J Pain Symptom Manage. 2024 Nov 6:S0885-3924(24)01112-6. doi: 10.1016/j.jpainsymman.2024.10.033. Online ahead of print.

ABSTRACT

CONTEXT: Opioids are the mainstay therapy for patients affected by cancer pain. However, about 10-20% of patients do not benefit from the received analgesic treatment or experience side effects. Genetic variability might account for the variation in individual responses to opioids, both in terms of efficacy and toxicity.

OBJECTIVES: The aim of this genome-wide association study (GWAS) was to identify genetic markers of opioid toxicity, in terms of nausea-vomiting.

METHODS: Cancer patients receiving morphine, oxycodone, buprenorphine, and fentanyl were recruited from different European countries. Data about toxicity (nausea-vomiting score, NVS) and other relevant clinical information were collected, as well as genotyping data. Regression analysis between genotypes of 2,052 patients and NVS was performed, using appropriate covariates, with REGENIE software.

RESULTS: We found 65 variants associated with NVS (P-value < 1.0×10-5). Of note, 14 intronic variants on chromosome 2 were in NPAS2 gene, encoding a circadian transcription factor reported to play a role in another opioid side effect, the alteration of sleep. Some of these variants were previously identified as splicing quantitative trait loci of the NPAS2 gene.

CONCLUSIONS: This is the first GWAS, performed in more than two thousand individually genotyped patients treated with opioids for cancer pain, that investigated the genetic bases of opioid-induced nausea-vomiting. Although further studies are needed to confirm our findings and to characterize the functional role of the identified variants, our results emphasize the importance of performing large pharmacogenomic studies to identify germline variants associated with opioid response, with the ultimate goal of tailoring cancer pain therapies.

PMID:39515597 | DOI:10.1016/j.jpainsymman.2024.10.033

J Psychiatr Res. 2024 Nov 4;180:327-332. doi: 10.1016/j.jpsychires.2024.11.007. Online ahead of print.

ABSTRACT

Comorbid cannabis use disorder (CUD) is disproportionately high in people with bipolar disorder (BD) and has been associated with worsening of BD symptoms. However, many people with BD report regularly using cannabis to ameliorate symptoms, including sleep disturbances. Sleep and circadian rhythm disturbances are hallmark features of BD that often precede the onset of mood symptoms. Genetic studies indicate that circadian disruption may predispose individuals towards both problematic cannabis use and BD, rather than cannabis use directly impacting BD symptoms. To further disentangle these hypotheses, we aimed to investigate the relationship between chronotype, cannabis use disorder (CUD) and BD mood symptoms. Data from 212 participants with BD I from the Pharmacogenomics of Bipolar Disorder study dataset were analyzed for this study. Participants were stratified by those diagnosed with co-morbid CUD and BD symptom variables, including the mean number of mood episodes per year and age of mood symptom onset for both depression and mania symptoms. The Basic Language Morningness scale (BALM) was used to assess chronotype. There was no interaction between morningness levels and CUD on BD symptoms, however both lower morningness and CUD were independently associated with earlier age of mood symptom onset. However, patients who reported initiating cannabis use post mood symptom onset had an earlier mood symptom age of onset compared to those who reported initiating cannabis use prior to mood symptom onset. These findings could provide further evidence that circadian rhythm disruption could be an underlying factor that predisposes individuals toward both CUD and BD.

PMID:39515185 | DOI:10.1016/j.jpsychires.2024.11.007

Front Cell Dev Biol. 2024 Oct 24;12:1462840. doi: 10.3389/fcell.2024.1462840. eCollection 2024.

ABSTRACT

INTRODUCTION: The topoisomerase 1 (TOP1) inhibitor irinotecan is a standard-of-care agent for relapsed Ewing sarcoma (EWS), but its efficacy is limited by chemical instability, rapid clearance and reversibility, and dose-limiting toxicities, such as diarrhea. Indenoisoquinolines (IIQs) represent a new class of clinical TOP1 inhibitors designed to address these limitations.

METHODS: In this study, we evaluated the preclinical efficacy of three IIQs (LMP400, LMP744, and LMP776) in relevant models of EWS. We characterized the pharmacokinetics of IIQs in orthotopic xenograft models of EWS, optimized the dosing regimen through tolerability studies, and tested the efficacy of IIQs in a panel of six molecularly heterogeneous EWS patient-derived xenograft (PDX) models. For each PDX, we conducted whole genome and RNA sequencing, and methylation analysis.

RESULTS: We show that IIQs potently inhibit the proliferation of EWS cells in vitro, inducing complete cell growth inhibition at nanomolar concentrations via induction of DNA damage and apoptotic cell death. LMP400 treatment induced ≥30% tumor regression in two of six PDX models, with more durable regression compared to irinotecan treatment in one of these models. RNA sequencing of PDX models identified a candidate predictive biomarker gene signature for LMP400 response. These data, along with pharmacogenomic data on IIQs in sarcoma cell lines, are available at a new interactive public website: https://discover.nci.nih.gov/rsconnect/EwingSarcomaMinerCDB/.

DISCUSSION: Our findings suggest that IIQs may be promising new agents for a subset of EWS patients.

PMID:39512899 | PMC:PMC11542432 | DOI:10.3389/fcell.2024.1462840

Front Pharmacol. 2024 Oct 24;15:1423049. doi: 10.3389/fphar.2024.1423049. eCollection 2024.

ABSTRACT

INTRODUCTION: L-Asparaginase (L-Asp) is a key drug in the treatment of acute lymphoblastic leukemia (ALL); however, it is commonly associated with the occurrence of adverse events (AE). Risk factors such as age, sex, nutritional status, and some single nucleotide variants (SNVs) in specific genes could be related to hypersensitivity reactions to L-Asp. The objective of this study was to identify the influence of individual characteristics and three SNVs in the GRIA1 and NFATC2 genes on the occurrence of the most significant adverse events caused by the use of L-Asp in Mexican children with ALL.

METHODS: Eighty-five children from ages 0-17 years old diagnosed with ALL were included. The patients were treated at two hospital centers in Mexico. The SNV genotypes of the GRI1A and NFATC2 genes studied were examined using real-time qPCR. The evaluation of AE was carried out according to the Common Terminology Criteria for adverse events, and the determination of anti-L-Asp antibodies was conducted using Western blot immunoassay.

RESULTS: Homozygosity (AA) of the GRIA1 rs4958351 SNV was significantly associated with the occurrence of AE with the use of L-Asp (OR = 4.05; 95% CI = 1.06 to 15.40, p = 0.04) and was strongly associated with the development of anti-L-Asp antibodies (OR = 3.4375, 95% CI = 1.04 to 11.25, p = 0.04). With this, we found a significant risk association for the SNV rs4958351 of the GRIA1 gene. On the other hand, we did not find significant risk associations for the GRIA1 rs6889909 and NFATC2 rs6021191 SNVs, although other populations have shown a significant risk.

DISCUSSION: Our study has some limitations, such as the small sample size, the heterogeneity in adverse events due to the patients' different regions of origin, and the limited ability to conduct a more detailed follow-up on pancreatitis. Additionally, since no significant associations were found between the NFATC2 rs6021191 and GRIA1 rs6889909 SNVs and the development of adverse events or the presence of antibodies due to the use of L-Asp, it is necessary to investigate new specific SNVs that may improve the efficacy and safety of treatment in Mexican children with ALL.

PMID:39512835 | PMC:PMC11540776 | DOI:10.3389/fphar.2024.1423049

Br J Clin Pharmacol. 2024 Nov 7. doi: 10.1111/bcp.16329. Online ahead of print.

ABSTRACT

We report a case of an adult woman of African ancestry who was hospitalized with statin induced- rhabdomyolysis. The patient presented to the emergency room with a 2-week history of worsening muscle pain, nausea, vomiting and low oral intake, 1 month after starting 40 mg daily dose of rosuvastatin. Sequencing of SLCO1B1 coding regions revealed the patient was heterozygous for two SLCO1B1 deleterious variants, c.481+1G>T and c.1463G>C (*9), which are more prevalent in patients of African ancestry. This highlights the importance of pharmacogenetic testing in SLCO1B1, which includes a broader range of genetic variants for patients of African ancestry.

PMID:39511784 | DOI:10.1111/bcp.16329

BMJ Open. 2024 Nov 7;14(11):e089823. doi: 10.1136/bmjopen-2024-089823.

ABSTRACT

INTRODUCTION: Genetic variations impact drug response, driving the need for personalised medicine through pre-emptive pharmacogenetic testing. However, the adoption of pre-emptive pharmacogenetic testing for commonly prescribed drugs, such as statins, outside of tertiary hospitals is limited due to a lack of pharmacoeconomic evidence to support widespread implementation by healthcare policy-makers. The Spanish Consortium for the Implementation of Pharmacogenetics (iPHARMGx Consortium) addresses this by developing a clinical trial master protocol that will govern multiple nested adaptive clinical trials that compare genotype-guided treatments to standard care in specific drug-gene-population triads, asses their cost-efficacy and identify novel biomarkers through advanced sequencing techniques. The first of these studies aims to assess whether a pre-emptive statin therapy genotyping scheme reduces the incidence of statin-associated muscle symptoms (SAMS) in a population at risk of cardiovascular disease susceptible of receiving high-intensity or moderate-intensity doses of statins: The PREVESTATGx trial.

METHODS AND ANALYSIS: the PREVESTATGX trial is a multicentre, adaptive randomised controlled pragmatic phase IV clinical trial nested to the iPHARMGx master protocol with two parallel arms, aiming for superiority. Randomisation will be conducted on an individual basis with a centralised approach and stratification by centre. After inclusion in the trial and genotyping has been performed, subjects will be randomly allocated to experimental group (pharmacogenetic genotype-guided statin prescription) or standard-of-care statin prescription (as deemed by attending physician). The main objective is to assess the efficacy of a statin pre-emptive genotyping strategy in reducing the incidence of SAMS. A total of 225 subjects will be recruited among the 10 participating centres if no futility/efficacy boundary is reached in the prespecified interim analyses. Recruitment will be carried out during a 12-month period and subjects will be followed for a 9-month period.

ETHICS AND DISSEMINATION: The PREVESTATGx trial received ethical approval on 24 April 2024. Results will be disseminated via publication in peer-reviewed journals as well as presentation at international conferences. Trial results will be submitted for publication in an open-access peer-reviewed medical speciality-specific publication.

TRIAL REGISTRATION NUMBER: EU CT number: 2023-509418-12-00/Clinical trial Identifier (ClinicalTrials.gov): NCT06262685. Protocol version 1.2 12 April 2024 (includes non-substantial modification number 14 June 2024). Trial registration of this study can be located at both the EU Clinical Trials Register available from https:// euclinicaltrials.eu/search-for-clinical-trials/?lang=en and https://clinicaltrials.gov. Registration on both websites was done before the enrolment of the first patient complying with European regulations. EU Clinical Trials Register is a primary registry according to the WHO.

PMID:39510769 | DOI:10.1136/bmjopen-2024-089823

PLoS One. 2024 Nov 7;19(11):e0307161. doi: 10.1371/journal.pone.0307161. eCollection 2024.

ABSTRACT

OBJECTIVE: Recent evidence suggests that elevated levels of PD-L1 expression may be linked to early resistance to TKI and reduced survival in NSCLC with EGFR mutations. This study aimed to characterize the clinical and molecular features of EGFR-mutated lung adenocarcinomas and determine the prognostic significance associated with high PD-L1 expression.

MATERIALS AND METHODS: We conducted a retrospective chart review of 103 consecutive patients with advanced EGFR-mutated NSCLC, who received treatment between 01/01/2016 and 30/12/2020, at our institution.

RESULTS: Among the tumors, 17% (n = 18) exhibited high PD-L1 expression (≥50% tumor proportion score), which was associated with a lower prevalence of common EGFR mutations (56% vs. 82%, p = 0.03) and a higher frequency of complex EGFR mutations (28% vs. 7%, p = 0.02). Univariate analysis did not reveal any significant differences in first-line response, progression-free survival, or overall survival between the PD-L1 ≥50% and <50% groups. However, multivariate analysis demonstrated that PD-L1 ≥50% was independently associated with shorter survival (HR = 2.57; 95%CI[1.20-5.55]; p = 0.02), along with male gender (HR = 2.77; 95%CI[1.54-4.19]; p<0.005), presence of liver metastases (HR = 5.80; 95%CI[2.86-11.75]; p<0.005) or brain metastases (HR = 1.99; 95%CI[1.13-3.52]; p = 0.02), and poor general condition at diagnosis (ECOG 3 and 4) (HR = 10.69; 95% CI[4.42-25.85]; p<0.005). Additionally, a trend towards a higher frequency of de novo resistance was observed in the PD-L1 >50% group (7% vs. 17%, p = 0.19).

CONCLUSION: High PD-L1 expression was more commonly found in lung adenocarcinomas with uncommon and complex EGFR mutations. Furthermore, high PD-L1 expression independently predicted poor survival. These findings warrant validation through prospective studies.

PMID:39509381 | DOI:10.1371/journal.pone.0307161

Front Pharmacol. 2024 Oct 23;15:1478381. doi: 10.3389/fphar.2024.1478381. eCollection 2024.

ABSTRACT

This report describes a pediatric case of isolated agranulocytosis occurring months after hematopoietic stem cell transplantation (HSCT). Secondary cytopenia, or secondary transplant failure, affects 10%-25% of HSCT recipients, with potential triggers including viral infection, graft-versus-host disease (GVHD), sepsis, and certain medications. Viral reactivation was ruled out based on negative PCR results, while GVHD and sepsis were ruled out based on the patient's clinical presentation. The patient, who received an HLA 10/10 unrelated donor T-cell transplant, underwent standard myeloablative conditioning to minimize the risk of graft rejection. However, agranulocytosis persisted even after discontinuation of myelotoxic drugs such as valganciclovir and ruxolitinib. Further investigation revealed that the patient had been taking febuxostat, which was subsequently discontinued, leading to a recovery of the neutrophil count. The European Medicines Agency lists agranulocytosis as a rare side effect of febuxostat. The effect of candidate genes and variants involved in febuxostat pharmacokinetics and pharmacodynamics was done using the Pharmacogenomics Knowledge Base (PharmGKB) to accurately evaluate an individual's risk for neutropenia. This case suggests that genetic variants in renal transporters ABCG2 (exonic non-synonymous variant, rs2231137), SLC29A1 (rs747199 and rs628031), and ABCC4 (3'UTR SNP, rs3742106 and rs11568658) may contribute to drug-induced agranulocytosis. This finding underscores the importance of genetic profiling in the management of patients undergoing HSCT to prevent adverse drug reactions.

PMID:39508043 | PMC:PMC11537990 | DOI:10.3389/fphar.2024.1478381

Front Pharmacol. 2024 Oct 23;15:1477755. doi: 10.3389/fphar.2024.1477755. eCollection 2024.

ABSTRACT

BACKGROUND AND AIMS: A number of case reports have documented the occurrence of acute hepatic and renal toxicity during treatment with deferasirox (DFX). The precise mechanisms underlying these adverse events remain unclear, with the time to toxicity varying considerably between patients-some experiencing it within weeks of treatment initiation, while others after several years. Recent studies have underscored the association of pharmacogenetic variants in genes responsible for the metabolism and clearance of DFX (ABCC2, ABCG2, and UGT1A1) in the development of toxicity. We present the case of an 8-year-old patient with beta thalassemia major who developed acute hepatic failure years after the initiation of DFX therapy. After ruling out the most likely causes, we performed a pharmacogenetic analysis, which suggested a possible link between the patient's genotype and the development of toxicity.

METHODS: Sanger sequencing was performed for the most extensively studied single nucleotide polymorphisms (SNPs) studied associated with changes in transporter/enzyme function: ABCC2 rs717620 (c.-24C>T), rs2273697 (c.1249G>A), rs8187710 (c.4544G>A), rs369192412 (g.99781071delG); ABCG2 rs2231142 (c.421C>A); UGT1A1 *6 rs4148323 (c.211G>A), *28 rs3064744 (g.233760235TA[8]), *36 rs3064744 (g.233760235TA[6]) and *37 rs3064744 (g.233760235TA[9]).

RESULTS: The patient is heterozygous for two ABCC2 variants, namely rs717620 (c.-24C>T) and rs2273697 (c.1249G>A). These variants have the potential to cause a reduction in transporter function, which could in turn result in decreased drug clearance and increased toxicity.

DISCUSSION: The precise mechanism by which toxicity developed in this case remains unclear and is likely multifactorial. However, it is probable that the presence of SNPs in the gene ABCC2 played a substantial role. Our findings align with those of previously published reports of remarkably similar cases, where patients also exhibited genetic variants in the gene ABCC2.

PMID:39508042 | PMC:PMC11538451 | DOI:10.3389/fphar.2024.1477755

Heliyon. 2024 Oct 18;10(20):e39157. doi: 10.1016/j.heliyon.2024.e39157. eCollection 2024 Oct 30.

ABSTRACT

BACKGROUND: Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases. Their treatment options are rather limited, and no neuroprotective or disease-modifying treatments are available. Anti-diabetic drugs, such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) agonists, have been suggested as a potential therapeutic option.

AIMS: Assess GLP1R and GIPR genetic variability in relation to AD- and PD-related phenotypes.

METHODS: AD, PD patients and healthy control subjects were included in the study. Cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease were measured in AD patients, while cognitive impairment was evaluated in PD. All participants were genotyped for three SNPs: GLP1R rs10305420, GLP1R rs6923761 and GIPR rs1800437.

RESULTS: GLP1R rs10305420 genotypes were associated with increased odds for AD and PD development. GLP1R rs10305420 and GLP1R rs6923761 genotypes were significantly associated with Aβ42/40 ratio (p = 0.041 and p = 0.050), while GLP1R rs6923761 was also associated with p-tau levels (p = 0.022). Finally, GIPR rs1800437 heterozygotes as well as carriers of at least one GIPR rs1800437 C allele presented with increased odds for the development of dementia in PD (OR = 1.92; 95 % CI = 1.05-3.51; p = 0.034 and OR = 1.95; 95 % CI = 1.08-3.52; p = 0.027, respectively).

CONCLUSION: GLP1R and GIPR genetic variability may affect the occurrence of AD and PD and is also associated with AD CSF biomarkers for Alzheimer's disease and dementia in PD. The data on GLP1R and GIPR genetic variability may support the function of incretin receptors in neurodegeneration.

PMID:39506938 | PMC:PMC11538737 | DOI:10.1016/j.heliyon.2024.e39157

Sci Rep. 2024 Nov 6;14(1):26988. doi: 10.1038/s41598-024-78619-5.

ABSTRACT

Natural killer (NK) cells recognize and may kill malignant cells via their cell surface receptors. Killer cell immunoglobulin-like receptor (KIR) genotypes of donors have been reported to adjust the risk of relapse after allogeneic stem cell transplantation (HSCT), particularly in patients with acute myeloid leukemia. To test whether non-KIR NK cell receptors have a similar effect, we screened 1,638 genetic polymorphisms in 21 non-KIR NK cell receptor genes for their associations with relapse and graft-versus-host disease (GVHD) after HSCT in 1,491 HSCT donors (from Finland, the UK, Spain, and Poland), divided into a discovery and replication cohort. Eleven polymorphisms regulating or located in CD226, CD244, FCGR3A, KLRD1, NCR3, and PVRIG were associated with the risks for relapse and GVHD. These associations could not be confirmed in the replication cohort. Blood donor NK cells carrying alleles showing genetic protection for relapse had a higher in vitro NK cell killing activity than non-carriers whereas those with alleles genetically protective for GVHD had lower cytotoxicity, potentially indicating functional effects. Taken together, these results show no robust effects of genetic variation in the tested non-KIR NK cell receptors on the outcome of HSCT.

PMID:39506082 | DOI:10.1038/s41598-024-78619-5

Cell Mol Neurobiol. 2024 Nov 6;44(1):74. doi: 10.1007/s10571-024-01504-2.

ABSTRACT

The global public health addiction crisis has been stark, with over 932,400 deaths in the USA and Canada from opioid overdose since 1999-2020, surpassing the mortality rates at the top of the HIV/AIDS epidemic. Both nations exhibit opioid consumption rates significantly above the norm for developed countries. Analgesic type of opioids present both therapeutic benefits and substantial health risks, necessitating balanced drug regulation, careful prescribing, and dedicated opioid stewardship. The role of the cytochrome P450 2D6 (CYP2D6) system (Enzymatic functions) in metabolizing opioids highlights the potential of genotype-guided analgesia. By integrating Pharmacogenomics (PGx), this approach aims to optimize pain management, enhance safety, and reduce addiction risks. This understanding prompted the utilization of multifactor dimensionality reduction (MDR) to explore a range of phenotypes including PGx and gene-gene interactions (GGI) in a healthy cohort, thereby personalizing pain management strategies. The study sampled 100 unrelated healthy Western Iranians and 100 individuals from the 1000 Genome Project. Pre-testing involved searching for PGx annotations (variants associated with drug-gene-diseases) related to pain sensitivity and inflammation using the PharmGKB database, which identified 128 relevant genes. A questionnaire helped select 100 participants who had never used potent opioids but also other psychoactive agents (e.g., nicotine, amphetamines, etc.) and disease-related drugs. Whole-exome sequencing (WES) was then employed to analyze these genes in an Iranian cohort. Further analyses included MDR for identifying synergistic gene annotations and GGI for exploring complex gene interactions through the Visualization of Statistical Epistasis Networks (ViSEN). The study identified a Pain, Anti-Inflammatory, and Immunomodulating agents (PAIma) panel from the 128 genes, resulting in 55,590 annotations across 21 curated pathways. After filtering, 54 significant structural or regulatory variants were identified. This research also highlighted novel gene relationships involving the CYP3A5 gene, hsa-miR-355-5p, Paliperidone, and CYP2D6, which warrant further investigation. This study offers a novel pharmacogenetic framework that could potentially transform opioid prescribing practices to mitigate misuse and enhance personalized pain management. Further validation of these findings from multi countries and ethnic groups could guide clinicians in implementing DNA-based opioid prescribing, aligning treatment more closely with individual genetic profiles.

PMID:39505757 | DOI:10.1007/s10571-024-01504-2

Transplant Cell Ther. 2024 Nov 4:S2666-6367(24)00745-0. doi: 10.1016/j.jtct.2024.10.016. Online ahead of print.

ABSTRACT

BACKGROUND: Malignancy is a well-known risk factor for venous thromboembolism (VTE), and the Khorana risk score is effective for screening solid tumor patients. However, there is a lack of validated screening tools and established risk factors for patients undergoing hematopoietic stem cell transplant (HCT). Current literature reports VTE incidence in HCT patients ranging from 2.5% to 8.5%. Anticoagulation is difficult to manage post-transplant given prolonged thrombocytopenia and the likelihood of bleeding. By identifying risk factors, a predictive model may be developed to prospectively test prophylaxis strategies in patients at the highest thromboembolic event (TE) risk.

OBJECTIVES: This study evaluated the cumulative incidence of TE at 6 months following allogeneic and autologous HCTs. This study also aimed to identify risk factors for developing TE, to evaluate time from HCT to TE, and to compare one-year survival following HCT between patients experiencing TE and those who did not.

STUDY DESIGN: This is a retrospective single-center study evaluating the incidence of TE events in adult subjects undergoing HCT between March 2014 and December 2019. ICD-9 and ICD-10 codes were used to determine cancer diagnosis, TE events up 180 days after HCT, and comorbidities of interest. Each subject was reviewed for data accuracy by manual retrospective chart review. The study employed statistical tests such as the cumulative incidence method with competing risks, Gray's test, and univariate and multivariate Cox proportional hazards models to analyze the time to first thromboembolic (TE) event, evaluate risk factors, and assess 1-year survival post-HCT in relation to TE events within 180 days of HCT. Variables examined included age, sex, body mass index (BMI), transplant type, hospital length of stay, history of TE prior to transplant, active infections, graft-versus-host disease (GVHD), veno-occlusive disorder (VOD), cytomegaly virus (CMV) and other factors.

RESULTS: The study included 636 evaluable patients; the majority were male (57.9%), white (68.7%), and underwent an autologous HCT (68.4%). Twenty-nine patients (4.6%) experienced a TE event within 180 days post-transplant. TE events were more common in the allogeneic transplant group (n=13/201, 6.5%) than the autologous transplant group (n=16/435, 3.7%) (p=0.122). The cumulative incidence of TE was higher in patients who developed an active infection than those who did not (7.6% vs 3.1%, P=.011). Hospital LOS [HR 1.03, 95% CI 1.0-1.06, p=0.036] and active infection [HR 2.34, 95% CI 1.1-4.95, p=0.027] were significantly associated with TE in the univariate analysis but were not retained in the final multivariate model. There was no difference in one-year survival among all patients who experienced a TE event and those who did not; however, in the autologous HCT subgroup, one-year survival rate was significantly lower in those with TE compared to those without TE (Figure 3c, 80.4% vs 95.3%, P=.01). Examined variables, including history of TE event and GVHD, were not associated with TE event risk.

CONCLUSION: While the overall incidence of TE in our study was low, many patients received pharmacologic or mechanical prophylaxis, suggesting such strategies may be effective in mitigating TE risk. Factors such as infection and hospital LOS may further increase TE risk. Providers should continuously monitor for risk factors and signs and symptoms of TE post-transplant. It is also imperative to consider chemical prophylaxis if counts are recovered while hospitalized.

PMID:39505211 | DOI:10.1016/j.jtct.2024.10.016

Ther Drug Monit. 2024 Nov 5. doi: 10.1097/FTD.0000000000001276. Online ahead of print.

ABSTRACT

The use of noninvasive biomarkers may reduce the need for biopsy and guide immunosuppression adjustments during transplantation. The scientific community in solid organ transplantation currently considers that chemokines, T- and B-cell immunophenotypes, and gene expression, among other molecular biomarkers, have great potential as diagnostic and predictive biomarkers for graft evolution; however, in clinical practice, few valid early biomarkers have emerged. This review focuses on the most relevant scientific advances in this field in the last 5 years regarding the role of 3 biomarkers: miRNAs, chemokines, and ddcf-DNA, in both adult and pediatric populations. An update was provided on the scores based on the combination of these biomarkers. The most-featured articles were identified through a literature search of the PubMed database. This review provides a comprehensive analysis of the potential clinical applications of these biomarkers in the diagnosis and prediction of graft outcomes and discusses the reasons why none have been implemented in clinical practice to date. Translating these biomarkers into routine clinical practice and combining them with pharmacogenetics and pharmacokinetic monitoring is challenging; however, it is the key to present/future individualized immunosuppressive therapies. It is essential that they be shown to be applicable and robust in real-life patient conditions and properly evaluate their added value when combined with the standard-of-care factor monitoring for graft clinical assessment. Partnership strategies among scientists, academic institutions, consortia, including expert working groups and scientific societies, and pharmaceutical and/or biotechnology companies should promote the development of prospective, randomized, multicenter intervention studies for adequate clinical validation of these biomarkers and their monitoring frequency, and their commercialization to make them available to transplant physicians.

PMID:39503575 | DOI:10.1097/FTD.0000000000001276

Drug Metab Pers Ther. 2024 Nov 6. doi: 10.1515/dmpt-2024-0015. Online ahead of print.

ABSTRACT

OBJECTIVES: Ibuprofen, a widely used non-steroidal anti-inflammatory (NSAID) for managing pain and inflammation in pediatric patients, is metabolized by the CYP2C8 enzyme. Studies suggest that the CYP2C8*2, *3, and *4 variations of the CYP2C8 gene diminish ibuprofen metabolism, increasing the risk of adverse reactions. The aim of this study was to determine the frequency of the CYP2C8*2, *3, and *4 alleles and genotypes in a pediatric population attending the King Abdulaziz University dental clinic and compare our findings to those of other populations.

METHODS: A cross-sectional study was conducted with 140 healthy Saudi children ages 6-12. Saliva samples were collected using Oragene™ DNA Sample Collection Kits and analyzed for polymorphisms using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).

RESULTS: The study identified that CYP2C8*2 AA, AT, and TT genotypes occurred at frequencies of 87.86 %, 9.29 %, and 2.86 %, respectively. For CYP2C8*3, AA, AG, and GG genotypes were found in 87.14 , 8.75, and 4.29 % of subjects, respectively. The CYP2C8*4 allele was less frequent, with CC and CG genotypes at 97.86 % and 2.14 %, respectively, and the GG genotype was absent. Allele frequencies for CYP2C8*2, *3, and *4 were 7.5 %, 8.57 %, and 1.07 %, respectively.

CONCLUSIONS: Our findings reveal that the allelic frequencies for the CYP2C8 polymorphisms in the Saudi pediatric cohort are substantially elevated compared to those reported in other Asian populations. This suggests Saudis may experience more varied drug responses, especially for medications that undergo metabolism by the CYP2C8 enzyme, like ibuprofen.

PMID:39501421 | DOI:10.1515/dmpt-2024-0015

NPJ Genom Med. 2024 Nov 5;9(1):56. doi: 10.1038/s41525-024-00443-7.

ABSTRACT

Vincristine-induced peripheral neuropathy is a common and highly debilitating toxicity from vincristine treatment that affects quality of life and often requires dose reduction, potentially affecting survival. Although previous studies demonstrated genetic factors are associated with vincristine neuropathy risk, the clinical relevance of most identified variants is limited by small sample sizes and unclear clinical phenotypes. A genome-wide association study was conducted in 1100 cases and controls matched by vincristine dose and genetic ancestry, uncovering a statistically significant (p < 5.0 × 10-8) variant in MCM3AP gene that substantially increases the risk of neuropathy and 12 variants protective against neuropathy within/near SPDYA, METTL8, PDE4D, FBN2, ZFAND3, NFIB, PAPPA, LRRTM3, NRG3, VTI1A, ARHGAP5, and ACTN1. A follow-up pathway analysis reveals the involvement of four key pathways, including nerve structure and development, myelination, neuronal transmission, and cytoskeleton/microfibril function pathways. These findings present potential actionable genomic markers of vincristine neuropathy and offer opportunities for tailored interventions to improve vincristine safety in children with cancer. This study is registered with ClinicalTrials.gov under the title National Active Surveillance Network and Pharmacogenomics of Adverse Drug Reactions in Children (ID NCT00414115, registered on December 21, 2006).

PMID:39500896 | DOI:10.1038/s41525-024-00443-7

Pharmacogenomics J. 2024 Nov 5;24(6):33. doi: 10.1038/s41397-024-00355-w.

ABSTRACT

Cisplatin is widely used as a conventional chemotherapy drug for lung adenocarcinoma (LUAD) patients. However, the chemical resistance greatly limits its therapeutic potential. The study aimed to uncover the specific role and new mechanisms of CPT1B in the cisplatin resistance of LUAD. Bioinformatics analysis was utilized to analyze the expression level and enriched pathway of CPT1B in LUAD. The expression of CPT1B in LUAD cells was determined by utilizing quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot (WB). The cisplatin resistance in LUAD was measured with IC50 values obtained from the CCK-8 assay. We used the corresponding reagent kit and WB analysis to determine the levels of triglycerides, cholesterol, phospholipids, fatty acid β-oxidation (FAO) rate, and expression of lipid metabolism-related proteins. Finally, the regulation relationship between CPT1B and ZNF263 was confirmed through bioinformatics analysis, dual-luciferase, and chromatin immunoprecipitation assays. The present investigation revealed that CPT1B was upregulated in LUAD, participating in fatty acid metabolism pathways. In vitro studies have shown that upregulation of CPT1B promoted cisplatin resistance in LUAD cells. This promotion effect induced by the high expression of CPT1B on cisplatin resistance in LUAD was weakened after the addition of the FAO inhibitor Etomoxir. Mechanistically, ZNF263 was capable of binding to the promoter of CPT1B to activate its transcription, thereby enhancing FAO and promoting cisplatin resistance in LUAD cells. In summary, ZNF263 enhances cisplatin resistance in LUAD cells by upregulating CPT1B expression. This study enriches the molecular mechanisms of LUAD chemotherapy resistance and provides new directions for exploring therapeutic targets for LUAD.

PMID:39500874 | DOI:10.1038/s41397-024-00355-w

BMJ Open. 2024 Nov 5;14(11):e087064. doi: 10.1136/bmjopen-2024-087064.

ABSTRACT

INTRODUCTION: Pharmacogenomic testing (PGx) plays a crucial role in improving patient medication safety, yet ethical concerns and limitations impede its clinical implementation in the primary care settings.

AIMS: To systematically review the current state of PGx in the primary care settings and determine the enablers and challenges of its implementation.

DESIGN: A scoping review was carried out by adhering to Arksey and O'Malley's 6-stage methodological framework and the 2020 Joanna Briggs Institute and Levac et al. DATA SOURCES: Cochrane Library, EMBASE, Global Health, MEDLINE and PubMed were searched up to 17 July 2023.

ELIGIBILITY CRITERIA: All peer-reviewed studies in English, reporting the enablers and the challenges of implementing PGx in the primary care settings were included.

DATE EXTRACTION AND SYNTHESIS: Two independent reviewers extracted the data. Information was synthesised based on the reported enablers and the challenges of implementing PGx testing in the primary care settings. Information was then presented to stakeholders for their inputs.

RESULTS: 78 studies discussing the implementation of PGx testing are included, of which 57% were published between 2019 and 2023. 68% of the studies discussed PGx testing in the primary care setting as a disease-specific themes. Healthcare professionals were the major stakeholders, with primary care physicians (55%) being the most represented. Enablers encompassed various advantages such as diagnostic and therapeutic benefits, cost reduction and the empowerment of healthcare professionals. Challenges included the absence of sufficient scientific evidence, insufficient training for healthcare professionals, ethical and legal aspects of PGx data, low patient awareness and acceptance and the high costs linked to PGx testing.

CONCLUSION: PGx testing integration in primary care requires increased consumer awareness, comprehensive healthcare provider training on legal and ethical aspects and global feasibility studies to better understand its implementation challenges. Managing high costs entails streamlining processes, advocating for reimbursement policies and investing in research on innovation and affordability research to improve life expectancy.

PMID:39500605 | DOI:10.1136/bmjopen-2024-087064

Drug Metab Dispos. 2024 Nov 5:DMD-AR-2024-001916. doi: 10.1124/dmd.124.001916. Online ahead of print.

ABSTRACT

Remimazolam (Byfavo®), a recent FDA-approved ester-linked benzodiazepine, offers advantages in sedation, such as rapid onset and predictable duration, making it suitable for broad anesthesia applications. Its favorable pharmacological profile is primarily attributed to rapid hydrolysis, the primary metabolism pathway for its deactivation. Thus, understanding remimazolam hydrolysis determinants is essential for optimizing its clinical use. This study aimed to identify the enzyme(s) and tissue(s) responsible for remimazolam hydrolysis and to evaluate the influence of genetic polymorphisms and drug-drug interactions (DDIs) on its hydrolysis in the human liver. An initial incubation study with remimazolam and phosphate buffer saline (PBS), human serum, and the S9 fractions of human liver and intestine demonstrated that remimazolam was exclusively hydrolyzed by human liver S9 fractions. Subsequent incubation studies utilizing a Carboxylesterase inhibitor (Bis-para-nitrophenylphosphate, BNPP), recombinant human Carboxylesterase1 (CES1) and Carboxylesterase 2 (CES2) confirmed that remimazolam is specifically hydrolyzed by CES1 in human liver. Furthermore, in vitro studies with wild-type CES1 and CES1 variants transfected cells revealed that certain genetic polymorphisms significantly impair remimazolam deactivation. Notably, the impact of CES1 G143E was verified using individual human liver samples. Moreover, our evaluation of the DDIs between remimazolam and several other substrates/inhibitors of CES1-including simvastatin, enalapril, clopidogrel and sacubitril- found that clopidogrel significantly inhibited remimazolam hydrolysis at clinically relevant concentrations, with CES1 genetic variants potentially influencing the interactions. In summary, CES1 genetic variants and its interacting drugs are crucial factors contributing to interindividual variability in remimazolam hepatic hydrolysis, holding the potential to serve as biomarkers for optimizing remimazolam use. Significance Statement This investigation demonstrates that remimazolam is deactivated by CES1 in the human liver, with CES1 genetic variants and DDIs significantly influencing its metabolism. These findings emphasize the need to consider CES1 genetic variability and potential DDIs in remimazolam use, especially in personalized pharmacotherapy to achieve optimal anesthetic outcomes.

PMID:39500567 | DOI:10.1124/dmd.124.001916

Heliyon. 2024 Oct 18;10(20):e39584. doi: 10.1016/j.heliyon.2024.e39584. eCollection 2024 Oct 30.

ABSTRACT

Traditional treatment strategies for recurrent pregnancy loss (RPL) and recurrent implantation failure (RIF) often result in limited success, placing significant emotional and financial burdens on couples. However, novel approaches such as diagnostic gene profiling, cell therapy, stem cell-derived exosome therapy, and pharmacogenomics offer promising, personalized treatments. Combining traditional treatments with precision and regenerative medicine may enhance the efficacy of these approaches and improve pregnancy outcomes. This review explores how integrating these strategies can potentially transform the lives of couples experiencing repeated pregnancy loss or implantation failure, providing hope for improved treatment success. Precision and regenerative medicine represent a new frontier for managing RPL and RIF, offering promising solutions.

PMID:39498089 | PMC:PMC11532865 | DOI:10.1016/j.heliyon.2024.e39584