BJPsych Open. 2024 Dec 5;10(6):e227. doi: 10.1192/bjo.2024.757.

ABSTRACT

BACKGROUND: Early worsening of plasma lipid levels (EWL; ≥5% change after 1 month) induced by at-risk psychotropic treatments predicts considerable exacerbation of plasma lipid levels and/or dyslipidaemia development in the longer term.

AIMS: We aimed to determine which clinical and genetic risk factors could predict EWL.

METHOD: Predictive values of baseline clinical characteristics and dyslipidaemia-associated single nucleotide polymorphisms (SNPs) on EWL were evaluated in a discovery sample (n = 177) and replicated in two samples from the same cohort (PsyMetab; n1 = 176; n2 = 86).

RESULTS: Low baseline levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C) and triglycerides, and high baseline levels of high-density lipoprotein cholesterol (HDL-C), were risk factors for early increase in total cholesterol (P = 0.002), LDL-C (P = 0.02) and triglycerides (P = 0.0006), and early decrease in HDL-C (P = 0.04). Adding genetic parameters (n = 17, 18, 19 and 16 SNPs for total cholesterol, LDL-C, HDL-C and triglycerides, respectively) improved areas under the curve for early worsening of total cholesterol (from 0.66 to 0.91), LDL-C (from 0.62 to 0.87), triglycerides (from 0.73 to 0.92) and HDL-C (from 0.69 to 0.89) (P ≤ 0.00003 in discovery sample). The additive value of genetics to predict early worsening of LDL-C levels was confirmed in two replication samples (P ≤ 0.004). In the combined sample (n ≥ 203), adding genetics improved the prediction of new-onset dyslipidaemia for total cholesterol, LDL-C and HDL-C (P ≤ 0.04).

CONCLUSIONS: Clinical and genetic factors contributed to the prediction of EWL and new-onset dyslipidaemia in three samples of patients who started at-risk psychotropic treatments. Future larger studies should be conducted to refine SNP estimates to be integrated into clinically applicable predictive models.

PMID:39635766 | DOI:10.1192/bjo.2024.757

BMC Psychiatry. 2024 Dec 4;24(1):885. doi: 10.1186/s12888-024-06319-5.

ABSTRACT

BACKGROUND: Strong evidence for therapeutic drug monitoring exists for olanzapine and clozapine, however, olanzapine therapeutic drug monitoring is often underutilized. Evidence for pharmacogenomic-guided dosing of antipsychotics is not as robust, especially for cytochrome P450 1A2 metabolized agents such as olanzapine and clozapine. Herein, we present a case involving a patient suspected of having poor CYP1A2 metabolism. Therapeutic drug monitoring of olanzapine was employed to guide the titration of clozapine following olanzapine failure. Despite pursuing pharmacogenetic testing, no meaningful results were obtained due to the omission of CYP1A2 variants associated with poor metabolism.

CASE PRESENTATION: A 32-year-old Caucasian male with schizoaffective disorder-bipolar type, ADHD, and autism spectrum disorder presented with extrapyramidal symptoms due to antipsychotic polypharmacy, resulting in multiple falls. He experienced a partial response to olanzapine 40 mg, thus his dose was increased to 50 mg. Sampling an olanzapine trough revealed a supratherapeutic level of 152 ng/mL. Given his history of EPS and other reported adverse effects from antipsychotics, including clozapine, pharmacogenomic testing was pursued. The patient cross-tapered to clozapine slowly, with the knowledge that the patient would likely exhibit elevated levels of olanzapine. Clozapine was efficacious and tolerated well. As expected, the patient exhibited higher clozapine trough concentrations for someone of his age, ethnicity, and gender. Pharmacogenomic testing yielded no relevant findings relating to olanzapine or clozapine metabolism.

CONCLUSION: This case highlights the utility of TDM over pharmacogenetic testing for patients on these medications with a suspected alteration in CYP1A2 metabolism. therapeutic drug monitoring emerges as a more practical approach with stronger evidence for its use, particularly in cases of suspected reduced CYP1A2 activity, where suballeles resulting in decreased enzyme function are not readily detectable on standard commercial pharmacogenomic panels.

PMID:39633320 | DOI:10.1186/s12888-024-06319-5

Nat Commun. 2024 Dec 4;15(1):10557. doi: 10.1038/s41467-024-54969-6.

ABSTRACT

Erythropoietic protoporphyria (EPP) is a genetic disease characterized by protoporphyrin IX-mediated painful phototoxicity. Currently, options for the management of EPP-associated phototoxicity are limited and no oral medication is available. Here, we investigated a novel therapy against EPP-associated phototoxicity by targeting the ATP-binding cassette subfamily G member 2 (ABCG2), the efflux transporter of protoporphyrin IX. Oral ABCG2 inhibitors were developed, and they successfully prevented EPP-associated phototoxicity in a genetically engineered EPP mouse model. Mechanistically, ABCG2 inhibitors suppress protoporphyrin IX release from erythroid cells and reduce the systemic exposure to protoporphyrin IX in EPP. In summary, our work establishes a novel strategy for EPP therapy by targeting ABCG2 and provides oral ABCG2 inhibitors that can effectively prevent protoporphyrin IX-mediated phototoxicity in mice.

PMID:39632884 | DOI:10.1038/s41467-024-54969-6

J Med Chem. 2024 Dec 4. doi: 10.1021/acs.jmedchem.4c02045. Online ahead of print.

ABSTRACT

Antihypertensive pharmacological therapy is often characterized by a coadministration of different classes of drugs. Therefore, analytical methods allowing the simultaneous quantification of many drugs are needed for therapeutic drug monitoring (TDM) purposes in this context. In particular, TDM represents a useful tool to discriminate poor adherence from real cases of resistant hypertension. For this reason, the aim of this study is to validate, following the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) guidelines, an ultrahigh-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) method for the simultaneous quantification of 18 antihypertensive drugs in human plasma. A LX-50 coupled with a QSight 220 UHPLC-MS/MS system with electrospray ionization and multiple reaction monitoring mode was used, after a binary gradient separation (13 min) on a reverse-phase Acquity UPLC HSS T3 [1.8 μm, 2.1 mm × 150 mm] column. Method validation showed a stable and acceptable matrix effect, recovery, high accuracy, and precision, assessing the eligibility of this method for routine use in the clinical context.

PMID:39630959 | DOI:10.1021/acs.jmedchem.4c02045

Eur J Pain. 2025 Jan;29(1):e4764. doi: 10.1002/ejp.4764.

ABSTRACT

BACKGROUND: Opioids in step III of the WHO analgesic ladder are the standard of care for treating cancer pain. However, a significant minority of patients do not benefit from therapy. Genetics might play a role in predisposing patients to a good or poor response to opioids. Here, we investigated this issue by conducting a genome-wide association study (GWAS).

METHODS: We genotyped 2057 European advanced cancer patients treated with morphine, buprenorphine, fentanyl and oxycodone. We carried out a whole-genome regression model (using REGENIE software) between genotypes and the opioid response phenotype, defined as a numerical score measuring patient pain intensity.

RESULTS: The GWAS identified five non-coding variants on chromosome 20 with a p-value <5.0 × 10-8. For all of them, the minor allele was associated with lower pain intensity. These variants were intronic to the PCMTD2 gene and were 200 kbp downstream of OPRL1, the opioid related nociceptin receptor 1. Notably according to the eQTLGen database, these variants act as expression quantitative trait loci, modulating the expression mainly of PCMTD2 but also of OPRL1. Variants in the same chromosomal region were recently reported to be significantly associated with pain intensity in a GWAS conducted in subjects with different chronic pain conditions.

CONCLUSIONS: Our results support the role of genetics in the opioid response in advanced cancer patients. Further functional analyses are needed to understand the biological mechanism underlying the observed association and lead to the development of individualized pain treatment plans, ultimately improving the quality of life for cancer patients.

SIGNIFICANCE STATEMENT: This genome-wide association study on European advanced cancer patients treated with opioids identifies novel regulatory variants on chromosome 20 (near PCMTD2 and OPRL1 genes) associated with pain intensity. These findings enhance our understanding of the genetic basis of opioid response, suggesting new potential markers for opioid efficacy. The study is a significant advancement in pharmacogenomics, providing a robust dataset and new insights into the genetic factors influencing pain intensity, which could lead to personalized cancer pain management.

PMID:39629963 | DOI:10.1002/ejp.4764

Cell Stress. 2024 Nov 28;11:112-124. doi: 10.15698/cst2024.11.301. eCollection 2024.

ABSTRACT

Human peripheral blood mononuclear cells (PBMCs) are used to examine biological processes and disease, when basal variability in cellular activation and splicing is described and unexplained. Using isolation systems that maintained buffy coat cells (PBMCs, platelets) in their own plasma, poly-A enriched RNA-sequencing (RNASeq) detected 42,720 Ensembl gene IDs, including >95% of the top 100 Genotype Tissue Expression Project (GTEx)-expressed genes in lung, colon, heart, skeletal muscle and liver, and 10/17 clinically-actionable genes listed by the Pharmacogenomics Knowledgebase. Transcriptome changes were defined after 1h treatment with 32°C hypothermia (hsp70 family member change), 10 μmol/L ferric citrate that had no discernible effect, and 100 μg/mL cycloheximide leading to induction of primary response (immediate early) genes including IL1B and TNF. Same-donor PBMCs prepared conventionally using washes then resuspension in serum-supplemented media demonstrated basal upregulation of stress signalling pathway genes that masked and overlapped differential gene expression profiles after 100 µg/L cycloheximide. Plasma-resuspended PBMCs demonstrated minor transcriptome changes after 40 μmol/L ferric citrate, whereas consistent and greater magnitude changes were observed for washed/media-resuspended PBMCs. We conclude that endogenous plasma-maintained PBMCs provide a more robust platform to interrogate acute cellular perturbations triggering innate immunity, and that varying susceptibility of PBMCs to preparative stresses is an important component of experimental variability.

PMID:39628848 | PMC:PMC11613960 | DOI:10.15698/cst2024.11.301

Pharmacogenomics. 2024 Dec 4:1-8. doi: 10.1080/14622416.2024.2430161. Online ahead of print.

ABSTRACT

AIMS: To examine the associations between CYP2D6 and CYP3A4 polymorphisms, plasma oxycodone and metabolite concentrations, and oxycodone response (dose, pain scores, and adverse effects) in people with pain from advanced cancer.

PATIENTS & METHODS: This multi-center prospective cohort study included clinical data, questionnaires (pain and adverse effects), and blood (pharmacokinetics, DNA). Negative binomial regression and logistic regression were used.

RESULTS: Within 33 participants, there were no differences in oxycodone response between CYP2D6 intermediate/poor metabolisers compared to normal metabolisers.Higher plasma noroxycodone and noroxycodone/oxycodone concentration ratios had higher odds of uncontrolled average pain (OR 2.44 (95%CI 1.00-5.95), p = 0.05 and OR 10.48 (95%CI 1.42-77.15), p = 0.02, respectively).

CONCLUSIONS: There was no observed benefit in CYP2D6 genotyping in oxycodone response, however monitoring noroxycodone and oxymorphone concentrations warrant further examination.

PMID:39628313 | DOI:10.1080/14622416.2024.2430161

Br J Pharmacol. 2024 Dec 3. doi: 10.1111/bph.17414. Online ahead of print.

ABSTRACT

Hypertension is a major contributor to cardiovascular disease and its associated morbidity and mortality. The low efficacy observed with some anti-hypertensive therapies has been attributed partly to inter-individual genetic variability. This paper reviews the major findings regarding these genetic variabilities that modulate responses to anti-hypertensive therapies such as angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), diuretics, calcium channel blockers (CCBs) and β-adrenoceptor blockers. The importance of studying these genetic polymorphisms stems from the goal to optimise anti-hypertensive therapy for each individual patient, aiming for the highest efficacy and lowest risk of adverse effects. It is important to recognise that environmental and epigenetic factors can contribute to the observed variations in drug responses. Owing to the multigenic and multifactorial nature of drug responses, further research is crucial for translating these findings into clinical practice and the establishment of reliable recommendations.

PMID:39627167 | DOI:10.1111/bph.17414

Curr Rev Clin Exp Pharmacol. 2024 Dec 2. doi: 10.2174/0127724328323600241120113500. Online ahead of print.

ABSTRACT

INTRODUCTION: Genomic variations among individuals can greatly affect their responses to different medications. Pharmacogenomics is the area of study that aims to understand the relationship between these various genetic variations and subsequent drug responses. Many medications used to optimize cardiovascular health are affected by these genetic variants and these relationships can subsequently impact dosing strategies in patients.

OBJECTIVE: This study aims to review the current literature on the clinical applications ofpharmacogenomics for commonly used cardiovascular medications such as Warfarin, Clopidogrel, Statins, Beta Blockers, and ACE-I/ARBs.

METHODS: Databases like PubMed were accessed to gather background information on pharmacogenomics and to collect data on relationships between genetic variants and subsequent drug response. Information on clinical applications and guidelines was obtained by accessing the CPIC and DPWG databases.

RESULTS: This article describes the most up-to-date data on pharmacogenomics relating to commonly used cardiovascular medications. It also discusses the clinical application of pharmacogenomic data as it pertains to medication selection/dosing by detailing current guidelines published by organizations such as the Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenetics Working Group.

CONCLUSION: In conclusion, this paper will help medical providers not only better understand pharmacogenomics but also apply it in their day-to-day practice. Clinical guidelines relating to the application of pharmacogenomic data were discussed both in text and graphical format, allowing providers to confidently select medications and adjust doses for common cardiovascular medications so that patients receive the maximum therapeutic benefit with minimal toxicity.

PMID:39623714 | DOI:10.2174/0127724328323600241120113500

Nat Commun. 2024 Dec 2;15(1):10479. doi: 10.1038/s41467-024-54905-8.

ABSTRACT

Proinsulin translation and folding is crucial for glucose homeostasis. However, islet β-cell control of Proinsulin translation remains incompletely understood. Here, we identify OSGEP, an enzyme responsible for t6A37 modification of tRNANNU that tunes glucose metabolism in β-cells. Global Osgep deletion causes glucose intolerance, while β-cell-specific deletion induces hyperglycemia and glucose intolerance due to impaired insulin activity. Transcriptomics and proteomics reveal activation of the unfolded protein response (UPR) and apoptosis signaling pathways in Osgep-deficient islets, linked to an increase in misfolded Proinsulin from reduced t6A37 modification. Osgep overexpression in pancreas rescues insulin secretion and mitigates diabetes in high-fat diet mice. Osgep enhances translational fidelity and alleviates UPR signaling, highlighting its potential as a therapeutic target for diabetes. Individuals carrying the C allele at rs74512655, which promotes OSGEP transcription, may show reduced susceptibility to T2DM. These findings show OSGEP is essential for islet β-cells and a potential diabetes therapy target.

PMID:39622811 | DOI:10.1038/s41467-024-54905-8

Br J Clin Pharmacol. 2024 Dec 2. doi: 10.1111/bcp.16359. Online ahead of print.

ABSTRACT

AIMS: Paclitaxel and nanoparticle albumin-bound (nab)-paclitaxel can cause early, extremely severe neutropenia, occasionally leading to fatal outcomes. As paclitaxel is a substrate of P-glycoprotein, this study aimed to investigate the impact of ABCB1 single-nucleotide variants, which encode P-glycoprotein, on early, extremely severe neutropenia in patients receiving paclitaxel/nab-paclitaxel plus ramucirumab as second-line therapy for unresectable advanced/recurrent gastric cancer.

METHODS: We analysed patients treated at Aichi Cancer Center Hospital from January 2018 to August 2023, with DNA samples stored in the Cancer BioBank Aichi. The impact of ABCB1 variants T1236C (rs1128503), G2677T/A (rs2032582) and C3435T (rs1045642) on early, extremely severe neutropenia was examined. Neutropenia was defined as a decline in neutrophil count to <100/μL within 28 days of therapy initiation. Firth's logistic regression evaluated the association between the ABCB1 C3435T (rs1045642) TT genotype and early, extremely severe neutropenia, adjusted for age, sex, baseline neutrophil count, and serum albumin and aspartate aminotransferase levels.

RESULTS: Of the 203 eligible patients, 5 (2%) experienced neutropenia with neutrophil counts of <100/μL. The odds ratio for neutrophil counts of <100/μL was 28.1 (95% confidence interval 2.8-283.3) in patients with the ABCB1 C3435T (rs1045642) TT genotype.

CONCLUSION: The ABCB1 C3435T (rs1045642) TT genotype was significantly associated with early, extremely severe neutropenia in patients receiving paclitaxel/nab-paclitaxel. Evaluating this genotype status may help predict those at increased risk for early, extremely severe neutropenia.

PMID:39622587 | DOI:10.1111/bcp.16359

BJA Educ. 2024 Nov;24(11):417-425. doi: 10.1016/j.bjae.2024.07.004. Epub 2024 Sep 14.

NO ABSTRACT

PMID:39620104 | PMC:PMC11602659 | DOI:10.1016/j.bjae.2024.07.004

Front Microbiol. 2024 Nov 13;15:1451303. doi: 10.3389/fmicb.2024.1451303. eCollection 2024.

ABSTRACT

Dysbiosis of the intestinal microbiota is prevalent among patients with colorectal cancer (CRC). This study aims to explore the anticancer roles of the fecal microbiota in inhibiting the progression of colorectal cancer and possible mechanisms. The intestinal microbial dysbiosis in CRC mice was significantly ameliorated by fecal microbiota transplantation (FMT), as indicated by the restored ACE index and Shannon index. The diameter and number of cancerous foci were significantly decreased in CRC mice treated with FMT, along with the restoration of the intestinal mucosal structure and the lessening of the gland arrangement disorder. Key factors in oxidative stress (TXN1, TXNRD1, and HIF-1α); cell cycle regulators (IGF-1, BIRC5, CDK8, HDAC2, EGFR, and CTSL); and a critical transcription factor of the innate immune signal pathway (IRF5) were among the repressed oncogenic targets engaged in the FMT treatment of CRC. Correlation analysis revealed that their expressions were positively correlated with uncultured_bacterium_o_Mollicutes_RF39, Rikenellaceae_RC9_gut_group, and negatively correlated with Bacillus, Marvinbryantia, Roseburia, Angelakisella, Enterorhabdus, Bacteroides, Muribaculum, and genera of uncultured_bacterium_f_Eggerthellaceae, uncultured_bacterium_f_Xanthobacteraceae, Prevotellaceae_UCG-001, uncultured_bacterium_f_Erysipelotrichaceae, uncul-tured_bacterium_f_Lachnospiraceae, uncultured_bacterium_f_Ruminococcaceae, Eubacterium_coprostanoligenes_group, Ruminococcaceae_UCG-005, and uncultured_bacterium_f_Peptococcaceae. This study provides more evidence for the application of FMT in the clinical treatment of CRC.

PMID:39619695 | PMC:PMC11605715 | DOI:10.3389/fmicb.2024.1451303

Clin Transl Sci. 2024 Dec;17(12):e70083. doi: 10.1111/cts.70083.

ABSTRACT

PACIFIC-PGx evaluated the feasibility of implementing pharmacogenetics (PGx) screening in Australia and the impact of DPYD/UGT1A1 genotype-guided dosing on severe fluoropyrimidine (FP) and irinotecan-related toxicities and hospitalizations, compared to historical controls. This prospective single arm trial enrolled patients starting FP/irinotecan for any cancer between 7 January 2021 and 25 February 2022 from four Australian hospitals (one metropolitan, three regional). During the accrual period, 462/487 (95%) consecutive patients screened for eligibility for DPYD and 50/109 (46%) for UGT1A1 were enrolled and genotyped (feasibility analysis), with 276/462 (60%) for DPYD and 30/50 (60%) for UGT1A1 received FP/irinotecan (safety analysis). DPYD genotyping identified 96% (n = 443/462) Wild-Type, 4% (n = 19/462) Intermediate Metabolizers (50% dose reduction), and 0% Poor Metabolizers. UGT1A1 genotyping identified 52% (n = 26/50) Wild-Type, 40% (n = 20/50) heterozygous, and 8% (n = 4/50) homozygous (30% dose reduction). Key demographics for the FP/irinotecan safety cohorts included: age range 23-89/34-74 years, male 56%/73%, Caucasian 83%/73%, lower gastrointestinal cancer 50%/57%. Genotype results were reported prior to cycle-1 (96%), average 5-7 days from sample collection. PGx-dosing for DPYD variant allele carriers reduced high-grade toxicities compared to historic controls (7% vs. 39%; OR = 0.11, 95% CI 0.01-0.97, p = 0.024). High-grade toxicities among Wild-Type were similar (14% vs. 14%; OR = 0.99, 95% CI 0.64-1.54, p = 0.490). PGx-dosing reduced FP-related hospitalizations (-22%) and deaths (-3.7%) compared to controls. There were no high-grade toxicities or hospitalizations for UGT1A1*28 homozygotes. PGx screening and prescribing were feasible in routine oncology care and improved patient outcomes. Findings may inform expanded PGx programs within cancer and other disease settings.

PMID:39614408 | DOI:10.1111/cts.70083

Heart Rhythm. 2024 Nov 27:S1547-5271(24)03625-7. doi: 10.1016/j.hrthm.2024.11.041. Online ahead of print.

ABSTRACT

Mavacamten is a selective, allosteric, and reversible cardiac myosin inhibitor, representing the first disease-specific treatment for obstructive hypertrophic cardiomyopathy (HCM) that targets the core pathophysiological mechanism of this condition. Clinical evidence supports its efficacy in improving symptoms, cardiac function and remodeling, thereby supplementing established treatment regimes. However, mavacamten is extensively metabolized by hepatic cytochromes and its half-life is contingent upon CYP2C19 phenotype. Consequently, co-administered medications that inhibit or induce these enzymes may significantly alter mavacamten pharmacokinetics, potentially leading to reversible systolic dysfunction or diminished therapeutic efficacy. This paper provides a comprehensive analysis of mavacamten pharmacokinetics and its potential interactions with antithrombotic and antiarrhythmic agents, which are the cornerstones of atrial fibrillation management in HCM population. Our aim is to offer clinicians practical guidance on safely administering mavacamten in conjunction with these medications, discuss the role of pharmacogenomics and outline rigorous patient safety monitoring strategies to ensure effective and individualized treatment.

PMID:39613202 | DOI:10.1016/j.hrthm.2024.11.041

Front Pharmacol. 2024 Nov 14;15:1480657. doi: 10.3389/fphar.2024.1480657. eCollection 2024.

ABSTRACT

BACKGROUND: Methotrexate (MTX) is the primary drug used in the treatment of pediatric acute lymphoblastic leukemia (ALL). However, some patients exhibit delayed clearance of high-dose (HD) MTX, which induces severe nephrotoxicity, mucositis, hepatotoxicity, and neurotoxicity. We sought to identify relevant variants associated with delayed clearance of HD-MTX in pediatric patients with ALL.

METHODS: Whole-exome sequencing of germline DNA was performed in 51 Korean pediatric patients with ALL. A total of 341 HD-MTX infusion data points from 51 patients were analyzed. MTX levels and laboratory measurements reflecting toxicity outcomes were obtained. Correlations between peak serum MTX levels at 24 h and toxicity outcomes were assessed. Analyses were performed to identify variants affecting delayed MTX clearance.

RESULTS: The 24 h MTX level strongly correlated with the subsequent creatinine (Cr) level. Moreover, rs2229866 in contactin 2 (CNTN2), rs200687372 in myotubularin Related Protein 9 (MTMR9), rs777260512 in polymerase iota (POLI), rs16954698 in polycystic kidney disease 1-like 2 (PKD1L2), rs117765468 in NSE1 Homolog, SMC5-SMC6 Complex Component (NSMCE1), and rs1800956 in endoglin (ENG) were identified as candidate variants associated with delayed MTX clearance. In particular, ENG rs1800956 was significantly associated with delayed MTX clearance in all analyses and PKD1L2 rs16954698 was replicated in an external dataset (phs000637.v1.p1) from the Database of Genotypes and Phenotypes (dbGaP).

CONCLUSION: This is the first whole-exome sequencing-based analysis of delayed MTX clearance in pediatric patients with ALL. ENG rs1800956 and PKD1L2 rs16954698 were found to be potentially influential variants associated with delayed MTX clearance. These findings provide insights into HD-MTX-induced nephrotoxicity and may contribute to reducing adverse reactions through treatment modification.

PMID:39611166 | PMC:PMC11603417 | DOI:10.3389/fphar.2024.1480657

Breast Cancer (Auckl). 2024 Nov 27;18:11782234241285411. doi: 10.1177/11782234241285411. eCollection 2024.

ABSTRACT

BACKGROUND: Breast cancer remains the most common invasive cancer in women worldwide. Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options. Trastuzumab (Tz) is typically used to treat HER2-positive breast cancers, but its potential in TNBC is unclear.

OBJECTIVES: To investigate the effects of trastuzumab on cell viability, apoptosis, cell cycle progression, and gene expression in TNBC cell lines compared with HER2-positive and normal cell lines.

DESIGN: This is an in vitro experimental pre-clinical study using cultured cancer cell lines.

METHODS: MDA-MB-231 and 4T1 (TNBC), MCF-7 (HER2-positive), and HSF (normal) cell lines were treated with 20 μg/mL trastuzumab for 24 hours. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, apoptosis by flow cytometry, cell cycle progression by DNA content analysis, and gene expression by qPCR.

RESULTS: Trastuzumab significantly reduced cell viability and induced apoptosis in TNBC cell lines, comparable to effects in HER2-positive MCF-7 cells. Cell cycle analysis revealed G2/M phase arrest in TNBC cells. Gene expression analysis showed upregulation of ERBB2, NOTCH1, EGFR, PIK3CA, and PTEN in MDA-MB-231 cells, while 4T1 cells exhibited downregulation of most genes except NOTCH1.

CONCLUSION: This study provides initial evidence for trastuzumab's potential therapeutic effects in TNBC, despite low HER2 expression. The observed cytotoxicity, apoptosis induction, and cell cycle modulation in TNBC cells warrant further investigation into trastuzumab's mechanisms of action in HER2-negative contexts and its potential repurposing for TNBC treatment.

PMID:39611037 | PMC:PMC11603482 | DOI:10.1177/11782234241285411

J Diabetes Metab Disord. 2024 Sep 23;23(2):2279-2287. doi: 10.1007/s40200-024-01495-3. eCollection 2024 Dec.

ABSTRACT

OBJECTIVES: The efficacy and safety of drug treatments vary widely due to genetic variations. Pharmacogenomics investigates the impact of genetic variations on patient drug response. This research investigates the frequency of UGT1A1 genetic variations in the Iranian population, comparing them with global data to provide insights into the pharmacogenomic approach in the Iranian population.

METHODS: The study was conducted using the data of the Bushehr Elderly Health (BEH) program, a population-based cohort study of the elderly population aged ≥ 60 years. Genotyping of three UGT1A1 variant alleles (UGT1A1*6, UGT1A1*27, and UGT1A1*80) was performed on a group of 2730 elderly Iranian participants with the Infinium Global Screening Array.

RESULTS: The genotyping analysis revealed significant differences compared to major global populations that were addressed in the gnomAD database. UGT1A1*80 was found at a high frequency (32.34%), and followed by UGT1A1*6 (0.76%) and UGT1A1*27 (0.018) at a low frequency in the Iranian group.

CONCLUSIONS: The UGT1A1*80 was the more prevalent allele between investigated alleles in the present study which can be considered as an important allele for pharmacogenomic testing.

PMID:39610552 | PMC:PMC11599689 | DOI:10.1007/s40200-024-01495-3

JAMA Neurol. 2024 Nov 29. doi: 10.1001/jamaneurol.2024.4487. Online ahead of print.

ABSTRACT

IMPORTANCE: Typical cysteine-altering NOTCH3 (NOTCH3cys) variants are highly prevalent (approximately 1 in 300 individuals) and are associated with a broad spectrum of small vessel disease (SVD), ranging from early-onset stroke and dementia (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]) to nonpenetrance. A staging system that captures the full NOTCH3-SVD severity spectrum is needed and currently lacking.

OBJECTIVE: To design a simple disease severity staging system that captures the broad clinicoradiological NOTCH3-SVD severity spectrum.

DESIGN, SETTING, AND PARTICIPANTS: A cohort study was performed in which the NOTCH3-SVD severity staging system was developed using a discovery cohort (2019-2020) and validated in independent international CADASIL cohorts (1999-2023) and the UK Biobank. Clinical and imaging data were collected from participants originating from 23 international CADASIL cohorts and from the UK Biobank. Eligibility criteria were presence of a NOTCH3cys variant, availability of brain magnetic resonance imaging, and modified Rankin Scale score. The discovery cohort consisted of 195 NOTCH3cys-positive cases from families with CADASIL; the validation set included 1713 NOTCH3cys-positive cases from 15 countries. The UK Biobank cohort consisted of 101 NOTCH3cys-positive individuals. Data from 2-year (2019-2023) and 18-year (1999-2017) follow-up studies were also analyzed. Data analysis was performed from July 2023 to August 2024.

MAIN OUTCOMES AND MEASURES: Percentage of cases following the sequence of events of the NOTCH3-SVD stages, and the association between the stages and ischemic stroke, intracerebral hemorrhage, global cognition, processing speed, brain volume, brain microstructural damage, and serum neurofilament light chain (NfL) level.

RESULTS: The NOTCH3-SVD staging system encompasses 9 disease stages or substages, ranging from stage 0 (premanifest stage) to stage 4B (end stage). Of all 1908 cases, which included 195 in the discovery cohort (mean [SD] age, 52.4 [12.2] years) and 1713 in the validation cohorts (mean [SD] age, 53.1 [13.0] years), 1789 (94%) followed the sequence of events defined by the NOTCH3-SVD staging system. The NOTCH3-SVD stages were associated with neuroimaging outcomes in the NOTCH3cys-positive cases in the CADASIL cohorts and in the UK Biobank and with cognitive outcomes and serum NfL level in cases from the CADASIL cohorts. The NOTCH3-SVD staging system captured disease progression and was associated with 18-year survival.

CONCLUSIONS AND RELEVANCE: The NOTCH3-SVD staging system captures the full disease spectrum, from asymptomatic individuals with a NOTCH3cys variant to patients with end-stage disease. The NOTCH3-SVD staging system is a simple but effective tool for uniform disease staging in the clinic and in research.

PMID:39610302 | DOI:10.1001/jamaneurol.2024.4487

Genetics. 2024 Nov 28:iyae170. doi: 10.1093/genetics/iyae170. Online ahead of print.

ABSTRACT

The glucose-6-phosphate dehydrogenase (G6PD) enzyme protects red blood cells against oxidative damage. Individuals with G6PD-impairing polymorphisms are at risk of hemolytic anemia from oxidative stressors. Prevention of G6PD deficiency-related hemolytic anemia is achievable by identifying affected individuals through G6PD genetic testing. However, accurately predicting the clinical consequence of G6PD variants is limited by over 800 G6PD variants which remain of uncertain significance (VUS). There also remains inconsistency in which deficiency-causing variants are included in genetic testing arrays: many institutions only test c.202G > A, though dozens of other variants can cause G6PD deficiency. Here, we improve G6PD genotype interpretations using the All of Us Research Program data and a yeast functional assay. We confirm that G6PD coding variants are the main contributor to decreased G6PD activity and that 13% of individuals in the All of Us data with deficiency-causing variants would be missed by only genotyping for c.202G > A. We expand clinical interpretation for G6PD VUS, reporting that c.595A > G ("Dagua" or "Açores") and the novel variant c.430C > G reduce activity sufficiently to lead to G6PD deficiency. We also provide evidence that 5 missense VUS are unlikely to lead to G6PD deficiency, and we applied the new World Health Organization (WHO) guidelines to recommend classifying 2 synonymous variants as WHO Class C. In total, we provide new or updated clinical interpretations for 9 G6PD variants. We anticipate these results will improve the accuracy, and prompt increased use, of G6PD genetic tests through a more complete clinical interpretation of G6PD variants.

PMID:39607789 | DOI:10.1093/genetics/iyae170