Int J Mol Sci. 2024 Nov 24;25(23):12613. doi: 10.3390/ijms252312613.

ABSTRACT

Neurodegenerative diseases, such as Alzheimer's, Parkinson's, ALS, and Huntington's, remain formidable challenges in medicine, with their relentless progression and limited therapeutic options. These diseases arise from a web of molecular disturbances-misfolded proteins, chronic neuroinflammation, mitochondrial dysfunction, and genetic mutations-that slowly dismantle neuronal integrity. Yet, recent scientific breakthroughs are opening new paths to intervene in these once-intractable conditions. This review synthesizes the latest insights into the underlying molecular dynamics of neurodegeneration, revealing how intertwined pathways drive the course of these diseases. With an eye on the most promising advances, we explore innovative therapies emerging from cutting-edge research: nanotechnology-based drug delivery systems capable of navigating the blood-brain barrier, gene-editing tools like CRISPR designed to correct harmful genetic variants, and stem cell strategies that not only replace lost neurons but foster neuroprotective environments. Pharmacogenomics is reshaping treatment personalization, enabling tailored therapies that align with individual genetic profiles, while molecular diagnostics and biomarkers are ushering in an era of early, precise disease detection. Furthermore, novel perspectives on the gut-brain axis are sparking interest as mounting evidence suggests that microbiome modulation may play a role in reducing neuroinflammatory responses linked to neurodegenerative progression. Taken together, these advances signal a shift toward a comprehensive, personalized approach that could transform neurodegenerative care. By integrating molecular insights and innovative therapeutic techniques, this review offers a forward-looking perspective on a future where treatments aim not just to manage symptoms but to fundamentally alter disease progression, presenting renewed hope for improved patient outcomes.

PMID:39684324 | DOI:10.3390/ijms252312613

Int J Mol Sci. 2024 Nov 21;25(23):12512. doi: 10.3390/ijms252312512.

ABSTRACT

RO and ChRCC are kidney tumours with overlapping characteristics, making differentiation between them challenging. The objective of this research is to create a radiogenomics map by correlating radiomic features to molecular phenotypes in ChRCC and RO, using resection as the gold standard. Fourteen patients (6 RO and 8 ChRCC) were included in the prospective study. A total of 1,875 radiomic features were extracted from CT scans, alongside 632 cytobands containing 16,303 genes from the genomic data. Feature selection algorithms applied to the radiomic features resulted in 13 key features. From the genomic data, 24 cytobands highly correlated with histology were selected and cross-correlated with the radiomic features. The analysis identified four radiomic features that were strongly associated with seven genomic features. These findings demonstrate the potential of integrating radiomic and genomic data to enhance the differential diagnosis of RO and ChRCC, paving the way for more precise and non-invasive diagnostic tools in clinical practice.

PMID:39684226 | DOI:10.3390/ijms252312512

Ann Lab Med. 2024 Dec 17. doi: 10.3343/alm.2024.0572. Online ahead of print.

ABSTRACT

In the era of precision medicine, pharmacogenetics has substantial potential for addressing inter-individual variability in drug responses. Although pharmacogenetics has been a research focus for many years, resulting in the establishment of several formal guidelines, its clinical implementation remains limited to several gene-drug combinations in most countries, including Korea. The main causes of delayed implementation are technical challenges in genotyping and knowledge gaps among healthcare providers; therefore, clinical laboratories play a critical role in the timely implementation of pharmacogenetics. This paper presents an update of the Clinical Pharmacogenetic Testing and Application guidelines issued by the Korean Society of Laboratory Medicine and aims to provide the necessary information for clinical laboratories planning to implement or expand their pharmacogenetic testing. Current knowledge regarding nomenclature, gene-drug relationships, genotyping technologies, testing strategies, methods for clinically relevant information delivery, QC, and reimbursements has been curated and described in this guideline.

PMID:39681357 | DOI:10.3343/alm.2024.0572

Adv Sci (Weinh). 2024 Dec 16:e2406445. doi: 10.1002/advs.202406445. Online ahead of print.

ABSTRACT

Primary sclerosing cholangitis (PSC) is characterized by abnormal bile acid metabolites and altered gut microbiota, with no effective treatments available. Vancomycin, a glycopeptide antibiotic, has emerged as a promising candidate. However, the mechanism by which vancomycin impacts the progression of PSC remains unknown. Mice treated with vancomycin exhibit increased hepatic collagen deposition and injury, due to the inhibition of intestinal FXR-FGF15/19 axis and the elevation of bile acid levels. These effects are associated with the reduction in Clostridia XIVa, especially Clostridium scindens (C. scindens). Gavage of C. scindens alleviates vancomycin-induced bile acid accumulation and liver fibrosis via activating intestinal FXR-FGF15/19 signaling. Similar effects are observed in mice treated with engineered Escherichia coli Nissle 1917 that are capable of expressing bile acid 7α-dehydratas (BaiE) from C. scindens (EcN-BaiE). Activating intestinal FXR-FGF15/19 signaling by fexaramine (Fex) or recombinant protein FGF19 reverse vancomycin-induced liver injury and fibrosis. These results demonstrate that long-term oral vancomycin exacerbates cholestatic liver injury, while C. scindens mitigates this effect by activating the intestinal FXR-FGF15/19 signaling pathway. This underscores the importance of monitoring bile acid levels in PSC patients receiving vancomycin treatment and suggests that C. scindens may serve as a potential therapeutic approach for PSC patients.

PMID:39680750 | DOI:10.1002/advs.202406445

Front Pharmacol. 2024 Nov 29;15:1501381. doi: 10.3389/fphar.2024.1501381. eCollection 2024.

ABSTRACT

BACKGROUND: In the treatment of depression, medication plays a crucial role. However, insufficient patient adherence to medication often results in unsatisfactory treatment outcomes, increasing both the recurrence and rehospitalization rates of depression, and consequently imposing a greater economic burden on the healthcare system.

OBJECTIVES: Our objective was to examine the impact of pharmacogenomic testing on medication adherence and antidepressant switching rates among individuals diagnosed with depression.

METHODS: This retrospective cohort study encompassed patients diagnosed with depression who were admitted to the First Hospital of Hebei Medical University between April 2022 and September 2023. Patients were categorized into a pharmacogenomics-guided treatment (PGxT) group and a treatment as usual (TAU) group based on whether pharmacogenetic testing was conducted. The primary outcome measures included the proportion of patients exhibiting medication adherence greater than 80% at three and 6 months post-discharge, as well as the proportion of patients experiencing changes in their prescribed medication types.

RESULTS: A total of 310 patients in the PGxT group and TAU group were obtained through propensity score matching. Among the 620 patients in both groups, 57.42% demonstrated good adherence (≥80%) at 3 months; this percentage dropped to 31.45% at 6 months. At 3 months of observation, the percentages of patients demonstrating good adherence were significantly different between the groups (64.52% in the PGxT group vs. 50.32% in the TAU group; p < 0.001). The difference was also significant after 6 months (38.06% in the PGxT group vs. 24.84% in the TAU group; p < 0.001). Furthermore, patients receiving PGxT (20.64%) exhibited a lower rate of antidepressant conversion compared to those receiving TAU (31.29%).

CONCLUSION: The findings of this study indicate that pharmacogenomics testing positively influences treatment adherence and may decrease the need to switch medications among patients with depression.

PMID:39679372 | PMC:PMC11639597 | DOI:10.3389/fphar.2024.1501381

Eur J Hum Genet. 2024 Dec 15. doi: 10.1038/s41431-024-01769-7. Online ahead of print.

ABSTRACT

Aligned with the mission of the Dutch Pharmacogenetics Working Group (DPWG) to promote the implementation of pharmacogenetics (PGx), this guideline is specifically designed to optimize pharmacotherapy of cholesterol lowering medication (statins) and glucose lowering medication (sulfonylureas). The SLCO1B1 c.521 T > C variant reduces the activity of the SLCO1B1 transporter involved in statin transport out of the blood into the liver. High blood concentrations of statins increase the risk of serious myopathy. For simvastatin, the DPWG recommends choosing an alternative in homozygotes for these gene variant and to preferably choose an alternative in heterozygotes. For atorvastatin, the DPWG recommends to preferably choose an alternative in carriers of this gene variant having additional risk factors for myopathy. For rosuvastatin, the DPWG recommends keeping the dose as low as possible in carriers of this gene variant with additional risk factors. No therapy adjustment is required for fluvastatin and pravastatin in carriers of this gene variant. Gene variants can diminish the activity of the enzyme CYP2C9, that converts sulfonylurea to less effective metabolites. Although CYP2C9 gene variants may lead to increased levels of glibenclamide, gliclazide, glimepiride, and tolbutamide, no therapy adjustments are required in patients with these variants. The main reason is that there was either no negative clinical effect or an increase in hypoglycemic, which is of less importance than the increase in effectiveness it signals. The DPWG classifies pre-emptive SLCO1B1 testing as 'essential' for simvastatin 80 mg/day, 'beneficial' for simvastatin up to 40 mg/day, and 'potentially beneficial' for atorvastatin and rosuvastatin.

PMID:39676086 | DOI:10.1038/s41431-024-01769-7

Am J Case Rep. 2024 Dec 15;25:e946306. doi: 10.12659/AJCR.946306.

ABSTRACT

BACKGROUND Malignant hyperthermia (MH) and anesthesia-induced rhabdomyolysis (AIR) are rare, yet life-threatening complications that need prompt therapeutic actions and logistic preparedness for treatment success. Both conditions are triggered by general anesthetics, particularly volatiles and depolarizing muscle relaxants. In comparison with MH, which is an inherited pharmacogenomic disease of calcium channel receptor subpopulation and arises only after trigger exposure, AIR has been described mostly in patients with muscular dystrophies. In perioperative settings, rhabdomyolysis is also observed during propofol infusion syndrome, neuroleptic malignant syndrome, and cocaine, heroin, and alcohol intoxication. Despite their diverse etiology, the main clinical manifestations of MH and AIR overlap: a hypermetabolic state, hyperpyrexia, hypercarbia, acute renal failure, and hyperkalemia progressing to cardiac arrest, making the therapeutic approach to the patient extremely difficult. CASE REPORT We present an unenviable and challenging clinical scenario of an obligatory general anesthesia with endotracheal intubation in a patient with difficult airways for breast conserving onco-surgery with simultaneous targeted intraoperative 20 Gy irradiation. The case was complicated even further by coincident suspicious clinical presentation of a mild and self-limited hypercarbia, together with a protracted rhabdomyolysis, without hyperpyrexia. Given the atypical and scarce clinical presentation leading to diagnosis uncertainty of MH or AIR, which was proved only after receiving the genetic results, dantrolene was not administered, and the patient underwent successful supportive treatment. CONCLUSIONS The study points to the diagnostic dilemma - crisis event MH or AIR - and raises issues about possible preoperative preventive measures and treatment options in patients with an uncertain diagnosis.

PMID:39674884 | DOI:10.12659/AJCR.946306

Clin Transl Sci. 2024 Dec;17(12):e70107. doi: 10.1111/cts.70107.

ABSTRACT

Unpredicted responses to sedatives and analgesics are common in critically ill patients on mechanical ventilation (MV) and may be attributed to genetic variation. Our primary aim was to investigate the association between the pharmacogenomic (PGx) variation and sedation outcomes. The secondary aim was to capture intensive care unit (ICU) participants' perceptions of PGx. This was a prospective, observational PGx association study. Adult ICU patients receiving acute MV and sedatives/analgesics were enrolled. The number of altered PGx phenotypes in genes relevant to fentanyl, propofol, and midazolam (CYP2D6, CYP3A4/5, COMT, OPRM1, and CYP2B6) were tested with logistic regression for association with achieving ≥60% and ≥70% of time within Richmond Agitation-Sedation Scale (RASS) target range (0 to -2) in the first 24 and 48 h of MV. Participants' perceptions of PGx testing and satisfaction with the return of PGx results were collected. Participants (n = 78) had a median of 2 altered PGx phenotypes. Fentanyl and propofol combination was the most frequently administered regimen. There were non-significant associations of worse sedation outcomes with an increasing number of altered PGx phenotypes (i.e., adjusted odds ratio of achieving target RASS range = 0.46 to 0.96 for each altered phenotype increase at both 24 and 48 h). Individuals participating in the post-discharge survey had positive perceptions toward PGx. There were no associations between sedation outcomes and PGx variants in the studied 6 genes. Larger studies are needed to investigate the impact of these genes and to evaluate additional genes. ICU participants had positive attitudes and perceptions toward PGx.

PMID:39673727 | DOI:10.1111/cts.70107

Per Med. 2024 Dec 14:1-7. doi: 10.1080/17410541.2024.2441651. Online ahead of print.

ABSTRACT

Pharmacogenomics (PGx), an integral part of functional genomics and molecular pharmacology, has evolved significantly over the past decade. Our study reveals that PGx education in China and the United States has made substantial progress, with a particular emphasis on integrating PGx into medical curricula and clinical practice, leading to improved therapeutic strategies and patient outcomes. Consequently, both China and the United States are dedicated to fostering advancements in PGx education. This paper reviews PGx education in these two countries, highlighting its importance and providing an in-depth look at the current status and challenges within universities and clinical settings. Furthermore, it offers recommendations for advancing PGx education and contemplates future trends in both nations.

PMID:39673279 | DOI:10.1080/17410541.2024.2441651

J Bone Miner Res. 2024 Dec 13:zjae200. doi: 10.1093/jbmr/zjae200. Online ahead of print.

ABSTRACT

Motivated by studies showing an association between beta blocker (BB) use and positive bone outcomes, a pilot randomized control trial (RCT) was performed at the Mayo Clinic which randomized postmenopausal women to placebo, propranolol (40 or 80 mg twice daily), atenolol (50 mg/day), or nebivolol (5 mg/day) to determine changes in bone turnover markers (BTMs) and in bone mineral density (BMD) over 20 weeks. Pharmacogenetic effects and microRNA-mediated mechanisms involving beta adrenergic receptor and related genes have previously been found. We sought to validate these effects and discover new candidates in an ancillary study to the pilot clinical trial. We genotyped all participants and performed microRNA (miRNA) sequencing at baseline and at 20 weeks for 24 participants from the atenolol or placebo groups. We discovered several variants in ADRB1, ADRB2, and HDAC4 which showed significant pharmacogenetic effects with BMD at multiple sites and with BTMs. Our miRNA results showed a significant treatment effect for miR-19a-3p over time with atenolol use in the low-responder group compared to placebo. Overall, the longitudinal miRNA analysis showed a large number of miRNAs which were up-regulated over the trial in the low responders but not the high responders compared to placebo, of which miR-19a-3p was one example. Finally, we compared the response to atenolol treatment for cardiovascular traits (pulse, blood pressure) with the response for the bone resorption marker, CTX, and found a largely independent effect. Our results have implications for personalized therapy and for understanding mechanisms of BB treatment effect on bone.

PMID:39673185 | DOI:10.1093/jbmr/zjae200

Eur J Pharm Sci. 2024 Dec 11:106987. doi: 10.1016/j.ejps.2024.106987. Online ahead of print.

ABSTRACT

BACKGROUND: Genetic variants in absorption, distribution, metabolism, and excretion (ADME) genes affect drug efficacy and side effects. Whole-exome sequencing (WES) effectively identifies these variants. Findings from Western populations may not apply to the Han Chinese population due to ethnic differences.

OBJECTIVE: This study aimed to investigate genetic variants, metabolic phenotypes, and drug impacts related to ADME genes in the Han Chinese population using WES data.

METHODS: ADME genes and drug profiles were sourced from multiple databases. WES data were collected from 357 samples at Third Xiangya Hospital and 5,000 samples from the "Huabiao Project." After WES, fastp was used for quality control; BWA, samtools, and the Picard software were used for comparison, sequencing, and de-duplication; GATK was used for base quality score recalibration; and variant quality score recalibration was carried out after detecting the variants, and the variants were annotated using ANNOVAR. ADME genes and drug profiles were obtained through PharmGKB and other databases, and then all variants in the exonic regions of ADME genes were extracted. The distributional characteristics of these variants, ethnic differences, and metabolic phenotype distribution of important ADME genes, such as CYP2B6, were analyzed. Prediction of deleterious variants of ADME gene employed the ADME gene variant prediction framework, and western blotting and enzyme assays were used to validate the impact of harmful variants.

RESULTS: We integrated 604 ADME genes and 972 drugs. There were 33,925 single nucleotide polymorphisms (SNPs) and 484 insertion-deletions (InDels) in 5,357 Han Chinese WES samples; 88.9% were rare. Of the SNPs, 60.9% are new functional mutations in enzyme and transporter genes; InDels also affected these genes. We discovered Chinese-specific variants in key ADME genes and ethnic-specific metabolic phenotypes that could affect drug use. Finally, we screened 3,657 potentially harmful mutations; 45.6% are novel. Western blotting and enzyme activity assays confirmed several harmful mutations significantly reduced CYP2C19 gene expression and function (P < 0.01).

PMID:39672213 | DOI:10.1016/j.ejps.2024.106987

Ageing Res Rev. 2024 Dec 11:102638. doi: 10.1016/j.arr.2024.102638. Online ahead of print.

ABSTRACT

Glial cell polarization plays a pivotal role in various neurological disorders. In response to distinct stimuli, glial cells undergo polarization to either mitigate neurotoxicity or facilitate neural repair following injury, underscoring the importance of glial phenotypic polarization in modulating central nervous system function. This review presents an overview of glial cell polarization, focusing on astrocytes and microglia. It explores the involvement of glial polarization in neurological diseases such as Alzheimer's disease, Parkinson's disease, stroke, epilepsy, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis and meningoencephalitis. Specifically, it emphasizes the role of glial cell polarization in disease pathogenesis through mechanisms including neuroinflammation, neurodegeneration, calcium signaling dysregulation, synaptic dysfunction and immune response. Additionally, it summarizes various therapeutic strategies including pharmacological treatments, dietary supplements and cell-based therapies, aimed at modulating glial cell polarization to ameliorate brain dysfunction. Future research focused on the spatio-temporal manipulation of glial polarization holds promise for advancing precision diagnosis and treatment of neurological diseases.

PMID:39672208 | DOI:10.1016/j.arr.2024.102638

Gynecol Oncol. 2024 Dec 12;192:145-154. doi: 10.1016/j.ygyno.2024.12.004. Online ahead of print.

ABSTRACT

OBJECTIVE: To evaluate the prognostic impact of circulating tumor DNA (ctDNA) detection at diagnosis (T0) and its early decrease after one cycle (T1) of neoadjuvant chemotherapy (NACT) in patients with advanced epithelial ovarian cancer (EOC) included in the CHIVA trial (NCT01583322).

METHODS: Blood samples were collected at T0 and before each administration of NACT. Circulating tumor DNA detection was performed by next-generation sequencing. Multivariate analysis was performed. A p-value of 0.05 was considered significant. Progression-free survival (PFS) and overall survival (OS) were compared between groups defined by ctDNA kinetic profile. Cox survival model was used to search variables associated with PFS and OS. Kaplan-Mayer curve was used to graphically express the differences in PFS and OS. A log-rank test compared the two curves.

RESULTS: 188 patients were included. Blood samples were available for 168 patients at T0 and for 160 patients at T0 and T1 to assess ctDNA ratio kinetics. At T0, 107 patients (63.7 %) had detectable ctDNA. At T1, 137 (85.6 %) patients had negative ctDNA or a decrease of more than 80 %. There was a significant benefit in either PFS (p = 0.0017) or OS (p = 0.0036) in favor of early decrease of ctDNA ratio. A favorable decrease was associated with a greater likelihood of being able to perform CRS (OR: 3.94 (CI95 % 1.45-10.70), p = 0.0074).

CONCLUSIONS: Early decrease of ctDNA ratio can provide prognostic information early in the management of patients, allowing a more accurate information to patients and an early preparation for CRS (prehabilitation).

PMID:39671779 | DOI:10.1016/j.ygyno.2024.12.004

Pac Symp Biocomput. 2025;30:457-472.

ABSTRACT

Adverse drug responses (ADRs) result in over 7,000 deaths annually. Pharmacogenomic studies have shown that many ADRs are partially attributable to genetics. However, emerging data suggest that epigenetic mechanisms, such as DNA methylation (DNAm) also contribute to this variance. Understanding the impact of DNA methylation on drug response may minimize ADRs and improve the personalization of drug regimens. In this work, we identify DNA methylation sites that likely impact drug response phenotypes for anticoagulant and cardiometabolic drugs. We use instrumental variable analysis to integrate genome-wide association study (GWAS) summary statistics derived from electronic health records (EHRs) within the U.K. Biobank (UKBB) with methylation quantitative trait loci (mQTL) data from the Genetics of DNA Methylation Consortium (GoDMC). This approach allows us to achieve a robust sample size using the largest publicly available pharmacogenomic GWAS. For warfarin, we find 71 DNAm sites. Of those, 8 are near the gene VKORC1 and 48 are on chromosome 6 near the human leukocyte antigen (HLA) gene family. We also find 2 warfarin DNAm sites near the genes CYP2C9 and CYP2C19. For statins, we identify 17 DNAm sites. Eight are near the APOB gene, which encodes a carrier protein for low-density lipoprotein cholesterol (LDL-C). We find no novel significant epigenetic results for metformin.

PMID:39670389

Pac Symp Biocomput. 2025;30:229-246.

ABSTRACT

Pharmacogenetics represents one of the most promising areas of precision medicine, with several guidelines for genetics-guided treatment ready for clinical use. Despite this, implementation has been slow, with few health systems incorporating the technology into their standard of care. One major barrier to uptake is the lack of education and awareness of pharmacogenetics among clinicians and patients. The introduction of large language models (LLMs) like GPT-4 has raised the possibility of medical chatbots that deliver timely information to clinicians, patients, and researchers with a simple interface. Although state-of-the-art LLMs have shown impressive performance at advanced tasks like medical licensing exams, in practice they still often provide false information, which is particularly hazardous in a clinical context. To quantify the extent of this issue, we developed a series of automated and expert-scored tests to evaluate the performance of chatbots in answering pharmacogenetics questions from the perspective of clinicians, patients, and researchers. We applied this benchmark to state-of-the-art LLMs and found that newer models like GPT-4o greatly outperform their predecessors, but still fall short of the standards required for clinical use. Our benchmark will be a valuable public resource for subsequent developments in this space as we work towards better clinical AI for pharmacogenetics.

PMID:39670373

Transl Lung Cancer Res. 2024 Nov 30;13(11):2903-2917. doi: 10.21037/tlcr-24-448. Epub 2024 Nov 5.

ABSTRACT

BACKGROUND: Despite the decrease of morbidity rate of non-small cell lung cancer (NSCLC) in recent years, it is still a cancer with poor prognosis. Lung cancers (LCs) are usually diagnosed at a late stage of the disease due to non-specific clinical symptoms. Proper regulation of carnitine levels is important in the context of development and increased risk of cancer cells proliferation. The expression profiles and clinical value of SLC family members in LC remain largely unexplored. The aim of the study was the assessment of SLC22A16, SLC22A5 and SLC6A14 mRNA expression level among patients suffering from NSCLC. The obtained results were compared with the clinical and the pathological features of NSCLC patients.

METHODS: Through reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and bioinformatics studies, the evaluation of carnitine transporting genes (SLC22A16, SLC22A5 and SLC6A14) mRNA levels was performed in order to elucidate their connection to clinical features of patients and influence on overall survival (OS).

RESULTS: The analysis showed a significant difference for the SLC22A5 gene of NSCLC patients and for SLC6A14 and SLC22A5 genes in LUSC patients in terms of sex (P=0.002, P=0.02 and P=0.001, respectively) and in terms of tobacco smoking (P=0.04). Analysis also revealed a significant negative correlation for SLC22A5 and SLC22A16 genes expression level in the lung adenocarcinoma (LUAD) subtype with standardized uptake value (SUV) (r=-0.40, P=0.02 and r=-0.43, P=0.04). The significant downregulation of gene expression compared to normal adjacent tissue was observed for SLC22A5 in lung squamous cell carcinoma (LUSC) and for SLC6A14 in both LUAD and LUSC subtypes. The effect of the SLC22A5, SLC22A16 and SLC6A14 gene expression at the time of diagnosis on the OS time of LC patients revealed that lower expression correlated with a shorter 5 years OS (all P values <0.01). The effects were distinct after division for LUAD and LUSC subtypes.

CONCLUSIONS: The expression levels of genes encoding carnitine transporters are diverse, hinting at a potentially altered carnitine metabolism in LC patients. Notably, this variance is not uniform and exhibits specificity across LC subtypes, with marked distinctions between LUAD and LUSC. The correlation between gene expression levels and OS of patients underlines the prognostic significance of SLC genes within these cancer subtypes.

PMID:39670016 | PMC:PMC11632432 | DOI:10.21037/tlcr-24-448

Genet Med Open. 2023 Mar 8;1(1):100779. doi: 10.1016/j.gimo.2023.100779. eCollection 2023.

NO ABSTRACT

PMID:39669236 | PMC:PMC11613548 | DOI:10.1016/j.gimo.2023.100779

Front Pharmacol. 2024 Nov 28;15:1423214. doi: 10.3389/fphar.2024.1423214. eCollection 2024.

ABSTRACT

BACKGROUND: High-dose methotrexate (HD-MTX) is commonly employed in the treatment of malignant tumors in children and young adults due to its distinctive therapeutic efficacy. Nonetheless, the systemic exposure to MTX often results in liver injury (drug induced liver injury, DILI), thereby imposing limitations on the sustained administration of HD-MTX. Additionally, individual variations including genetic underpinnings attributable to disparities in therapeutic effects and clinical toxicity remain to be elucidated.

METHODS: A total of 374 patients receiving initial HD-MTX treatment were selected for this study, which aimed to establish a predictive model using binary logistic regression and a visual nomogram for DILI risk assessment. Demographic and clinical characteristics were collected at baseline and post-HD-MTX to explore their correlations with the occurrence of DILI. Additionally, genotyping of 25 single nucleotide polymorphisms from drug transporters and enzymes in the folic acid cycle was performed.

RESULT: G allele mutation in ABCB1 rs1128503, *1b/*1b and *1b/*15 haplotypic mutation in SLCO1B1, female gender, and MTX dosage were identified as independent factors for moderate/severe DILI. Patients with GA or AA genotype in ABCB1 rs1128503 showed significant higher 24h MTX concentration than GG, and those with *1b/*1b haplotype group in SLCO1B1 exhibited lower dose adjusted concentration (C/D) than *1a/*1a group. Besides, patient administrated with HD-MTX were more prevalent to have higher C/D levels when using intravenous plus triple intrathecal injection route than those who were using intravenous injection alone. The composite predictive model (ROC curve: AUC = 0.805), comprising above four factors and 24h MTX concentration, exhibited high accuracy.

CONCLUSION: Female gender, recessive mutation in ABCB1 rs1128503, and a range of MTX concentration may be risk factors for increased susceptibility to DILI. Conversely, the *1b/*1b and *1b/*15 mutations in SLCO1B1 may have a protective effect against DILI. The proposed predictive model facilitates early individual risk assessment, enabling the implementation of proactive prevention strategies.

PMID:39669197 | PMC:PMC11634619 | DOI:10.3389/fphar.2024.1423214

J Am Med Inform Assoc. 2024 Dec 12:ocae293. doi: 10.1093/jamia/ocae293. Online ahead of print.

ABSTRACT

OBJECTIVE: This article describes the implementation of preemptive clinical pharmacogenomics (PGx) testing linked to an automated clinical decision support (CDS) system delivering actionable PGx information to clinicians at the point of care at UCSF Health, a large Academic Medical Center.

METHODS: A multidisciplinary team developed the strategic vision for the PGx program. Drug-gene interactions of interest were compiled, and actionable alleles identified. A genotyping platform was selected and validated in-house. Following HIPAA protocols, genotype results were electronically transferred and stored in electronic health records (EHRs). CDS was developed and integrated with electronic prescribing.

RESULTS: We developed a customized PGx program for 56 medications and 15 genes. Two hundred thirty-three pharmacogenomic prescribing alerts and 15 pharmacogenomic testing prompts, approved by clinicians, were built into EHR to deliver actionable clinical PGx information to clinicians.

CONCLUSIONS: Our multidisciplinary team successfully implemented preemptive PGx testing linked to point-of-care CDS to guide clinicians with precise medication decision-making.

PMID:39665424 | DOI:10.1093/jamia/ocae293

Drug Metab Pers Ther. 2024 Dec 13. doi: 10.1515/dmpt-2024-0093. Online ahead of print.

ABSTRACT

The CYP2C19 enzyme is implicated in the metabolism of several clinically used drugs. Its phenotype is usually predicted by genotyping and indicates the expected enzymatic activity for each patient. However, with a few exceptions, CYP2C19 genotyping has not resulted in a reliable prediction of the metabolizer status, since most of the evidence currently available for this prediction comes from research into populations of predominantly European ancestry. Therefore, this review discusses the main factors that may alter the expected phenotype, as well as the urgent need to include ethnically diverse populations in further studies, so that, in the long term, it is possible to establish guidelines appropriate to these groups.

PMID:39663234 | DOI:10.1515/dmpt-2024-0093