Int Immunopharmacol. 2025 Jan 3;147:113933. doi: 10.1016/j.intimp.2024.113933. Online ahead of print.

ABSTRACT

BACKGROUND: Neoadjuvant chemotherapy, particularly the use of platinum-based compounds and taxanes, is pivotal in the treatment of epithelial-derived tumors, such as cervical cancer and esophageal squamous cell carcinoma (ESCC); however, resistance remains a significant challenge. Utilizing Mendelian randomization (MR) with pharmacogenomics offers a novel approach to understanding the genetic underpinnings of drug responses, thereby aiding in personalized treatment.

METHODS: Single-cell RNA sequencing (scRNA-seq) analysis revealed a shared cellular subpopulation of CD8 + T effector memory (CD8 + TEM) cells that are pivotal in mediating chemotherapy resistance in ESCC and cervical cancer. A two-sample approach was employed for MR using data from genome-wide association studies, focusing on single nucleotide polymorphisms (SNPs) linked to CD8 + TEM cell expression. The SNPs were carefully selected, and statistical models, including the Wald ratio and inverse variance weighted methods, were used for robust causal effect estimation. These were supplemented by MR-Egger and weighted median analyses to address pleiotropy and variant heterogeneity. 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) and immunohistochemistry assays were used to verify the relationship between the gene and drug sensitivity.

RESULTS: Increased proportion of CD8 + TEM cells were observed in resistant samples. MR identified IL32, SPOCK1, and TRBC2 as key genes associated with resistance to cisplatin, carboplatin, and paclitaxel, respectively. These findings were validated across various cohorts and underscored the role of CD8 + TEM cells in drug responsiveness. The results of the MTT and immunohistochemistry assays confirmed the MR findings.

CONCLUSIONS: Our study highlights the significant role of CD8 + TEM cells in the chemoresistance of ESCC and cervical cancer and identified three genetic markers crucial for resistance to common chemotherapeutic agents. These findings suggest potential pathways for developing personalized treatment strategies, offering clinically relevant insights that could enhance therapeutic efficacy and help overcome drug resistance in patients with ESCC or cervical cancer.

PMID:39755112 | DOI:10.1016/j.intimp.2024.113933

J Cannabis Res. 2025 Jan 4;7(1):1. doi: 10.1186/s42238-024-00256-6.

ABSTRACT

BACKGROUND: Differences in cannabinoid metabolism and patient responses can arise even with equivalent doses and formulations. Genetic polymorphisms in genes responsible for cannabinoid metabolism and medications that alter CYP450 pathways responsible for metabolism of cannabinoids may account for some of this variability.

MATERIALS AND METHODS: A retrospective chart review was conducted on a cohort of unselected patients who had previously completed pharmacogenomic testing and reported oral cannabis use, as defined as "oral" or "by mouth" route of administration. The objective was to identify atypical variants and medications in this cohort and formulate a hypothesis on how these variables influence the metabolism of Tetrahydrocannabinol (THC) and Cannabidiol (CBD).

RESULTS: Oral cannabis use was confirmed in 71 patients, with an average age of 68.5 years, and primarily white women. Of the 71 patients, 10 had no atypical variants; 31 had atypical variants in CYP2C9; 37 had atypical variants in CYP2C19; 6 had atypical variants in CYP3A4; and 15 had atypical variants in CYP3A5. Of the 71 patients, 5 were taking medications that could interact with THC, and 8 were taking medications that could interact with CBD.

CONCLUSION: The results this study reveal the spectrum of hypothesized alterations in THC and CBD metabolism due to atypical genetic variants and medications. The absence of published clinical outcomes in this field renders it challenging to estimate clinical significance of these findings. Until such data become available, clinicians should remain aware of the possibility that atypical variants and medications may impact patients' responses to THC and CBD.

PMID:39754268 | DOI:10.1186/s42238-024-00256-6

Cell. 2024 Dec 31:S0092-8674(24)01380-1. doi: 10.1016/j.cell.2024.12.001. Online ahead of print.

ABSTRACT

Animals have evolved pH-sensing membrane receptors, such as G-protein-coupled receptor 4 (GPR4), to monitor pH changes related to their physiology and generate adaptive reactions. However, the evolutionary trajectory and structural mechanism of proton sensing by GPR4 remain unresolved. Here, we observed a positive correlation between the optimal pH of GPR4 activity and the blood pH range across different species. By solving 7-cryoelectron microscopy (cryo-EM) structures of Xenopus tropicalis GPR4 (xtGPR4) and Mus musculus GPR4 (mmGPR4) under varying pH conditions, we identified that protonation of HECL2-45.47 and H7.36 enabled polar network establishment and tighter association between the extracellular loop 2 (ECL2) and 7 transmembrane (7TM) domain, as well as a conserved propagating path, which are common mechanisms underlying protonation-induced GPR4 activation across different species. Moreover, protonation of distinct extracellular HECL2-45.41 contributed to the more acidic optimal pH range of xtGPR4. Overall, our study revealed common and distinct mechanisms of proton sensing by GPR4, from a structural, functional, and evolutionary perspective.

PMID:39753131 | DOI:10.1016/j.cell.2024.12.001

Forensic Sci Int Genet. 2024 Dec 24;76:103218. doi: 10.1016/j.fsigen.2024.103218. Online ahead of print.

ABSTRACT

Genetic polymorphism can cause variation in tramadol (TR) pharmacokinetic characteristics and the expected clinical response. In forensic toxicology, the data about parent and metabolite concentrations (MRs; metabolic ratios) could facilitate to determine the cause of death and to assess time between drug intake and death. In this study, the aim was to investigate if UGT1A8, UGT2B7, ABCC2, and SLC22A1 genotyping can facilitate interpretation by investigating the frequency of UGT1A8, UGT2B7, ABCC2, and SLC22A1 genotypes in forensic autopsy cases positive for TR and to assess whether there is a correlation between these genetic variants and MRs. Cases positive for TR (n = 48) were genotyped by HaloPlex Target Enrichment system for UGT1A8, UGT2B7, ABCC2, and SLC22A1 sequencing, in order to identify single nucleotide polymorphisms (SNPs) and/or insertion deletion (INDELs). In addition to, the concentrations of TR and its metabolites (M1 & M2) were determined by LC-MS/MS. Cases were categorized by cause of death. The investigated SNPs/INDELs were not overrepresented in any group. We found significant correlations between several loci (12 out of 73) in UGT1A8, ABCC2, and SLC22A1 genes and MRs (M2/M1, TR/M2, and TR/M1) in post-mortem TR cases. These results indicate these polymorphisms in the 4 investigated genes might influence TR pharmacokinetics leading to an unsatisfactory therapeutic effect or increasing the risk of toxicity. However, these findings should be supported in future studies with larger groups of cases.

PMID:39752799 | DOI:10.1016/j.fsigen.2024.103218

Clin Chem. 2025 Jan 3;71(1):36-44. doi: 10.1093/clinchem/hvae181.

ABSTRACT

Pharmacogenomics (PGx) is focused on the relationship between an individual's genetic makeup and their response to medications, with the overarching aim of guiding prescribing decisions to improve drug efficacy and reduce adverse events. The PGx and genomic medicine communities have worked independently for over 2 decades, developing separate standards and terminology, making implementation of PGx across all areas of genomic medicine difficult. To address this issue, the Clinical Genome Resource (ClinGen) Pharmacogenomics Working Group (PGxWG) was established by the National Institutes of Health (NIH)-funded ClinGen to initially create frameworks for evaluating gene-drug response clinical validity and actionability aligned with the ClinGen frameworks for evaluating monogenic gene-disease relationships, and a framework for classifying germline PGx variants similar to the American College of Medical Genetics (ACMG) and Association of Molecular Pathology (AMP) system for interpretation of disease-causing variants. These frameworks will leverage decades of work from well-established PGx resources facilitating buy-in among PGx stakeholders. In this report, we describe the background and major activities of the ClinGen PGxWG, and how this initiative will facilitate the critical inclusion of PGx into the larger context of genomic medicine.

PMID:39749515 | DOI:10.1093/clinchem/hvae181

Eur Rev Med Pharmacol Sci. 2024 Dec;28(24):4712-4722. doi: 10.26355/eurrev_202412_37005.

ABSTRACT

OBJECTIVE: CYP2D6 plays a critical role in metabolizing tamoxifen into its active metabolite, endoxifen, which is crucial for its therapeutic effect in estrogen receptor-positive breast cancer. Single nucleotide polymorphisms (SNPs) in the CYP2D6 gene can affect enzyme activity and thus impact tamoxifen efficacy. This study aimed to use machine learning algorithms (MLAs) to identify significant predictors of Breast Cancer-Free Interval (BCFI) and to apply bioinformatics tools to investigate the structural and functional implications of CYP2D6 SNPs.

PATIENTS AND METHODS: The study utilized data from 4,974 breast cancer patients recruited by the International Tamoxifen Pharmacogenomics Consortium (ITPC), focusing on 898 patients with available BCFI data. Predictors included age, ethnicity, menopausal status, breast cancer grade, CYP2D6 genotype, and BCFI. An ensemble MLA model was developed, incorporating regression, CHAID, artificial neural networks (ANN), and classification and regression trees (CART). Bioinformatics tools, such as STRING-DB and GEPIA2, were used to analyze protein-protein interactions and survival data related to CYP2D6.

RESULTS: The ensemble model identified age and CYP2D6 genotypes as significant predictors of BCFI. The mean prediction error for the training and testing cohorts was 13.8 and 40.2 days, respectively. Bioinformatics analysis revealed reduced CYP2D6 functional activity associated with decreased survival, and Kaplan-Meier analysis demonstrated that lower CYP2D6 expression significantly reduced survival rates.

CONCLUSIONS: This study highlights the utility of MLAs in identifying key predictors of tamoxifen response and the value of bioinformatics in understanding CYP2D6's role in breast cancer outcomes. Personalized treatment approaches based on CYP2D6 metabolizer status could enhance tamoxifen therapy effectiveness.

PMID:39749373 | DOI:10.26355/eurrev_202412_37005

Pathologica. 2024 Oct;116(5):303-309. doi: 10.32074/1591-951X-1010.

ABSTRACT

OBJECTIVE: Prostate cancer (PCa) is the most common cause of cancer-related deaths in men worldwide. BRCA1/2 genes are reported altered in approximately 1% and 8% of PCa cases, respectively. To date, formalin-fixed paraffin-embedded (FFPE) tissues have a consolidate use in the clinical practice, but with a significant drawback related to DNA/RNA degradation during the pre-analytical process. The purpose of this study is to evaluate the feasibility of detecting BRCA1/2 alterations in DNA extracted from FFPE tissues collected from PCa patients after various years of storage in seven Italian hospitals.

METHODS: A total of 241 DNA samples were extracted from FFPE tissue with different storage times (1-12 y) and sequenced with NGS technology. BRCA1/2 evaluability was assessed performing data analysis with a chi-square test to study the impact of the storage time on the DNA degradation.

RESULTS: The data collected showed a strict relation not only between the storage time and the BRCA1/2 evaluability, but even between the storage time and DNA degradation (DIN). Taken together, all the parameters considered decrease with an increase in the storage time.

CONCLUSIONS: Excessive FFPE tissues storage time (more than 3 years) can harshly affect DNA analysis and evaluability, hindering the achievement of a result useful in the clinical practice. Hence, it should be considered to perform the analysis as soon as possible to increase the evaluability of the test.

PMID:39748712 | DOI:10.32074/1591-951X-1010

Ann Acad Med Singap. 2024 Dec 26;53(12):734-741. doi: 10.47102/annals-acadmedsg.2024217.

ABSTRACT

INTRODUCTION: Pharmacogenomic testing in psychiatry is an emerging area with potential clinical application of guiding medication choice and dosing. Interest has been fanned by commercial pharmacogenomic providers who have commonly marketed combinatorial panels that are direct-to-consumer. However, this has not been adopted widely due to a combination of barriers that include a varying evidence base, clinician and patient familiarity and acceptance, uncertainty about cost-effectiveness, and regulatory requirements. This review aims to examine recent updates in this field and provide a contextualised summary and recom-mendations for Asian populations in order to guide healthcare professionals in psychiatric practice.

METHOD: A review of recent literature about current evidence and guidelines surrounding pharmacoge-nomics in psychiatric practice was carried out with particular attention paid to literature evaluating Asian populations. The Grading of Recommendations Assessment, Development and Evaluation Evidence to Decision framework was applied. Consensus meetings comprising workgroup psychiatrists from the public and private sectors were held prior to arriving at the key recommendations.

RESULTS: Pharmacogenomic testing should be mainly limited to drug-gene pairs with established clinical evidence, such as antidepressants and CYP2C19/ CYP2D6. Direct-to-consumer pharmacogenomic panels that assay multiple genes and analyse them via proprietary algorithms, are not presently recommended in Singapore's psychiatric setting due to inconclusive evidence on clinical outcomes.

CONCLUSION: Pharmacogenomic testing in psychiatry is not recommended as standard clinical practice. Exceptions may include concerns about drug concentrations or potential severe adverse drug reactions. Studies investigating newly identified drug-gene associations, and clinical effectiveness and cost-effectiveness of utilising pharmacogenomic testing in psychiatry is encouraged.

PMID:39748172 | DOI:10.47102/annals-acadmedsg.2024217

Ann Acad Med Singap. 2024 Dec 26;53(12):710-712. doi: 10.47102/annals-acadmedsg.2024367.

NO ABSTRACT

PMID:39748169 | DOI:10.47102/annals-acadmedsg.2024367

Neuro Oncol. 2025 Jan 2:noae275. doi: 10.1093/neuonc/noae275. Online ahead of print.

ABSTRACT

BACKGROUND: Temozolomide (TMZ) treatment has demonstrated, but variable, impact on glioma prognosis. This study examines associations of survival with DNA repair gene germline polymorphisms among glioma patients who did and did not have TMZ treatment. Identifying genetic markers which sensitize tumor cells to TMZ could personalize therapy and improve outcomes.

METHODS: We evaluated TMZ-related survival associations of pathogenic germline SNPs and genetically predicted transcript levels within 34 DNA repair genes among 1504 glioma patients from the UCSF Adult Glioma Study and Mayo Clinic whose diagnoses spanned pre- and post-TMZ eras within the major known glioma prognostic molecular subtypes.

RESULTS: Among those who received TMZ, 5 SNPs were associated with overall survival, but not in those who did not receive TMZ. Only rs2308321-G, in MGMT, was associated with decreased survival (HR=1.21, p=0.019) for all glioma subtypes. Rs73191162-T (near UNG), rs13076508-C (near PARP3), rs7840433-A (near NEIL2), and rs3130618-A (near MSH5) were only associated with survival and TMZ treatment for certain subtypes, suggesting subtype-specific germline chemo-sensitization.Genetically predicted elevated compared to normal brain expression of PNKP was associated with dramatically worse survival for TMZ-treated patients with IDH-mutant and 1p/19q non-codeleted gliomas (p=0.015), with a median difference of over 70 months in overall survival times. Similarly, NEIL2 and TDG expressions were associated with altered TMZ-related survival only among certain subtypes.

CONCLUSIONS: Functional germline alterations within DNA repair genes were associated with TMZ sensitivity, measured by overall survival, among adults with glioma, these variants should be evaluated in prospective analyses and functional studies.

PMID:39745907 | DOI:10.1093/neuonc/noae275

Drug Metab Pers Ther. 2025 Jan 2. doi: 10.1515/dmpt-2024-0091. Online ahead of print.

NO ABSTRACT

PMID:39744835 | DOI:10.1515/dmpt-2024-0091

Psychopharmacol Bull. 2025 Jan 1;55(1):8-25.

ABSTRACT

BACKGROUND: Immunologic measures have been studied as predictors of who will respond to standard antidepressants. Two previous, small studies of pretreatment leukocyte mRNA expression levels of the cytokines macrophage migration inhibitory factor (MIF) and interleukin 1-beta (IL1-β) identified antidepressant treatment responders.

METHODS: We tested these findings in 1,299 patients from the PRIME Care study, a multi-center pharmacogenetic depression treatment trial. Patients underwent 5 depression-symptom assessments over 24 weeks. mRNA was extracted from peripheral blood, purified, and assayed with TaqMan gene expression assays and a known copy number calibrator to yield relative quantification and copy numbers for each sample. In generalized estimating equations models, we regressed the repeated depression measures and a binary treatment response measure on the baseline MIF and IL-1β measures and relevant covariates.

RESULTS: Participants' depression scores decreased monotonically during treatment, with the treatment response percentage increasing concomitantly. We found no significant associations of the cytokine concentrations with either the change in depression scores or the likelihood of a treatment response. A secondary analysis limited to a subsample of 126 participants selected to remove the potential for confounding also showed no significant associations.

LIMITATIONS: Despite efforts to control for sample and assay method differences, these could have contributed to the lack of replication of prior research.

CONCLUSIONS: We did not replicate prior findings that pre-treatment expression levels for two cytokines predicted antidepressant treatment response. This raises questions about the clinical utility of using these biomarkers in treating depression.

PMID:39744412 | PMC:PMC11626916

Psychopharmacol Bull. 2025 Jan 1;55(1):37-46.

ABSTRACT

INTRODUCTION: Alcoholic hallucinosis (AH) is one of the severe complications of chronic alcoholism, characterized by psychotic symptoms such as auditory hallucinations and delusions. Haloperidol is widely used to treat AH; however, its therapy is often complicated by side effects. A personalized approach using pharmacogenetic testing (particularly the CYP2D6 polymorphism) allows individualization of haloperidol dosage, improving both safety and efficacy of therapy.

MATERIALS AND METHODS: The study included 100 men diagnosed with "psychotic disorder induced by alcohol use." Patients were randomized into two groups: the main group (45 patients) received haloperidol based on the results of pharmacogenetic testing, while the control group (55 patients) received standard dosing. Genotyping was conducted for the CYP2D6 1846G > A polymorphism. The effectiveness was assessed using the PANSS, UKU, and SAS scales.

RESULTS: Genotyping showed an even distribution of CYP2D6 polymorphisms in both groups. The main group demonstrated a significant reduction in side effects and improvement in psychotic symptoms compared to the control group. Differences on the UKU, SAS, and PANSS scales reached statistical significance on days 3-5 of treatment.

CONCLUSION: Using pharmacogenetic testing to adjust haloperidol dosage improves therapy tolerability and accelerates the resolution of psychotic symptoms in patients with alcoholic hallucinosis, confirming the feasibility of a personalized approach in psychopharmacotherapy.

PMID:39744406 | PMC:PMC11626915

Crit Rev Clin Lab Sci. 2025 Jan 1:1-22. doi: 10.1080/10408363.2024.2431853. Online ahead of print.

ABSTRACT

We present a series of three articles on the genetics and pharmacogenetics of G protein- coupled receptors (GPCR). In the first article, we discuss genetic variants of the G protein subunits and accessory proteins that are associated with human phenotypes; in the second article, we build upon this to discuss "G protein-coupled receptor (GPCR) gene variants and human genetic disease" and in the third article, we survey "G protein-coupled receptor pharmacogenomics". In the present article, we review the processes of ligand binding, GPCR activation, inactivation, and receptor trafficking to the membrane in the context of human genetic disease resulting from pathogenic variants of accessory proteins and G proteins. Pathogenic variants of the genes encoding G protein α and β subunits are examined in diverse phenotypes. Variants in the genes encoding accessory proteins that modify or organize G protein coupling have been associated with disease; these include the contribution of variants of the regulator of G protein signaling (RGS) to hypertension; the role of variants of activator of G protein signaling type III in phenotypes such as hypoxia; the contribution of variation at the RGS10 gene to short stature and immunological compromise; and the involvement of variants of G protein-coupled receptor kinases (GRKs), such as GRK4, in hypertension. Variation in genes that encode proteins involved in GPCR signaling are outlined in the context of the changes in structure and function that may be associated with human phenotypes.

PMID:39743506 | DOI:10.1080/10408363.2024.2431853

Prog Neuropsychopharmacol Biol Psychiatry. 2024 Dec 30:111240. doi: 10.1016/j.pnpbp.2024.111240. Online ahead of print.

ABSTRACT

Brain-derived neurotrophic factor (BDNF) is implicated in the etiology of schizophrenia, and peripheral BDNF levels are affected by the short-term antipsychotic treatment. However, the data on their long-term effects on BDNF levels are scarce, and there is no information whether BDNF levels change during sustained remission in relation to values in healthy individuals. The aim of the present study was to compare serum BDNF levels in patients in long-term remission and healthy controls. This study is an extension of our previous research on the effects of olanzapine and risperidone on serum BDNF in acute-episode patients with schizophrenia. Patients who remained in remission for at least 3 years on the same antipsychotic regimen (40 % of the initial cohort) were included. Symptoms were assessed by the Positive and Negative Syndrome Scale (PANSS). Serum BDNF levels were measured by ELISA in patients in remission (N = 20), evaluated at baseline, after 6 weeks of treatment and after 3 years of treatment, and in healthy individuals (N = 40). At baseline (p = 0.046) and after 6 weeks of treatment (p = 0.028), patients had significantly lower BDNF levels than controls. However, after 3 years of continuous antipsychotic maintenance treatment, serum BDNF levels were increased compared to baseline and values after 6 weeks of treatment in remitted patients, and were also significantly higher in patients than in healthy controls (p = 0.002). Antipsychotic medications appear to have distinct effects on serum BDNF levels in short-and long-term treatment. It remains to be determined if such finding may be related to potential neuroprotective effects of antipsychotic maintenance treatment.

PMID:39743169 | DOI:10.1016/j.pnpbp.2024.111240

Forensic Sci Int Genet. 2024 Dec 25;76:103219. doi: 10.1016/j.fsigen.2024.103219. Online ahead of print.

ABSTRACT

Interpreting postmortem concentrations of 3,4-Methylenedioxymethamphetamine (MDMA) remains challenging due to the wide range of reported results and the potential idiosyncratic nature of MDMA toxicity. Consequently, forensic pathologists often rely on a body of evidence to establish conclusions regarding the cause and the manner of death in death involving MDMA. Given these issues, implementing pharmacogenetics' (PGx)' testing may be beneficial. Here, this report discusses an MDMA-related fatality and explores the benefits and limitations of implementing pharmacogenetics (PGx) analysis in such cases. A 34-year-old white European male was found dead at home, lying naked on his bed in a state of marked rigor mortis. MDMA and methylenedioxyamphetamine were quantified using liquid chromatography coupled to tandem mass spectrometry at respectively 3800 and 170 µg/L in femoral blood. PGx analysis was performed on a peripheral blood sample collected in EDTA tube. Deep analysis of cytochrome P450 (CYP) 2D6, 1A2, 2B6, 2C19, 3A4 and catechol-O-methyltransferase (COMT) genes (including copy number variations analysis) was performed by Next Generation Sequencing (NGS) on an Illumina MiSeq® sequencer using the Pharmacogenomics community panel (SOPHIA genetics® x RNPGx). The data obtained was analyzed using Sophia DDM® software. PGx analysis revealed three variants in CYP2C19 (rs75087398, rs12248560 and rs11188072) resulting in a CYP2C19 * 1/* 17 genotype, predictive of a rapid metabolism phenotype, implying greater MDMA elimination. Additionally, two variants were found in the COMT gene (rs4633TT, rs4680AA). In the literature, carriers of rs4680AA or rs4680GA genotypes exhibit lower enzyme activity compared to those homozygous for the G allele. Low COMT activity level has been associated with increased MDMA cardiovascular effects and biological changes, including an increased risk of hyponatremia which is particularly relevant here regarding the potential mechanism of death. Despite these findings, there are currently too few available studies to draw any definitive conclusions, indicating a need for further research in this area to fully understand all the implications. Moreover, focusing solely on metabolic enzymes may not fully explain all the variability in MDMA toxicity. A holistic genetic approach is necessary, incorporating both metabolic enzymes and pharmacological targets, including serotonin, dopamine, and norepinephrine transporters and receptors.

PMID:39742700 | DOI:10.1016/j.fsigen.2024.103219

EBioMedicine. 2024 Dec 31;112:105550. doi: 10.1016/j.ebiom.2024.105550. Online ahead of print.

ABSTRACT

BACKGROUND: Large-scale multicentre studies are needed to understand complex relationships between the gut microbiota, health and disease. Interrogating the mucosal microbiota may identify important biology not captured by stool analysis. Gold standard tissue cryopreservation ('flash freezing') limits large-scale study feasibility. We aimed to compare gut microbiota in gold standard and pragmatic mucosal biopsy storage conditions.

METHODS: We collected endoscopic recto-sigmoid biopsies from 20 adults with inflammatory bowel disease. Biopsies were preserved using three methods: (i) flash freezing (most proximal and distal biopsy sites); (ii) nucleic acid preservative reagents (QIAGEN Allprotect®, Invitrogen RNAlater™, and Zymo DNA/RNA Shield™); and (iii) formalin fixation with paraffin embedding (FFPE), which is used to preserve tissue for clinical histopathology within healthcare settings. Microbiota were sequenced on the MiSeq platform (V4 region, 16S rRNA gene).

FINDINGS: Tissue microbiota were consistent between most proximal and distal tissue suggesting any within-patient variation observed reflected storage condition, not biopsy location. There was no significant difference in alpha-diversity or microbial community profiles of reagent-preserved versus gold standard tissue. FFPE community structure was significantly dissimilar to other tissue samples, driven by differential relative abundance of obligate gut anaerobes; Faecalibacterium, Anaerostipes and Lachnospiraceae. Despite these differences, tissue microbiota grouped by participant regardless of preservation and storage conditions.

INTERPRETATION: Preservative reagents offer a convenient alternative to flash freezing tissue in prospective large-scale mucosal microbiota studies. Whilst less comparable, FFPE provides potential for retrospective microbiota studies using historical samples.

FUNDING: Medical Research Council (MR/T032162/1) and The Leona M. and Harry B. Helmsley Charitable Trust (G-2002-04255).

PMID:39742562 | DOI:10.1016/j.ebiom.2024.105550

Front Pharmacol. 2024 Dec 16;15:1477485. doi: 10.3389/fphar.2024.1477485. eCollection 2024.

ABSTRACT

Flecainide acetate is a Class 1c anti-arrhythmic with a potent sodium voltage gated channel blockade which is utilized for the second-line treatment of tachyarrhythmias in children and adults. Given its narrow therapeutic index, the individualization of drug therapy is of utmost importance for clinicians. Despite efforts to improve anti-arrhythmic drug therapy, there remain knowledge gaps regarding the impact of variation in the genes relevant to flecainide's disposition and response. This variability is compounded in developing children whose drug disposition and response pathways may remain immature. The purpose of this comprehensive review is to outline flecainide's disposition and response pathways while simultaneously highlighting opportunities for prospective investigation in the pediatric population.

PMID:39741635 | PMC:PMC11686437 | DOI:10.3389/fphar.2024.1477485

BMJ Open. 2024 Dec 31;14(12):e088389. doi: 10.1136/bmjopen-2024-088389.

ABSTRACT

INTRODUCTION: Tuberculosis (TB) is the leading infectious cause of death globally. Despite WHO recommendations for TB preventive therapy (TPT), challenges persist, including incompletion of treatment and adverse drug reactions (ADRs). There is limited data on the 3-month isoniazid and rifapentine (3HP) pharmacokinetics, pharmacogenomics and their relation with ADRs. Our study aims to describe the pharmacokinetic and pharmacogenomics of 3HP used for TPT, the ADRs and their association with completion rates, and TPT outcomes, providing vital insights for TB control strategies in resource-limited settings.

METHODS: This is an observational cohort study with a nested case-control study. We enrolled consecutive patients who had been initiated on TPT using the 3HP regimen. These are followed up biweekly and then monthly during the active phase of treatment and 3 monthly for 2 years following completion of TPT. ADR evaluation includes clinical assessment and liver function tests. Cases are selected from those who experience ADRs and controls from those who do not. Serum isoniazid and rifapentine concentrations are measured and pharmacogenomic analysis for NAT2, AADAC and CYP2E1 polymorphisms are done. Participants are followed up for 2 years to determine TPT outcomes.

ANALYSIS: The safety profile of 3HP will be assessed using descriptive statistics, including proportions of patients experiencing ADRs and grade 3 or above events related to treatment. χ2 tests and regression models will determine predictors of ADRs and their impact on treatment completion. Pharmacokinetic-pharmacodynamic modelling will establish population parameters and factors influencing rifapentine and isoniazid concentrations.

ETHICS AND DISSEMINATION: Ethical approval of this study inclusive of all the appropriate documents was obtained from the Infectious Diseases Institute Research and Ethics Committee and the Uganda National Council of Science and Technology. The study adheres to legal, ethical and Good Clinical Practice (GCP) guidelines. Deidentified genotype data from 300 patients will be shared after publication. The protocol and phenotype data will be publicly accessible. Abstracts will be submitted to conferences, and a manuscript will be published poststudy.

PMID:39740953 | DOI:10.1136/bmjopen-2024-088389

J Pharm Biomed Anal. 2024 Dec 25;255:116652. doi: 10.1016/j.jpba.2024.116652. Online ahead of print.

ABSTRACT

Clinically heterogeneous spectrum and molecular phenotypes of inflammatory bowel disease (IBD) remain to be comprehensively elucidated. This exploratory multi-omics study investigated the serum molecular profiles of Crohn's disease (CD) and ulcerative colitis (UC), in association with elevated fecal calprotectin and disease activity states. The serum proteome, metabolome, and lipidome of 75 treated IBD patients were profiled. Single- and multi-omic data analysis was performed to determine differential analytes and integrative biosignatures for biological interpretations. We found that chronic inflammation, phosphatidylcholines and bile acid homeostasis disturbances underlined the differences between CD and UC. Besides, elevated calprotectin was associated with higher levels of inflammatory proteins and sphingomyelins (SM) and lower levels of bile acids, amino acids, and triacylglycerols (TG). Relative to the remission disease state, the active form was characterized by decreased abundances of SMs and increased abundances of inflammatory proteins and TGs. We also observed that molecular changes upon treatment escalation were putatively related to altered levels of inflammatory response proteins, amino acids, and TGs. ISM1, ANGPTL4, chenodeoxycholate, Cer(18:1;2 O/24:1), and TG were identified as candidates subject to further investigation. Altogether, our study revealed that disturbances in immune response, bile acid homeostasis, amino acids, and lipids potentially underlie the clinically heterogeneous spectrum of IBD.

PMID:39740478 | DOI:10.1016/j.jpba.2024.116652