Expert Rev Clin Pharmacol. 2024 Feb 2:1-10. doi: 10.1080/17512433.2024.2314726. Online ahead of print.

ABSTRACT

INTRODUCTION: Pharmacogenomics (PGx) is touted as essential for the future of precision medicine. But the opportunity cost of PGx from the prescribers' perspective is rarely considered. The aim of this article is to critique PGx-guided prescribing using clinical pharmacology principles so that important cases for PGx testing are not missed by doctors responsible for therapeutic decision making.

AREAS COVERED: Three categories of PGx and their limitations are outlined - exposure PGx, response PGx, and immune-mediated safety PGx. Clinical pharmacology reasons are given for the narrow scope of PGx-guided prescribing apart from a few medical specialties. Clinical problems for doctors that may arise from PGx are then explained, including mismatch between patients' expectations of PGx testing and the benefits or answers it provides.

EXPERT OPINION: Contrary to popular opinion, PGx is unlikely to become the cornerstone of precision medicine. Sound clinical pharmacology reasons explain why PGx-guided prescribing is unnecessary for most drugs. Pharmacogenomics is important for niche areas of prescribing but has limited clinical utility more broadly. The opportunity cost of PGx-guided prescribing is currently too great for most doctors.

PMID:38307498 | DOI:10.1080/17512433.2024.2314726

Pharmacogenomics. 2024 Jan;25(2):97-111. doi: 10.2217/pgs-2023-0173. Epub 2024 Feb 2.

ABSTRACT

HLA alleles, part of the major histocompatibility complex, are strongly associated with adverse drug reactions (ADRs). This review focuses on HLA-B*15:02 and explores its association with ADRs in various ethnic populations and with different drugs, aiming to provide insights into the safe clinical use of drugs and minimize the occurrence of ADRs. Furthermore, the review explores the potential mechanisms by which HLA-B*15:02 may be associated with ADRs, aiming to gain new insights into drug modification and identification of haptens. In addition, it analyzes the frequency of the HLA-B*15:02, genotyping methods, cost-effectiveness and treatment measures for adverse reactions, thereby providing a theoretical basis for formulating clinical treatment plans.

PMID:38305022 | DOI:10.2217/pgs-2023-0173

Front Immunol. 2024 Jan 18;14:1289434. doi: 10.3389/fimmu.2023.1289434. eCollection 2023.

ABSTRACT

BACKGROUND: Consolidative thoracic radiotherapy (TRT) has been commonly used in the management of extensive-stage small cell lung cancer (ES-SCLC). Nevertheless, phase III trials exploring first-line chemoimmunotherapy have excluded this treatment approach. However, there is a strong biological rationale to support the use of radiotherapy (RT) as a boost to sustain anti-tumor immune responses. Currently, the benefit of TRT after chemoimmunotherapy remains unclear. The present report describes the real-world experiences of 120 patients with ES-SCLC treated with different chemoimmunotherapy combinations. Preclinical data supporting the hypothesis of anti-tumor immune responses induced by RT are also presented.

METHODS: A total of 120 ES-SCLC patients treated with chemoimmunotherapy since 2019 in the South of Italy were retrospectively analyzed. None of the patients included in the analysis experienced disease progression after undergoing first-line chemoimmunotherapy. Of these, 59 patients underwent TRT after a multidisciplinary decision by the treatment team. Patient characteristics, chemoimmunotherapy schedule, and timing of TRT onset were assessed. Safety served as the primary endpoint, while efficacy measured in terms of overall survival (OS) and progression-free survival (PFS) was used as the secondary endpoint. Immune pathway activation induced by RT in SCLC cells was explored to investigate the biological rationale for combining RT and immunotherapy.

RESULTS: Preclinical data supported the activation of innate immune pathways, including the STimulator of INterferon pathway (STING), gamma-interferon-inducible protein (IFI-16), and mitochondrial antiviral-signaling protein (MAVS) related to DNA and RNA release. Clinical data showed that TRT was associated with a good safety profile. Of the 59 patients treated with TRT, only 10% experienced radiation toxicity, while no ≥ G3 radiation-induced adverse events occurred. The median time for TRT onset after cycles of chemoimmunotherapy was 62 days. Total radiation dose and fraction dose of TRT include from 30 Gy in 10 fractions, up to definitive dose in selected patients. Consolidative TRT was associated with a significantly longer PFS than systemic therapy alone (one-year PFS of 61% vs. 31%, p<0.001), with a trend toward improved OS (one-year OS of 80% vs. 61%, p=0.027).

CONCLUSION: Multi-center data from establishments in the South of Italy provide a general confidence in using TRT as a consolidative strategy after chemoimmunotherapy. Considering the limits of a restrospective analysis, these preliminary results support the feasibility of the approach and encourage a prospective evaluation.

PMID:38304255 | PMC:PMC10830694 | DOI:10.3389/fimmu.2023.1289434

Breast Cancer Res Treat. 2024 Jan 10. doi: 10.1007/s10549-023-07218-1. Online ahead of print.

ABSTRACT

PURPOSE: Polypharmacy is associated with negative health outcomes and decreased medication adherence. Polypharmacy is common in cancer populations, but few studies have evaluated the relationship between polypharmacy and aromatase inhibitor (AI) adherence. No studies have evaluated the relationship between over-the-counter (OTC) supplements and AI adherence. Our primary hypothesis was that polypharmacy would be associated with increased risk of premature AI discontinuation.

METHODS: This exploratory analysis used data from the Exemestane and Letrozole Pharmacogenetics (ELPh) trial, a prospective, multicenter, randomized controlled trial that enrolled participants from 2005 to 2009. Included patients were female, postmenopausal, with stage 0-III breast cancer, who had completed indicated chemotherapy, surgery, and radiation. Participants were randomized to adjuvant exemestane or letrozole and completed serial clinical examinations and questionnaires for two years. Concomitant medication data were collected prospectively. Cox proportion models were used for statistical analysis of the relationship between polypharmacy, OTCs, medication class, and AI adherence.

RESULTS: In the 490 analyzed participants, use of any prescription medications at baseline was associated with decreased risk of premature AI discontinuation (HR 0.56, p = 0.02). Use of selective serotonin reuptake inhibitors (SSRIs) or selective serotonin and norepinephrine reuptake inhibitors (SNRIs) at baseline was associated with decreased risk of premature AI discontinuation (HR 0.67, p = 0.04). Use of any OTCs was not associated with AI discontinuation.

CONCLUSION: Baseline use of prescription medications but not OTCs was associated with increased AI persistence. Future research is needed to understand how this can be utilized to promote AI adherence.

PMID:38198070 | DOI:10.1007/s10549-023-07218-1

Clin Cancer Res. 2024 Jan 10. doi: 10.1158/1078-0432.CCR-23-2073. Online ahead of print.

ABSTRACT

PURPOSE: Comprehensive pharmacogenomics (PGx) evaluation of calicheamicin-pathway to identify predictive PGx markers of response to gemtuzumab ozogamicin (GO) treatment in acute myeloid leukemia (AML).

PATIENTS AND METHODS: Single nucleotide polymorphisms (SNPs) in DNA-damage response (DDR) pathway genes were tested for association with event-free survival (EFS), overall-survival (OS), risk of relapse after induction 1 (RR1) in patients treated with standard chemotherapy consisting of Ara-C, Daunorubicin and Etoposide (ADE) with or without addition of GO on COG-AAML03P1 and COG-AAAML0531 trials (ADE+GO, n=755; ADE n=470). SNPs with significant association with any endpoint within ADE+GO arm but not in the ADE arm were tested using multi-SNP modeling to develop DDR_PGx7 Score.

RESULTS: Patients with low-DDR_PGx7 score (<0) had significantly worse EFS (HR=1.51, 95%CI (1.21-1.89), P<0.001), worse OS (HR=1.59, 95%CI (1.22-2.08), P<0.001), and higher RR1 (HR=1.87, 95%CI(1.41-2.47), P<0.0001) compared to patients with high-DDR_PGx7 score (≥0) when treated with GO (ADE+GO cohort). However, no difference between low and high DDR_PGx7 score groups was observed for EFS, OS, and RR1 (all P>0.3) in patients treated on ADE arm.

CONCLUSIONS: Our results suggest that DDR pathway-based pharmacogenomic score holds potential to predict outcome in patients treated with GO which consists of DNA damaging cytotoxin, calicheamicin. The potential clinical relevance for this score to personalize GO in AML requires further validation in independent and expanded cohorts.

PMID:38197878 | DOI:10.1158/1078-0432.CCR-23-2073

Sci Rep. 2024 Jan 9;14(1):880. doi: 10.1038/s41598-024-51458-0.

ABSTRACT

Genotyping of gDNA rs12041331 (PEAR1), rs6065 (GP1BA), and rs730012 (LTC4S) can provide systematic guidance on the use of aspirin. However, an accurate, reliable and economical approach to simultaneous detection of the above single nucleotide polymorphisms (SNPs) is not reported. Herein, we designed and substantiated an allele-specific (AS) forward primer-superposed amplification analysis for measurement of the SNPs in PEAR1, GP1BA and LTC4S genes, in which the values of ∆Cq (differences in threshold cycles between the wild-type forward primer-based assay and the mutated-type forward primer-based assay) were employed to decide genotype. Mismatch AS forward primers were screened with the singleplex amplification analysis. Moreover, Cq extension optimized by AS forward primer superposition was observed in the selected forward primer-based triplex analysis. Further, robustness assessment of the triplex analysis showed the amplification efficiency ranging from 0.9 to 1.1. Precision test demonstrated the coefficient of variation of less than 2%. And the detective results of 189 DNA samples was completely concordant with that of commercial Sanger sequencing. In summary, we developed a simple, accurate and economical approach to genotyping of rs12041331 (PEAR1), rs6065 (GP1BA) and rs730012 (LTC4S) to provide a valuable pharmacogenomics tool for guidance of aspirin delivery.

PMID:38195704 | DOI:10.1038/s41598-024-51458-0

Drug Metab Dispos. 2024 Jan 9:DMD-AR-2023-001542. doi: 10.1124/dmd.123.001542. Online ahead of print.

ABSTRACT

Cytochrome P450 3A4 (CYP3A4), a key enzyme, is pivotal in metabolizing approximately half of the drugs used clinically. The genetic polymorphism of the CYP3A4 gene significantly influences individual variations in drug metabolism, potentially leading to the severe adverse drug reactions (ADRs). In this study, we conducted a genetic analysis on CYP3A4 gene in 1,163 Chinese Han individuals to identify the genetic variations that might affect their drug metabolism capabilities. For this purpose, a multiplex PCR amplicon sequencing technique was developed, enabling us to perform the genotyping of CYP3A4 gene efficiently and economically on a large scale. As a result, a total of 14 CYP3A4 allelic variants were identified, comprising 6 previously reported alleles and 8 new non-synonymous variants that were nominated as new allelic variants *39-*46 by the PharmVar Association. Further, functional assessments of these novel CYP3A4 variants were undertaken by co-expressing them with CYPOR in S. cerevisiae microsomes. Immunoblot analysis indicated that with the exception of CYP3A4.40 and CYP3A4.45, the protein expression levels of most new variants were similar to that of the wild-type CYP3A4.1 in yeast cells. To evaluate their catalytic activities, midazolam was utilized as a probe drug. The results showed that variant CYP3A4.45 had almost no catalytic activity, while the other variants exhibited significantly reduced drug metabolism abilities. This suggests that the majority of the CYP3A4 variants identified in the Chinese population possess markedly altered capacities for drug metabolism. Significance Statement In this study, we established a multiplex PCR amplicon sequencing method and detected the maximum number of new CYP3A4 variants in a single ethnic population. Additionally, we performed the functional characterizations of these 8 novel CYP3A4 allele variants in vitro This study not only contributes to the understanding of CYP3A4 genetic polymorphism in the Chinese Han population but also holds substantial reference value for their potential clinical applications in personalized medicine.

PMID:38195522 | DOI:10.1124/dmd.123.001542

Innov Clin Neurosci. 2023 Dec 1;20(10-12):12-17. eCollection 2023 Oct-Dec.

ABSTRACT

Point-of-care genetic testing for single nucleotide polymorphisms (SNPs) to improve psychiatric treatment in outpatient settings remains a challenge. The presence or absence of certain genomic alleles determines the activity of the encoded enzymes, which ultimately defines the individual's drug metabolism rate. Classification of poor metabolizers (PMs) and rapid/ultrarapid metabolizers (RMs/UMs) would facilitate personalization and precision of treatment. However, current pharmacogenomic (PGx) testing of multiple genes is comprehensive and requires quantitative analyses for interpretations. We recommend qualitative, fast-track, point-of-care screenings, which are one- or-two gene-based analyses, as a quick initial screening tool to potentially eliminate the need for an expensive quantitative send-out test, which is a costly and lengthy process. We speculate that these tests will be relevant in two major scenarios: 1) clinical psychiatry for treating disease states such as major depressive disorder (MDD) and posttraumatic stress disorder (PTSD), where trial and error is still the mainstay of drug selection and symptom management, a process that is associated with significant delay in optimizing individualized treatment and dose, and thus response; and 2) pain management, where quickly determining an effective level of analgesia while avoiding a toxic level can cause a drastic improvement in mental health.

PMID:38193100 | PMC:PMC10773601

Cancer Chemother Pharmacol. 2024 Jan 9. doi: 10.1007/s00280-023-04623-7. Online ahead of print.

ABSTRACT

BACKGROUND: Artemisinin (ART) and its derivatives are important antimalaria agents and have received increased attention due to their broad biomedical effects, such as anticancer and anti-inflammation activities. Recently, ruthenium-derived complexes have attracted considerable attention as their anticancer potentials were observed in preclinical and clinical studies.

METHODS: To explore an innovative approach in colorectal cancer (CRC) management, we synthesized ruthenium-dihydroartemisinin complex (D-Ru), a novel metal-based artemisinin derivative molecule, and investigated its anticancer, anti-inflammation, and adaptive immune regulatory properties.

RESULTS: Compared with its parent compound, ART, D-Ru showed stronger antiproliferative effects on the human CRC cell lines HCT-116 and HT-29. The cancer cell inhibition of D-Ru comprised G1 cell cycle arrest via the downregulation of cyclin A and the induction of apoptosis. ART and D-Ru downregulated the expressions of pro-inflammatory cytokines IL-1β, IL-6, and IL-8. Although ART and D-Ru did not suppress Treg cell differentiation, they significantly inhibited Th1 and Th17 cell differentiation.

CONCLUSIONS: Our results demonstrated that D-Ru, a novel ruthenium complexation of ART, remarkably enhanced its parent compound's anticancer action, while the anti-inflammatory potential was not compromised. The molecular mechanisms of action of D-Ru include inhibition of cancer cell growth via cell cycle arrest, induction of apoptosis, and anti-inflammation via regulation of adaptive immunity.

PMID:38191768 | DOI:10.1007/s00280-023-04623-7

Pharmacogenomics. 2024 Jan 8. doi: 10.2217/pgs-2023-0204. Online ahead of print.

ABSTRACT

Aim: Successful treatment with tacrolimus to prevent graft versus host disease (GVHD) and minimize tacrolimus-related toxicities among allogeneic hematopoietic cell transplantation (alloHCT) recipients is contingent upon quickly achieving and maintaining concentrations within a narrow therapeutic range. The primary objective was to investigate associations between CYP3A4, CYP3A5 or ABCB1 genotype and the proportion of patients that attained an initial tacrolimus goal concentration following initiation of intravenous (iv.) and conversion to oral administration. Materials & methods: We retrospectively evaluated 86 patients who underwent HLA-matched (8/8) related donor alloHCT and were prescribed a tacrolimus-based regimen for GVHD prophylaxis. Results & conclusion: The findings of the present study suggests that CYP3A5 genotype may impact attainment of initial therapeutic tacrolimus concentrations with oral administration in alloHCT recipients.

PMID:38189154 | DOI:10.2217/pgs-2023-0204

Biol Sport. 2024 Jan;41(1):17-27. doi: 10.5114/biolsport.2024.125591. Epub 2023 May 25.

ABSTRACT

Exercise-induced metabolic processes induce muscle acidification which contributes to a reduction in the ability to perform repeated efforts. Alkalizing agents such as sodium bicarbonate (NaHCO3) prevent large blood pH changes, however, there is no evidence on whether regulation of acid-base balance may also support whole body homeostasis monitored through heamatological and biochemical blood markers in a dose-dependent manner. Thirty Cross-Fit-trained participants were studied in a randomized, multi cross-over, placebo (PLA)-controlled double-blind manner in which they performed a control session (CTRL, without supplementation), three NaHCO3 visits (three different doses) and PLA (sodium chloride in an equimolar amount of sodium as NaHCO3). Each visit consisted of two 30-s Wingate tests separated by CrossFit-specific benchmarks (Wall Balls and Burpees - both performed for 3 min). Blood samples were collected at rest, immediately post-exercise and after 45 min recovery. Significant differences between visits appeared for blood pH, percentage of lymphocytes and granulocytes, red blood cells count and haemoglobin concentration at post-exercise and 45-min recovery, and for white blood cells count, percentage of monocytes, concentration of magnesium and creatinine at 45-min recovery. Most of the observed differences for heamatological and biochemical markers were significant compared to CTRL, but not different after PLA. NaHCO3 supplementation compared to PLA did not significantly affect exercise or recovery shifts in studied blood indicators. However, the changes in these markers after NaHCO3 and PLA in relation to CTRL indicate a possible role of sodium.

PMID:38188117 | PMC:PMC10765444 | DOI:10.5114/biolsport.2024.125591

Heliyon. 2023 Dec 14;10(1):e23682. doi: 10.1016/j.heliyon.2023.e23682. eCollection 2024 Jan 15.

ABSTRACT

Cardiovascular diseases are the leading cause of death worldwide, with heart failure being a complex condition that affects millions of individuals. Single-nucleus RNA sequencing has recently emerged as a powerful tool for unraveling the molecular mechanisms behind cardiovascular diseases. This cutting-edge technology enables the identification of molecular signatures, intracellular networks, and spatial relationships among cardiac cells, including cardiomyocytes, mast cells, lymphocytes, macrophages, lymphatic endothelial cells, endocardial cells, endothelial cells, epicardial cells, adipocytes, fibroblasts, neuronal cells, pericytes, and vascular smooth muscle cells. Despite these advancements, the discovery of essential therapeutic targets and drugs for precision cardiology remains a challenge. To bridge this gap, we conducted comprehensive in silico analyses of single-nucleus RNA sequencing data, functional enrichment, protein interactome network, and identification of the shortest pathways to physiological phenotypes. This integrated multi-omics analysis generated CardiOmics signatures, which allowed us to pinpoint three therapeutically actionable targets (ADRA1A1, PPARG, and ROCK2) and 15 effective drugs, including adrenergic receptor agonists, adrenergic receptor antagonists, norepinephrine precursors, PPAR receptor agonists, and Rho-associated kinase inhibitors, involved in late-stage cardiovascular disease clinical trials.

PMID:38187312 | PMC:PMC10770621 | DOI:10.1016/j.heliyon.2023.e23682

Brain Behav Immun Health. 2023 Dec 20;35:100717. doi: 10.1016/j.bbih.2023.100717. eCollection 2024 Feb.

ABSTRACT

Recent observations suggest a role of the volume of the cerebral ventricle volume, corpus callosum (CC) segment volume, in particular that of the central-anterior part, and choroid plexus (CP) volume for treatment resistance of major depressive disorder (MDD). An increased CP volume has been associated with increased inflammatory activity and changes in the structure of the ventricles and corpus callosum. We attempt to replicate and confirm that these imaging markers are associated with clinical outcome in subjects from the EMBARC study, as implied by a recent pilot study. The EMBARC study is a placebo controlled randomized study comparing sertraline vs. placebo in patients with MDD to identify biological markers of therapy resistance. Association of baseline volumes of the lateral ventricles (LVV), choroid plexus volume (CPV) and volume of segments of the CC with treatment response after 4 weeks treatment was evaluated. 171 subjects (61 male, 110 female) completed the 4 week assessments; gender and age were taken into account for this analyses. As previously reported, no treatment effect of sertraline vs. placebo was observed, therefore the study characterized prognostic markers of response in the pooled population. Change in depression severity was identified by the ratio of the Hamilton-Depression rating scale 17 (HAMD-17) at week 4 divided by the HAMD-17 at baseline (HAMD-17 ratio). Volumes of the lateral ventricles and choroid plexi were positively correlated with the HAMD-17 ratio, indication worse outcome with larger ventricles and choroid plexus volumes, whereas the volume of the central-anterior corpus callosum was negatively correlated with the HAMD-17 ratio. Responders (n = 54) had significantly smaller volumes of the lateral ventricles and CP compared to non-responders (n = 117), whereas the volume of mid-anterior CC was significantly larger compared to non-responders (n = 117), confirming our previous findings. In an exploratory way associations between enlarged LVV and CPV and signs of lipid dysregulation were observed. In conclusion, we confirmed that volumes of lateral ventricles, choroid plexi and the mid-anterior corpus callosum are associated with clinical improvement of depression and may be indicators of metabolic/inflammatory activity.

PMID:38186634 | PMC:PMC10767278 | DOI:10.1016/j.bbih.2023.100717

J Adv Nurs. 2024 Jan 7. doi: 10.1111/jan.16045. Online ahead of print.

ABSTRACT

AIM: To explore the views of neonatal intensive care nursing staff on the deliverability of a novel genetic point-of-care test detecting a genetic variant associated with antibiotic-induced ototoxicity.

DESIGN: An interpretive, descriptive, qualitative interview study.

METHODS: Data were collected using semi-structured interviews undertaken between January and November 2020. Participants were neonatal intensive care nursing staff taking part in the Pharmacogenetics to Avoid Loss of Hearing trial.

RESULTS: Thematic analysis resulted in four themes: perceived clinical utility; the golden hour; point-of-care device; training and support. Recommendations were made to streamline the protocol and ongoing training and support were considered key to incorporating the test into routine care.

CONCLUSION: Exploring the views of nurses involved in the delivery of the point-of-care test was essential in its implementation. By the study endpoint, all participants could see the value of routine clinical introduction of the point-of care test.

IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: Nurses are in a key position to support the delivery of point-of-care genetic testing into mainstream settings. This study has implications for the successful integration of other genetic point-of-care tests in acute healthcare settings.

IMPACT: The study will help to tailor the training and support required for routine deployment of the genetic point-of-care test. The study has relevance for nurses involved in the development and delivery of genetic point-of-care tests in other acute hospital settings.

REPORTING METHOD: This qualitative study adheres to the Standards for Reporting Qualitative Research EQUATOR guidelines and utilizes COREQ and SRQR checklists.

PATIENT OR PUBLIC CONTRIBUTION: All staff working on the participating neonatal intensive care units were trained to use the genetic point-of-care test. All inpatients on the participating units were eligible to have testing via the point-of-care test. The Pharmacogenetics to Avoid Loss of Hearing Patient and Public Involvement and Engagement group provided valuable feedback.

TRIAL AND PROTOCOL REGISTRATION: Registered within the University of Manchester. Ethics approval reference numbers: IRAS: 253102 REC reference: 19/NW/0400. Also registered with the ISRCTN ref: ISRCTN13704894.

PMID:38186205 | DOI:10.1111/jan.16045

Expert Rev Mol Med. 2024 Jan 8;26:e1. doi: 10.1017/erm.2023.26.

ABSTRACT

The host immune system status remains an unresolved mystery among several malignancies. An immune-compromised state or smart immune-surveillance tactics orchestrated by cancer cells are the primary cause of cancer invasion and metastasis. Taking a closer look at the tumour-immune microenvironment, a complex network and crosstalk between infiltrating immune cells and cancer cells mediated by cytokines, chemokines, exosomal mediators and shed ligands are present. Cytokines such as interleukins can influence all components of the tumour microenvironment (TME), consequently promoting or suppressing tumour invasion based on their secreting source. Interleukin-10 (IL-10) is an interlocked cytokine that has been associated with several types of malignancies and proved to have paradoxical effects. IL-10 has multiple functions on cellular and non-cellular components within the TME. In this review, the authors shed the light on the regulatory role of IL-10 in the TME of several malignant contexts. Moreover, detailed epigenomic and pharmacogenomic approaches for the regulation of IL-10 were presented and discussed.

PMID:38186186 | DOI:10.1017/erm.2023.26

BMC Med Genomics. 2024 Jan 6;17(1):14. doi: 10.1186/s12920-023-01788-1.

ABSTRACT

BACKGROUND: Though persons of African descent have one of the widest genetic variability, genetic polymorphisms of drug-metabolising enzymes such as N-Acetyltransferase-2 (NAT2) are understudied. This study aimed to identify prevalent NAT2 single nucleotide polymorphisms (SNPs) and infer their potential effects on enzyme function among Kenyan volunteers with tuberculosis (TB) infection. Genotypic distribution at each SNP and non-random association of alleles were evaluated by testing for Hardy-Weinberg Equilibrium (HWE) and Linkage Disequilibrium (LD).

METHODS: We isolated genomic DNA from cryopreserved Peripheral Blood Mononuclear Cells of 79 volunteers. We amplified the protein-coding region of the NAT2 gene by polymerase chain reaction (PCR) and sequenced PCR products using the Sanger sequencing method. Sequencing reads were mapped and aligned to the NAT2 reference using the Geneious software (Auckland, New Zealand). Statistical analyses were performed using RStudio version 4.3.2 (2023.09.1 + 494).

RESULTS: The most frequent haplotype was the wild type NAT2*4 (37%). Five genetic variants: 282C > T (NAT2*13), 341 T > C (NAT2*5), 803A > G (NAT2*12), 590G > A (NAT2*6) and 481C > T (NAT2*11) were observed with allele frequencies of 29%, 18%, 6%, 6%, and 4% respectively. According to the bimodal distribution of acetylation activity, the predicted phenotype was 76% rapid (mainly consisting of the wildtype NAT2*4 and the NAT2*13A variant). A higher proportion of rapid acetylators were female, 72% vs 28% male (p = 0.022, odds ratio [OR] 3.48, 95% confidence interval [CI] 1.21 to 10.48). All variants were in HWE. NAT2 341 T > C was in strong complete LD with the 590G > A variant (D' = 1.0, r2 = - 0.39) but not complete LD with the 282C > T variant (D' = 0.94, r2 = - 0.54).

CONCLUSION: The rapid acetylation haplotypes predominated. Despite the LD observed, none of the SNPs could be termed tag SNP. This study adds to the genetic characterisation data of African populations at NAT2, which may be useful for developing relevant pharmacogenomic tools for TB therapy. To support optimised, pharmacogenomics-guided TB therapy, we recommend genotype-phenotype studies, including studies designed to explore gender-associated differences.

PMID:38184575 | DOI:10.1186/s12920-023-01788-1

Brief Funct Genomics. 2024 Jan 5:elad056. doi: 10.1093/bfgp/elad056. Online ahead of print.

ABSTRACT

Combination therapy is a promising strategy for cancers, increasing therapeutic options and reducing drug resistance. Yet, systematic identification of efficacious drug combinations is limited by the combinatorial explosion caused by a large number of possible drug pairs and diseases. At present, machine learning techniques have been widely applied to predict drug combinations, but most studies rely on the response of drug combinations to specific cell lines and are not entirely satisfactory in terms of mechanism interpretability and model scalability. Here, we proposed a novel network propagation-based machine learning framework to predict synergistic drug combinations. Based on the topological information of a comprehensive drug-drug association network, we innovatively introduced an affinity score between drug pairs as one of the features to train machine learning models. We applied network-based strategy to evaluate their therapeutic potential to different cancer types. Finally, we identified 17 specific-, 21 general- and 40 broad-spectrum antitumor drug combinations, in which 69% drug combinations were validated by vitro cellular experiments, 83% drug combinations were validated by literature reports and 100% drug combinations were validated by biological function analyses. By quantifying the network relationships between drug targets and cancer-related driver genes in the human protein-protein interactome, we show the existence of four distinct patterns of drug-drug-disease relationships. We also revealed that 32 biological pathways were correlated with the synergistic mechanism of broad-spectrum antitumor drug combinations. Overall, our model offers a powerful scalable screening framework for cancer treatments.

PMID:38183214 | DOI:10.1093/bfgp/elad056

Pathologica. 2023 Dec;115(6):292-301. doi: 10.32074/1591-951X-942.

ABSTRACT

This work explores the complex field of HER2 testing in the HER2-low breast cancer era, with a focus on methodological aspects. We aim to propose clear positions to scientific societies, institutions, pathologists, and oncologists to guide and shape the appropriate diagnostic strategies for HER2-low breast cancer. The fundamental question at hand is whether the necessary tools to effectively translate our knowledge about HER2 into practical diagnostic schemes for the lower spectrum of expression are available. Our investigation is centered on the significance of distinguishing between an immunohistochemistry (IHC) score 0 and score 1+ in light of the clinical implications now apparent, as patients with HER2-low breast cancer become eligible for trastuzumab-deruxtecan treatment. Furthermore, we discuss the definition of HER2-low beyond its conventional boundaries and assess the reliability of established diagnostic procedures designed at a time when therapeutic perspectives were non-existent for these cases. In this regard, we examine potential complementary technologies, such as gene expression analysis and liquid biopsy. Ultimately, we consider the potential role of artificial intelligence (AI) in the field of digital pathology and its integration into HER2 testing, with a particular emphasis on its application in the context of HER2-low breast cancer.

PMID:38180137 | PMC:PMC10767801 | DOI:10.32074/1591-951X-942

Clin Biochem. 2024 Jan 3:110707. doi: 10.1016/j.clinbiochem.2024.110707. Online ahead of print.

ABSTRACT

Atorvastatin (ATV) and other statins are highly effective in reducing cholesterol levels. However, in some patients, the development of drug-associated muscle side effects remains an issue as it compromises the adherence to treatment. Since the toxicity is dose-dependent, exploring factors modulating pharmacokinetics (PK) appears fundamental. The purpose of this review aims at reporting the current state of knowledge about the singular genetic susceptibilities influencing the risk of developing ATV muscle adverse events through PK modulations. Multiple single nucleotide polymorphisms (SNP) in efflux (ABCB1, ABCC1, ABCC2, ABCC4 and ABCG2) and influx (SLCO1B1, SLCO1B3 and SLCO2B1) transporters have been explored for their association with ATV PK modulation or with statin-related myotoxicities (SRM) development. The most convincing pharmacogenetic association with ATV remains the influence of the rs4149056 (c.521 T > C) in SLCO1B1 on ATV PK and pharmacodynamics. This SNP has been robustly associated with increased ATV systemic exposure and consequently, an increased risk of SRM. Additionally, the SNP rs2231142 (c.421C > A) in ABCG2 has also been associated with increased drug exposure and higher risk of SRM occurrence. SLCO1B1 and ABCG2 pharmacogenetic associations highlight that modulation of ATV systemic exposure is important to explain the risk of developing SRM. However, some novel observations credit the hypothesis that additional genes (e.g. SLCO2B1 or ABCC1) might be important for explaining local PK modulations within the muscle tissue, indicating that studying the local PK directly at the skeletal muscle level might pave the way for additional understanding.

PMID:38182100 | DOI:10.1016/j.clinbiochem.2024.110707

Am J Hum Genet. 2024 Jan 4;111(1):11-23. doi: 10.1016/j.ajhg.2023.12.001.

ABSTRACT

Precision medicine initiatives across the globe have led to a revolution of repositories linking large-scale genomic data with electronic health records, enabling genomic analyses across the entire phenome. Many of these initiatives focus solely on research insights, leading to limited direct benefit to patients. We describe the biobank at the Colorado Center for Personalized Medicine (CCPM Biobank) that was jointly developed by the University of Colorado Anschutz Medical Campus and UCHealth to serve as a unique, dual-purpose research and clinical resource accelerating personalized medicine. This living resource currently has more than 200,000 participants with ongoing recruitment. We highlight the clinical, laboratory, regulatory, and HIPAA-compliant informatics infrastructure along with our stakeholder engagement, consent, recontact, and participant engagement strategies. We characterize aspects of genetic and geographic diversity unique to the Rocky Mountain region, the primary catchment area for CCPM Biobank participants. We leverage linked health and demographic information of the CCPM Biobank participant population to demonstrate the utility of the CCPM Biobank to replicate complex trait associations in the first 33,674 genotyped individuals across multiple disease domains. Finally, we describe our current efforts toward return of clinical genetic test results, including high-impact pathogenic variants and pharmacogenetic information, and our broader goals as the CCPM Biobank continues to grow. Bringing clinical and research interests together fosters unique clinical and translational questions that can be addressed from the large EHR-linked CCPM Biobank resource within a HIPAA- and CLIA-certified environment.

PMID:38181729 | DOI:10.1016/j.ajhg.2023.12.001