Int J Biochem Cell Biol. 2024 Apr 10:106571. doi: 10.1016/j.biocel.2024.106571. Online ahead of print.

ABSTRACT

Current treatment options for triple-negative breast cancer (TNBC) are limited to toxic drug combinations of low efficacy. We recently identified an aryl-substituted fatty acid analogue, termed CTU, that effectively killed TNBC cells in vitro and in mouse xenograft models in vivo without producing toxicity. However, there was a residual cell population that survived treatment. The present study evaluated the mechanisms that underlie survival and renewal in CTU-treated MDA-MB-231 TNBC cells. RNA-seq profiling identified several pro-inflammatory signaling pathways that were activated in treated cells. Increased expression of cyclooxygenase-2 and the cytokines IL-6, IL-8 and GM-CSF was confirmed by real-time RT-PCR, ELISA and Western blot analysis. Increased self-renewal was confirmed using the non-adherent, in vitro colony-forming mammosphere assay. Neutralizing antibodies to IL-6, IL-8 and GM-CSF, as well as cyclooxygenase-2 inhibition suppressed the self-renewal of MDA-MB-231 cells post-CTU treatment. IPA network analysis identified major NF-κB and XBP1 gene networks that were activated by CTU; chemical inhibitors of these pathways and esiRNA knock-down decreased the production of pro-inflammatory mediators. NF-κB and XBP1 signaling was in turn activated by the endoplasmic reticulum (ER)-stress sensor inositol-requiring enzyme 1 (IRE1), which mediates the unfolded protein response. Co-treatment with an inhibitor of IRE1 kinase and RNase activities, decreased phospho-NF-κB and XBP1s expression and the production of pro-inflammatory mediators. Further, IRE1 inhibition also enhanced apoptotic cell death and prevented the activation of self-renewal by CTU. Taken together, the present findings indicate that the IRE1 ER-stress pathway is activated by the anti-cancer lipid analogue CTU, which then activates secondary self-renewal in TNBC cells.

PMID:38608921 | DOI:10.1016/j.biocel.2024.106571

Bioinform Adv. 2024 Mar 26;4(1):vbae047. doi: 10.1093/bioadv/vbae047. eCollection 2024.

ABSTRACT

MOTIVATION: Predicting anticancer treatment response from baseline genomic data is a critical obstacle in personalized medicine. Machine learning methods are commonly used for predicting drug response from gene expression data. In the process of constructing these machine learning models, one of the most significant challenges is identifying appropriate features among a massive number of genes.

RESULTS: In this study, we utilize features (genes) extracted using the text-mining of scientific literatures. Using two independent cancer pharmacogenomic datasets, we demonstrate that text-mining-based features outperform traditional feature selection techniques in machine learning tasks. In addition, our analysis reveals that text-mining feature-based machine learning models trained on in vitro data also perform well when predicting the response of in vivo cancer models. Our results demonstrate that text-mining-based feature selection is an easy to implement approach that is suitable for building machine learning models for anticancer drug response prediction.

AVAILABILITY AND IMPLEMENTATION: https://github.com/merlab/text_features.

PMID:38606185 | PMC:PMC11009020 | DOI:10.1093/bioadv/vbae047

Clin Pharmacol Ther. 2024 Apr 11. doi: 10.1002/cpt.3264. Online ahead of print.

NO ABSTRACT

PMID:38605551 | DOI:10.1002/cpt.3264

Cancer Treat Rev. 2024 Apr 3;126:102734. doi: 10.1016/j.ctrv.2024.102734. Online ahead of print.

ABSTRACT

Immunotherapy with immune checkpoint inhibitors (ICI) is increasingly employed in oncology. National and international endocrine and oncologic scientific societies have provided guidelines for the management of endocrine immune-related adverse events. However, guidelines recommendations differ according to the specific filed, particularly pertaining to recommendations for the timing of endocrine testing. In this position paper, a panel of experts of the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE), and Italian Society of Pharmacology (SIF) offers a critical multidisciplinary consensus for a clear, simple, useful, and easily applicable endocrine-metabolic assessment checklist for cancer patients on immunotherapy.

PMID:38604051 | DOI:10.1016/j.ctrv.2024.102734

J Nat Prod. 2024 Apr 11. doi: 10.1021/acs.jnatprod.3c00782. Online ahead of print.

ABSTRACT

Epithelial ovarian cancer is among the deadliest gynecological tumors worldwide. Clinical treatment usually consists of surgery and adjuvant chemo- and radiotherapies. Due to the high rate of recurrence and rapid development of drug resistance, the current focus of research is on finding effective natural products with minimal toxic side effects for treating epithelial ovarian tumors. Cannabidiol is among the most abundant cannabinoids and has a non-psychoactive effect compared to tetrahydrocannabinol, which is a key advantage for clinical application. Studies have shown that cannabidiol has antiproliferative, pro-apoptotic, cytotoxic, antiangiogenic, anti-inflammatory, and immunomodulatory properties. However, its therapeutic value for epithelial ovarian tumors remains unclear. This study aims to investigate the effects of cannabidiol on epithelial ovarian tumors and to elucidate the underlying mechanisms. The results showed that cannabidiol has a significant inhibitory effect on epithelial ovarian tumors. In vivo experiments demonstrated that cannabidiol could inhibit tumor growth by modulating the intestinal microbiome and increasing the abundance of beneficial bacteria. Western blot assays showed that cannabidiol bound to EGFR/AKT/MMPs proteins and suppressed EGFR/AKT/MMPs expression in a dose-dependent manner. Network pharmacology and molecular docking results suggested that cannabidiol could affect the EGFR/AKT/MMPs signaling pathway.

PMID:38603577 | DOI:10.1021/acs.jnatprod.3c00782

Heliyon. 2024 Mar 29;10(7):e28983. doi: 10.1016/j.heliyon.2024.e28983. eCollection 2024 Apr 15.

ABSTRACT

BACKGROUND: Coronary artery disease (CAD) is the most common reason for mortality and disability-adjusted life years (DALYs) lost globally. This study aimed to suggest a new gene list for the treatment of CAD by a systematic review of bioinformatics analyses of pharmacogenomics impacts of potential genes and variants.

METHODS: PubMed search was filtered by the title including Coronary Artery Disease during 2020-2023. To find the genes with pharmacogenetic impact on the CAD, additional filtrations were considered according to the variant annotations. Protein-Protein Interactions (PPIs), Gene-miRNA Interactions (GMIs), Protein-Drug Interactions (PDIs), and variant annotation assessments (VAAs) performed by STRING-MODEL (ver. 12), Cytoscape (ver. 3.10), miRTargetLink.2., NetworkAnalyst (ver 0.3.0), and PharmGKB.

RESULTS: Results revealed 5618 publications, 1290 papers were qualified, and finally, 650 papers were included. 4608 protein-coding genes were extracted, among them, 1432 unique genes were distinguished and 530 evidence-based repeated genes remained. 71 genes showed a pharmacogenetics-related variant annotation in at least (entirely 6331 annotations). Variant annotation assessment (VAA) showed 532 potential variants for the final report, and finally, the concluding PGs list represented 175 variants. Based on the function and MAF, 57 nonsynonymous variants of 29 Pharmacogenomics-related genes were associated with CAD.

CONCLUSION: Conclusively, evaluating circulating miR33a in individuals' plasma with CAD, and genotyping of rs2230806, rs2230808, rs2487032, rs12003906, rs2472507, rs2515629, and rs4149297 (ABCA1 variants) lead to precisely prescribing of well-known drugs. Also, the findings of this review can be used in both whole-genome sequencing (WGS) and whole-exome sequencing (WES) analysis in the prognosis and diagnosis of CAD.

PMID:38601677 | PMC:PMC11004819 | DOI:10.1016/j.heliyon.2024.e28983

Brief Bioinform. 2024 Mar 27;25(3):bbae153. doi: 10.1093/bib/bbae153.

ABSTRACT

Predicting the drug response of cancer cell lines is crucial for advancing personalized cancer treatment, yet remains challenging due to tumor heterogeneity and individual diversity. In this study, we present a deep learning-based framework named Deep neural network Integrating Prior Knowledge (DIPK) (DIPK), which adopts self-supervised techniques to integrate multiple valuable information, including gene interaction relationships, gene expression profiles and molecular topologies, to enhance prediction accuracy and robustness. We demonstrated the superior performance of DIPK compared to existing methods on both known and novel cells and drugs, underscoring the importance of gene interaction relationships in drug response prediction. In addition, DIPK extends its applicability to single-cell RNA sequencing data, showcasing its capability for single-cell-level response prediction and cell identification. Further, we assess the applicability of DIPK on clinical data. DIPK accurately predicted a higher response to paclitaxel in the pathological complete response (pCR) group compared to the residual disease group, affirming the better response of the pCR group to the chemotherapy compound. We believe that the integration of DIPK into clinical decision-making processes has the potential to enhance individualized treatment strategies for cancer patients.

PMID:38600666 | DOI:10.1093/bib/bbae153

J Am Coll Cardiol. 2024 Apr 16;83(15):1370-1381. doi: 10.1016/j.jacc.2024.02.015.

ABSTRACT

BACKGROUND: An ABCD-GENE (age, body mass index, chronic kidney disease, diabetes, and CYP2C19 genetic variants) score ≥10 predicts reduced clopidogrel effectiveness, but its association with response to alternative therapy remains unclear.

OBJECTIVES: The aim of this study was to evaluate the association between ABCD-GENE score and the effectiveness of clopidogrel vs alternative P2Y12 inhibitor (prasugrel or ticagrelor) therapy after percutaneous coronary intervention (PCI).

METHODS: A total of 4,335 patients who underwent PCI, CYP2C19 genotyping, and P2Y12 inhibitor treatment were included. The primary outcome was major atherothrombotic events (MAE) within 1 year after PCI. Cox regression was performed to assess event risk in clopidogrel-treated (reference) vs alternatively treated patients, with stabilized inverse probability weights derived from exposure propensity scores after stratifying by ABCD-GENE score and further by CYP2C19 loss-of-function (LOF) genotype.

RESULTS: Among patients with scores <10 (n = 3,200), MAE was not different with alternative therapy vs clopidogrel (weighted HR: 0.89; 95% CI: 0.65-1.22; P = 0.475). The risk for MAE also did not significantly differ by treatment among patients with scores ≥10 (n = 1,135; weighted HR: 0.75; 95% CI: 0.51-1.11; P = 0.155). Among CYP2C19 LOF allele carriers, MAE risk appeared lower with alternative therapy in both the group with scores <10 (weighted HR: 0.50; 95% CI: 0.25-1.01; P = 0.052) and the group with scores ≥10 (weighted HR: 0.48; 95% CI: 0.29-0.80; P = 0.004), while there was no difference in the group with scores <10 and no LOF alleles (weighted HR: 1.03; 95% CI: 0.70-1.51; P = 0.885).

CONCLUSIONS: These data support the use of alternative therapy over clopidogrel in CYP2C19 LOF allele carriers after PCI, regardless of ABCD-GENE score, while clopidogrel is as effective as alternative therapy in non-LOF patients with scores <10.

PMID:38599713 | DOI:10.1016/j.jacc.2024.02.015

J Korean Med Sci. 2024 Apr 8;39(13):e104. doi: 10.3346/jkms.2024.39.e104.

ABSTRACT

BACKGROUND: The hollow-fiber infection model (HFIM) is a valuable tool for evaluating pharmacokinetics/pharmacodynamics relationships and determining the optimal antibiotic dose in monotherapy or combination therapy, but the application for personalized precision medicine in tuberculosis treatment remains limited. This study aimed to evaluate the efficacy of adjusted antibiotic doses for a tuberculosis patient using HFIM.

METHODS: Model-based Bayesian forecasting was utilized to assess the proposed reduction of the isoniazid dose from 300 mg daily to 150 mg daily in a patient with an ultra-slow-acetylation phenotype. The efficacy of the adjusted 150-mg dose was evaluated in a time-to-kill assay performed using the bacterial isolate Mycobacterium tuberculosis (Mtb) H37Ra in a HFIM that mimicked the individual pharmacokinetic profile of the patient.

RESULTS: The isoniazid concentration observed in the HFIM adequately reflected the target drug exposures simulated by the model. After 7 days of repeated dose administration, isoniazid killed 4 log10 Mtb CFU/mL in the treatment arm, while the control arm without isoniazid increased 1.6 log10 CFU/mL.

CONCLUSION: Our results provide an example of the utility of the HFIM for predicting the efficacy of specific recommended doses of anti-tuberculosis drugs in real clinical setting.

PMID:38599596 | DOI:10.3346/jkms.2024.39.e104

J Ethnopharmacol. 2024 Apr 8:118161. doi: 10.1016/j.jep.2024.118161. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Kai-Xin-San (KXS) is a classic herbal formula for the treatment and prevention of AD (Alzheimer's disease) with definite curative effect, but its mechanism, which involves multiple components, pathways, and targets, is not yet fully understood.

AIM OF THE STUDY: To verify the effect of KXS on gut microbiota and explore its anti-AD mechanism related with gut microbiota.

MATERIALS AND METHODS: AD rat model was established and evaluated by intraperitoneal injection of D-gal and bilateral hippocampal CA1 injections of Aβ25-35. The pharmacodynamics of KXS in vivo includes general behavior, Morris water maze test, ELISA, Nissl & HE staining and immunofluorescence. Systematic analysis of gut microbiota was conducted using 16S rRNA gene sequencing technology. The potential role of gut microbiota in the anti-AD effect of KXS was validated with fecal microbiota transplantation (FMT) experiments.

RESULTS: KXS could significantly improve cognitive impairment, reduce neuronal damage and attenuate neuroinflammation and colonic inflammation in vivo in AD model rats. Nine differential intestinal bacteria associated with AD were screened, in which four bacteria (Lactobacillus murinus, Ligilactobacillus, Alloprevotella, Prevotellaceae_NK3B31_group) were very significant.

CONCLUSION: KXS can maintain the ecological balance of intestinal microbiota and exert its anti-AD effect by regulating the composition and proportion of gut microbiota in AD rats through the microbiota-gut-brain axis.

PMID:38599474 | DOI:10.1016/j.jep.2024.118161

PLoS One. 2024 Apr 10;19(4):e0300511. doi: 10.1371/journal.pone.0300511. eCollection 2024.

ABSTRACT

OBJECTIVES: The response to antipsychotic therapy is highly variable. Pharmacogenomic (PGx) factors play a major role in deciding the effectiveness and safety of antipsychotic drugs. A hybrid type 2 effectiveness-implementation research will be conducted to evaluate the clinical utility (safety and efficacy), cost-effectiveness, and facilitators and barriers in implementing PGx-assisted management compared to standard of care in patients with schizophrenia attending a tertiary care hospital in eastern India.

METHODS: In part 1, a randomized controlled trial will be conducted. Adult patients with schizophrenia will be randomized (2: 1) to receive PGx-assisted treatment (drug and regimen selection depending on the results of single-nucleotide polymorphisms in genes DRD2, HTR1A, HTR2C, ABCB1, CYP2D6, CYP3A5, and CYP1A2) or the standard of care. Serum drug levels will be measured. The patients will be followed up for 12 weeks. The primary endpoint is the difference in the Udvalg for Kliniske Undersøgelser Side-Effect Rating Scale score between the two arms. In part 2, the cost-effectiveness of PGx-assisted treatment will be evaluated. In part 3, the facilitators and barriers to implementing PGx-assisted treatment for schizophrenia will be explored using a qualitative design.

EXPECTED OUTCOME: The study findings will help in understanding whether PGx-assisted management has a clinical utility, whether it is cost-effective, and what are the facilitators and barriers to implementing it in the management of schizophrenia.

TRIAL REGISTRATION: The study has been registered with the Clinical Trials Registry-India (CTRI/2023/08/056210).

PMID:38598465 | DOI:10.1371/journal.pone.0300511

Nicotine Tob Res. 2024 Apr 10:ntae074. doi: 10.1093/ntr/ntae074. Online ahead of print.

ABSTRACT

BACKGROUND: Popular "pod-style" e-cigarettes commonly use nicotine salt-based e-liquids that cause less irritation when inhaled and can deliver higher nicotine concentrations than free-base nicotine. We aimed to investigate the pharmacokinetic and pharmacodynamic effects of different nicotine formulations (salt vs. free-base) and concentrations that might influence systemic nicotine absorption and appeal of e-cigarettes.

METHODS: In this randomized, double-blind, within-subject crossover study, 20 non nicotine-naïve participants were switched among three e-liquids (free-base nicotine 20mg/mL, nicotine salt 20mg/mL, nicotine salt 40mg/mL) using a refillable pod system and a standardized vaping protocol (one puff every 30 seconds, 10 puffs total). Serum nicotine concentrations and vital signs were assessed over 180 minutes; direct effects, craving, satisfaction, withdrawal, and respiratory symptoms were measured using questionnaires. CYP2A6 genotypes and the nicotine metabolite ratio were also assessed.

RESULTS: Eleven (55%) participants were male and the median age was 23.5 years (range 18-67). All three formulations differed significantly in peak serum nicotine concentration (baseline adjusted Cmax, median (range): 12.0ng/mL (1.6-27.3), 5.4ng/mL (1.9-18.7) and 3.0ng/mL (1.3-8.8) for nicotine salt 40mg/mL, nicotine salt 20mg/mL and free-base 20mg/mL, respectively). All groups reached Cmax 2.0-2.5min (median) after their last puff. Differences in subjective effects were not statistically significant. No serious adverse events were observed.

CONCLUSION: Free-base 20mg/mL formulations achieved lower blood nicotine concentrations than nicotine salt 20mg/mL, while 40mg/mL nicotine salt yielded concentrations similar to cigarette smoking. The findings can inform regulatory policy regarding e-liquids and their potential use in smoking cessation.

IMPLICATIONS: Nicotine salt formulations inhaled by an e-cigarette led to higher nicotine delivery compared to nicotine free-base formulations with the same nicotine concentration. These findings should be considered in future regulatory discussions. The 40mg/mL nicotine salt formulation showed similar nicotine delivery as combustible cigarettes, albeit at concentrations over the maximum limit for e-liquids allowed in the European Union. Nicotine delivery resembling combustible cigarettes might be beneficial for smokers willing to quit to adequately alleviate withdrawal symptoms. However, increased nicotine delivery can also pose a public health risk, raising concerns about abuse liability, especially among youth and non-smokers.

PMID:38597729 | DOI:10.1093/ntr/ntae074

Digit Health. 2024 Apr 7;10:20552076241242661. doi: 10.1177/20552076241242661. eCollection 2024 Jan-Dec.

ABSTRACT

OBJECTIVE: This study aimed at developing and validating a web application on hypertension management called the D-PATH website.

METHODS: The website development involved three stages: content analysis, web development, and validation. The model of Internet Intervention was used to guide the development of the website, in addition to other learning and multimedia theories. The content was developed based on literature reviews and clinical guidelines on hypertension. Then, thirteen experts evaluated the website using Fuzzy Delphi Technique.

RESULTS: The website was successfully developed and contains six learning units. Thirteen experts rated the website based on content themes, presentation, interactivity, and instructional strategies. All experts reached a consensus that the web is acceptable to be used for nutrition education intervention.

CONCLUSION: D-PATH is a valid web-based educational tool ready to be used to help disseminate information on dietary and physical activity to manage hypertension. This web application was suitable for sharing information on dietary and physical activity recommendations for hypertension patients.

PMID:38596405 | PMC:PMC11003341 | DOI:10.1177/20552076241242661

J Am Assoc Nurse Pract. 2024 Apr 9. doi: 10.1097/JXX.0000000000001007. Online ahead of print.

ABSTRACT

BACKGROUND: Guided by Clinical Pharmacogenomic Implementation Consortium (CPIC) guidelines for >140 medications, pharmacogenomic tests inform medication selection and dosing to optimize efficacy while minimizing toxicities.

PURPOSE: This study assessed pharmacogenomic self-reported curricular content, knowledge, skills, attitudes, and usage in advanced practice registered nurses (APRNs) with prescriptive privileges.

METHODOLOGY: An online survey was administered assessing pharmacogenomic curricular content, knowledge, skills, attitudes, and usage.

RESULTS: Data from 266 APRNs were analyzed. Most graduated with their highest nursing degree ∼10 years ago and reported pharmacogenomic curricular content (n = 124, 48%). Pharmacogenomic curricular content was associated with pharmacogenomic familiarity (p = .045) but not with knowledge confidence (p = .615). Pharmacogenomic usage, defined as ordering a pharmacogenomic test within the past year, was low (n = 76, 29%) and most (n = 210, 84%) reported never using CPIC Guidelines. Advanced practice registered nurses (n = 162) who did not anticipate ordering a pharmacogenomic test in the next year (n = 77, 48%) indicated that they did not know what test to order.

CONCLUSIONS: Deficits were identified in APRN pharmacogenomic knowledge and skills despite academic training. Most reported not ordering pharmacogenomic tests, did not know what test to order, and did not use CPIC guidelines.

IMPLICATIONS: Pharmacogenomics is a quality and safety issue. Academic training did not result in practice integration and most reported capacity deficits. Recommendation for overcoming academic deficits include: (1) assessment of pharmacogenomics curricular content and faculty teaching capacity; (2) training addressing identified deficiencies; and (3) Commission of Collegiate Nursing Education policies that include pharmacogenomics in advanced pharmacology. Practicing APRN plans include on-the-job training and/or mandatory training at the time of relicensure.

PMID:38595133 | DOI:10.1097/JXX.0000000000001007

Cancer Cell. 2024 Apr 8;42(4):535-551.e8. doi: 10.1016/j.ccell.2024.03.004.

ABSTRACT

Inter- and intra-tumor heterogeneity is a major hurdle in primary liver cancer (PLC) precision therapy. Here, we establish a PLC biobank, consisting of 399 tumor organoids derived from 144 patients, which recapitulates histopathology and genomic landscape of parental tumors, and is reliable for drug sensitivity screening, as evidenced by both in vivo models and patient response. Integrative analysis dissects PLC heterogeneity, regarding genomic/transcriptomic characteristics and sensitivity to seven clinically relevant drugs, as well as clinical associations. Pharmacogenomic analysis identifies and validates multi-gene expression signatures predicting drug response for better patient stratification. Furthermore, we reveal c-Jun as a major mediator of lenvatinib resistance through JNK and β-catenin signaling. A compound (PKUF-01) comprising moieties of lenvatinib and veratramine (c-Jun inhibitor) is synthesized and screened, exhibiting a marked synergistic effect. Together, our study characterizes the landscape of PLC heterogeneity, develops predictive biomarker panels, and identifies a lenvatinib-resistant mechanism for combination therapy.

PMID:38593780 | DOI:10.1016/j.ccell.2024.03.004

Pharmacogenomics J. 2024 Apr 9;24(3):11. doi: 10.1038/s41397-024-00331-4.

ABSTRACT

OBJECTIVE: To investigate factors affecting the efficacy and tolerability of verapamil for migraine prevention using individual pharmacogenomic phenotypes.

BACKGROUND: Verapamil has a wide range of dosing in headache disorders without reliable tools to predict the optimal doses for an individual.

METHODS: This is a retrospective chart review examining adults with existing pharmacogenomic reports at Mayo Clinic who had used verapamil for migraine. Effects of six cytochrome P450 phenotypes on the doses of verapamil for migraine prevention were assessed.

RESULTS: Our final analysis included 33 migraine patients (82% with aura). The mean minimum effective and maximum tolerable doses of verapamil were 178.2(20-320) mg and 227.9(20-480) mg. A variety of CYP2C9, CYP2D6, and CYP3A5 phenotypes were found, without significant association with the verapamil doses after adjusting for age, sex, body mass index, and smoking status.

CONCLUSIONS: We demonstrated a wide range of effective and tolerable verapamil doses used for migraine in a cohort with various pharmacogenomic phenotypes.

PMID:38594235 | DOI:10.1038/s41397-024-00331-4

BMC Pulm Med. 2024 Apr 8;24(1):167. doi: 10.1186/s12890-024-02983-1.

ABSTRACT

BACKGROUND: Cyclin D1 (CCND1) plays a pivotal role in cancer susceptibility and the platinum-based chemotherapy response. This study aims to assess the relationship between a common polymorphism (rs9344 G > A) in CCND1 gene with cancer susceptibility, platinum-based chemotherapy response, toxicities and prognosis of patients with lung cancer.

METHODS: This study involved 498 lung cancer patients and 213 healthy controls. Among them, 467 patients received at least two cycles of platinum-based chemotherapy. Unconditional logistical regression analysis and meta-analysis were performed to evaluate the associations.

RESULTS: The lung adenocarcinoma risk was significantly higher in patients with AA than GG + GA genotype (adjusted OR = 1.755, 95%CI = 1.057-2.912, P = 0.030). CCND1 rs9344 was significantly correlated with platinum-based therapy response in patients receiving PP regimen (additive model: adjusted OR = 1.926, 95%CI = 1.029-3.605, P = 0.040; recessive model: adjusted OR = 11.340, 95%CI = 1.428-90.100, P = 0.022) and in the ADC subgroups (recessive model: adjusted OR = 3.345, 95%CI = 1.276-8.765, P = 0.014). Furthermore, an increased risk of overall toxicity was found in NSCLC patients (additive model: adjusted OR = 1.395, 95%CI = 1.025-1.897, P = 0.034; recessive model: adjusted OR = 1.852, 95%CI = 1.088-3.152, P = 0.023), especially ADC subgroups (additive model: adjusted OR = 1.547, 95%CI = 1.015-2.359, P = 0.043; recessive model: adjusted OR = 2.030, 95%CI = 1.017-4.052, P = 0.045). Additionally, CCND1 rs9344 was associated with an increased risk of gastrointestinal toxicity in non-smokers (recessive model: adjusted OR = 2.620, 95%CI = 1.083-6.336, P = 0.035). Non-significant differences were observed in the 5-year overall survival rate between CCND1 rs9344 genotypes. A meta-analysis of 5432 cases and 6452 control samples did not find a significant association between lung cancer risk and CCND1 rs9344 polymorphism.

CONCLUSION: This study suggests that in the Chinese population, CCND1 rs9344 could potentially serve as a candidate biomarker for cancer susceptibility and treatment outcomes in specific subgroups of patients.

PMID:38589850 | DOI:10.1186/s12890-024-02983-1

J Community Genet. 2024 Apr 8. doi: 10.1007/s12687-024-00705-y. Online ahead of print.

ABSTRACT

Many patients with major depressive disorder (MDD) try multiple antidepressants before finding one that works well and is tolerable. Pharmacogenomic (PGx) testing was developed to facilitate more efficacious prescribing. This technology has not been robustly implemented clinically. Patient perspectives are critical to policy decisions, but the views of patients with MDD about the use of PGx testing to guide antidepressant prescribing have not been extensively examined, particularly in publicly funded healthcare systems. The purpose of this qualitative description study was to produce actionable patient perspectives evidence to inform future technology assessment of PGx testing. We conducted semi-structured interviews with 21 adults with MDD for which antidepressants were indicated in Ontario, Canada, and used the Ontario Decision Determinants Framework to conduct an unconstrained deductive content analysis. Patients expressed views about the overall clinical benefit of PGx testing in depression care, preferences for deployment of testing, perspectives on ethical considerations, opinions about equity and patient care, and beliefs regarding the feasibility of adopting PGx testing into the healthcare system. They also worried about the possibility of conflicts of interest between PGx test manufacturers and pharmaceutical companies. This study provides policymakers with patient priorities to facilitate the development of patient-centred policies. It highlights that formal adoption of PGx testing into the healthcare system requires a focus on equity of access and health outcomes.

PMID:38587601 | DOI:10.1007/s12687-024-00705-y

Heliyon. 2024 Mar 27;10(7):e28566. doi: 10.1016/j.heliyon.2024.e28566. eCollection 2024 Apr 15.

ABSTRACT

INTRODUCTION: CYP2C19 is a highly polymorphic gene responsible for metabolizing commonly used drugs. CYP2C19*2,*3 (loss of activity alleles) and *17 (increased activity allele) are the principal alleles included in clinical guidelines, however their prevalence varies among different ethnicities. Ecuadorian population is formed by Mestizos, Afrodescendants and Native Americans and frequency of CYP2C19 alleles could be different among them. The objective of this study was to establish the frequency of these variants in the different populations of Ecuador and to compare them with other populations.

MATERIALS AND METHODS: DNA from 105 Afrodescendants, 75 Native Americans of the Kichwa ethnicity, and 33 Mestizos Ecuadorians was analyzed by nested-PCR to identify CYP2C19*17 carriers. CYP2C19*2 allele was analyzed in DNA from 78 Afrodescendants, 29 Native Americans of the Kichwa, and 16 Mestizos by TaqMan Allelic Discrimination Assay. CYP2C19*3 was analyzed in 33 Afrodescendants by nested-PCR.

RESULTS: The global frequencies of the alternate alleles were 14.22% (CYP2C19*2) and 2.10% (CYP2C19*17). No differences (p > 0.05) were observed among the subgroups. No CYP2C19*3 carrier was identified. CYP2C19*2 frequencies in Ecuador were similar to the ones reported in Europe, Africa and Middle East countries and to some American populations. Low CYP2C19*17 frequencies, like the ones in our population, were also observed in East and South Asia and in Native American groups.

DISCUSSION: Absence of differences in the ethnic groups in Ecuador for CYP2C19*2 and *17 could be due to either a bias in sample selection (ethnic group was assed by self-identification) or to a high interethnic admixture in the Ecuadorian population that would had diluted genetic differences. In addition, CYP2C19*2, *3, and *17 alleles frequencies in our study suggest that Ecuadorians ancestry is mostly of Native American origin.

PMID:38586400 | PMC:PMC10998100 | DOI:10.1016/j.heliyon.2024.e28566

Transl Clin Pharmacol. 2024 Mar;32(1):1-17. doi: 10.12793/tcp.2024.32.e5. Epub 2024 Mar 25.

ABSTRACT

Insomnia, commonly treated with benzodiazepine (BZD) receptor agonists, presents challenges due to associated serious side effects such as abuse and dependence. To address these concerns, many researches have been conducted to develop and advance both pharmacological and non-pharmacological interventions. Dual orexin receptor antagonists (DORAs), which include suvorexant, daridorexant and lemborexant, have recently been approved by United States Food and Drug Administration (US FDA) as a novel pharmacotherapeutic alternative. Unlike BZD receptor agonists that act as positive allosteric modulators of the gamma-aminobutyric acid type A subunit alpha 1 receptor, DORAs function by binding to both orexin receptor types 1 and 2, and inhibiting the action of the wake-promoting orexin neuropeptide. These drugs induce normal sleep without sleep stage change, do not impair attention and memory performance, and facilitate easier awakening. However, more real-world safety information is needed. Selective orexin-2 receptor antagonists (2-SORAs) is under clinical developments. This review provides an overview of the mechanism of action in relation to insomnia, pharmacokinetics, efficacy and safety information of DORAs and SORA. According to insomnia management guidelines, the first-line treatment for chronic insomnia is cognitive behavioral therapy for insomnia (CBT-I). Although it has proven effective in improving sleep-related quality of life, it has several restrictions limitations due to a face-to-face format. Recently, prescription digital therapy such as Somryst® was approved by US FDA. Somryst®, a smartphone app-based CBT-I, demonstrated meaningful responses in patients. However, digital limitations may impact scalability. Overall, these developments offer promising alternatives for insomnia treatment, emphasizing safety, efficacy, and accessibility.

PMID:38586124 | PMC:PMC10990727 | DOI:10.12793/tcp.2024.32.e5