5418156/v1.

ABSTRACT

Background: Human genetic variants can affect TB and HIV drug metabolism, which may lead to toxicity or treatment failure. We evaluated associations between genetic variants of antiretroviral therapy (ART) and HIV-1 outcomes among TB/HIV patients. Methods: We included RePORT-Brazil participants with TB/HIV who initiated standard TB treatment [2 months of isoniazid/rifampicin (or rifabutin)/pyrazinamide/ethambutol, then 4 months or more of isoniazid/rifampicin (or rifabutin)], and ART. The endpoint was HIV-1 virologic suppression (defined as <1,000 HIV-1 RNA copies/mL, for primary analysis, and <50 HIV-1 RNA copies/mL, for secondary analysis) after at least 2 weeks of ART. We compared non-nucleoside reverse transcriptase inhibitor (NNRTI)-based and integrase strand transfer inhibitor (INSTI)-based ART regimens. We genotyped CYP2B6 (rs3745274, rs28399499, rs4803419; affects efavirenz metabolism) and UGT1A1 (rs887829; affects dolutegravir and raltegravir metabolism); all have defined normal, intermediate, and slow genotypes. Genotyping was performed by MassARRAY iPLEX Gold. We compared outcome proportions (Fisher's test) and time-to- virologic suppression (survival analysis, Wilcoxon-Gehan test). Results: Among 194 TB/HIV participants included, efavirenz was the most frequent NNRTI ([n=76], one participant received etravirine), and raltegravir was the most frequent INSTI (n=88). The overall virologic suppression was suboptimal, with 32% (n=62) of participants not achieving HIV-1 virologic suppression. Among them, 36% (n=28) used efavirenz-based ART and were more likely to be CYP2B6 normal metabolizers (n=8, 44%); and 30% (n=30) used INSTI-based ART and the UGT1A1 normal genotype was also the most common (n=13, 50%). The median time to virologic suppression for efavirenz-based ART was 184 days (95% Confidence Interval (CI)160-207), and for INSTI-based ART, 188 days (95% CI 144-231) (p=0.84). No significant associations were found comparing the proportions and time to virologic suppression among CYP2B6 and UGT1A1 genotypes. Conclusions : In this observational cohort of patients treated for TB/HIV, the proportion of participants achieving virologic suppression was low, and genetic variants affecting ART metabolism were not significantly associated with the likelihood of virologic suppression.

PMID:39764089 | PMC:PMC11702782 | DOI:10.21203/rs.3.rs-5418156/v1

Front Pharmacol. 2024 Dec 20;15:1478964. doi: 10.3389/fphar.2024.1478964. eCollection 2024.

ABSTRACT

Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are characterized by the progressive degeneration of neuronal structure and function, leading to severe cognitive and motor impairments. These conditions present significant challenges to healthcare systems, and traditional treatments often fail to account for genetic variability among patients, resulting in inconsistent therapeutic outcomes. Pharmacogenomics aims to tailor medical treatments based on an individual's genetic profile, thereby improving therapeutic efficacy and reducing adverse effects. This focused review explores the genetic factors influencing drug responses in neurodegenerative diseases and the potential of pharmacogenomics to revolutionize their treatment. Key genetic markers, such as the APOE ε4 allele in AD and the CYP2D6 polymorphisms in PD, are highlighted for their roles in modulating drug efficacy. Additionally, advancements in pharmacogenomic tools, including genome-wide association studies (GWAS), next-generation sequencing (NGS), and CRISPR-Cas9, are discussed for their contributions to personalized medicine. The application of pharmacogenomics in clinical practice and its prospects, including ethical and data integration challenges, are also examined.

PMID:39759457 | PMC:PMC11695131 | DOI:10.3389/fphar.2024.1478964

Front Pharmacol. 2024 Dec 20;15:1458095. doi: 10.3389/fphar.2024.1458095. eCollection 2024.

ABSTRACT

INTRODUCTION: The Precision Medicine Program (PMP) at the University of Florida (UF) focuses on advancing pharmacogenomics (PGx) to improve patient care.

METHODS: The UF PMP, in collaboration with the UF Health Pathology Laboratory (UFHPL), utilized Health Level Seven (HL7) standards to integrate PGx data into Epic's Genomic Module to enhance the management and utilization of PGx data in clinical practice.

RESULTS: A key feature of the Genomic Module is the introduction of genomic indicators-innovative tools that flag actionable genetic information directly within the electronic health record (EHR). These indicators enable the effective presentation of phenotypic information and, when leveraged with existing clinical decision support (CDS) alerts, help provide timely and informed therapeutic decisions based on genomic data.

DISCUSSION: This advancement represents a significant shift in the utilization of genetic data, moving beyond traditional PDF reports to provide a comprehensive understanding of PGx data. Ultimately, this integration empowers healthcare providers with genomics-guided recommendations, enhancing precision and personalization in patient care, contributing significantly to the advancement of personalized medicine.

PMID:39759455 | PMC:PMC11695119 | DOI:10.3389/fphar.2024.1458095

Phytother Res. 2025 Jan 6. doi: 10.1002/ptr.8385. Online ahead of print.

ABSTRACT

Ginsenoside compound K (GCK) has been proved to have great hypoglycemic effect pertinent to gut microbiota. However, the improvement of high-fat-diet (HFD)-induced type 2 diabetes (T2D) as well as the mechanism of GCK mediated by gut microbiota is not well-known. This study aimed to investigate the hypoglycemic effects and mechanism of GCK on a HFD-induced diabetic mouse model. HFD-induced pseudo-germ free (GF) T2D mice model and fecal microbiota transplantation (FMT) experiments were performed to clarify the role of gut microbiota in the hypoglycemic effect of GCK. Differential metabolites were screened by untargeted metabolomics analysis and their functions were verified by suppling to T2D mice. The level of glucagon-like peptide-1 (GLP-1) in plasma was detected by ELISA analysis to explore the potential hypoglycemic mechanism of GCK. The results showed GCK alleviated metabolic disorders and altered gut microbiota in HFD-induced diabetic mice, which was transmitted to pseudo-GF diabetic mice via FMT experiment to reproduce the hypoglycemic effect. Non-targeted metabolites analysis on cecal content samples indicated that N-acetylserotonin (NAS) was markedly increased after GCK treatment. Moreover, gavage with NAS improved insulin sensitivity and increased the secretion of GLP-1 in HFD mice. Our study showed that GCK had hypoglycemic effect through modifying gut microbiota profiling.

PMID:39757809 | DOI:10.1002/ptr.8385