Head Neck. 2025 May 8. doi: 10.1002/hed.28179. Online ahead of print.

ABSTRACT

BACKGROUND: This study investigated the roles of single nucleotide variants (SNVs) in genes of CDDP metabolism and their association with kidney dysfunction in patients with head and neck squamous cell carcinoma (HNSCC).

METHODS: A total of 109 patients with locally advanced HNSCC, treated with CDDP, had renal function evaluated by serum creatinine level and CKD-EPI formula, and underwent genotyping by polymerase chain reaction.

RESULTS: Patients with GSTT1 present and ERCC1 c.354CT or TT genotypes showed 4.94% and 8.94% renal function reduction, respectively. GSTT1 present with TP53 c.215G>C (17.67%), GSTP1 c.313A>G with ERCC1 c.354C>T (17.57%), GSTP1 c.313A>G with MLH1 c.93G>A (12.49%), GSTP1 c.313A>G with MSH3 c.3133A>G (12.19%), ERCC1 c.354C>T with MLH1 c.93G>A (18.85%) and ERCC1 c.354C>T with MSH3 c.3133A>G (13.38%) combined genotypes were also associated with substantial declines in renal function.

CONCLUSIONS: Our data suggest that isolated and combined SNVs in genes enrolled in CDDP metabolism can be used to select patients for treatments that spare the kidneys from adverse effects.

PMID:40342074 | DOI:10.1002/hed.28179

NPJ Vaccines. 2025 May 8;10(1):88. doi: 10.1038/s41541-025-01139-4.

ABSTRACT

This genome-wide association study (GWAS) explores the genetic components of severe adverse events following COVID-19 vaccination, with focus on myocarditis and pericarditis. Three SNPs (rs536572545, rs146289966 and rs142297026) near the SCAF11 gene were linked to pericarditis, while rs570375365 in the LRRC4C gene was associated with myocarditis. These findings suggest that genetic variants may influence inflammation pathways, providing a basis for further investigation into the immunological responses triggered by vaccines.

PMID:40341528 | DOI:10.1038/s41541-025-01139-4

Mol Med. 2025 May 8;31(1):179. doi: 10.1186/s10020-025-01237-y.

ABSTRACT

BACKGROUND: The remodeling of the extracellular matrix (ECM) plays a pivotal role in tumor progression and drug resistance. However, the compositional patterns of ECM in breast cancer and their underlying biological functions remain elusive.

METHODS: Transcriptome and genome data of breast cancer patients from TCGA database was downloaded. Patients were classified into different clusters by using non-negative matrix factorization (NMF) based on signatures of ECM components and regulators. Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify core genes related to ECM clusters. Additional 10 independent public cohorts including Metabric, SCAN_B, GSE12276, GSE16446, GSE19615, GSE20685, GSE21653, GSE58644, GSE58812, and GSE88770 were collected to construct Training or Testing cohort, following machine learning calculating ECM correlated index (ECI) for survival analysis. Pathway enrichment and correlation analysis were used to explore the relationship among ECM clusters, ECI and TME. Single-cell transcriptome data from GSE161529 was processed for uncovering the differences among ECM clusters.

RESULTS: Using NMF, we identified three ECM clusters in the TCGA database: C1 (Neuron), C2 (ECM), and C3 (Immune). Subsequently, WGCNA was employed to pinpoint cluster-specific genes and develop a prognostic model. This model demonstrated robust predictive power for breast cancer patient survival in both the Training cohort (n = 5,392, AUC = 0.861) and the Testing cohort (n = 1,344, AUC = 0.711). Upon analyzing the tumor microenvironment (TME), we discovered that fibroblasts and B cell lineage were the core cell types associated with the ECM cluster phenotypes. Single-cell RNA sequencing data further revealed that angiopoietin like 4 (ANGPTL4)+ fibroblasts were specifically linked to the C2 phenotype, while complement factor D (CFD)+ fibroblasts characterized the other ECM clusters. CellChat analysis indicated that ANGPTL4+ and CFD+ fibroblasts regulate B cell lineage via distinct signaling pathways. Additionally, analysis using the Kaplan-Meier Plotter website showed that CFD was favorable for immunotherapy response, whereas ANGPTL4 negatively impacted the outcomes of cancer patients receiving immunotherapy.

CONCLUSION: We identified distinct ECM clusters in breast cancer patients, irrespective of molecular subtypes. Additionally, we constructed an effective prognostic model based on these ECM clusters and recognized ANGPTL4+ and CFD+ fibroblasts as potential biomarkers for immunotherapy in breast cancer.

PMID:40340806 | DOI:10.1186/s10020-025-01237-y

Hematol Transfus Cell Ther. 2025 May 7;47(2):103759. doi: 10.1016/j.htct.2025.103759. Online ahead of print.

ABSTRACT

OBJECTIVE: This study aimed to determine the frequency of genetic alterations as deletions and duplications in cytochrome P450 (CYP450) and glutathione S-transferases (GST) genes, as well as to investigate whether there is a relationship between these alterations and neutrophilic hematologic recovery in adult patients diagnosed with acute myeloid leukemia.

METHOD: DNA samples from 70 patients diagnosed with acute myeloid leukemia were evaluated using the Multiplex Ligation-dependent Probe Amplification technique. The presence or absence of polymorphisms was compared regarding the time to neutrophilic recovery (neutrophil count ≥1.0 × 109/L) using Kaplan-Meier curves, with the comparison between the curves being performed using the non-parametric log-rank test.

RESULTS: The median age of the participants was 57 years, with a higher proportion of females (57.2%) and white individuals (61.4%)'. A total of 76 polymorphisms (CYP450 + GST) were identified, comprising 38 deletions and 38 duplications. Kaplan-Meier curves revealed that the neutrophilic recovery time was longer for the group with polymorphisms (p-value = 0.0056).

CONCLUSION: The study demonstrated that CYP450 and GST genes are polymorphic, and these polymorphisms may lead to longer neutrophilic recovery after induction treatment of acute myeloid leukemia remission.

PMID:40339533 | DOI:10.1016/j.htct.2025.103759

Early Hum Dev. 2025 May 1;206:106272. doi: 10.1016/j.earlhumdev.2025.106272. Online ahead of print.

ABSTRACT

Physical activity (PA) during pregnancy may have a positive effect on the fetal cardiac maturation which is reflected in a decreasing resting heart rate and increasing heart rate variability (HRV). Different types of PA, for example during leisure or work time, have differential effects on HRV; however, this relationship has not yet been investigated in pregnancy. In our work, we related different types of PA during pregnancy with maternal and fetal HRV. We assessed the levels of PA in 95 pregnant women between 28 and 32 weeks of gestational age using the Baecke Physical Activity Questionnaire. Maternal and fetal heart rate and HRV were extracted from magnetocardiography recordings at rest, and maternal anthropometric and metabolic parameters were measured, such as fasting glucose and insulin levels, body mass index, and blood pressure. Pearson correlations were calculated between HRV, PA, and maternal parameters. Principal component analysis and generalized linear models were implemented to further investigate these relationships. Our findings indicate that habitual physical activity, whether during leisure or work, has no significant effect on maternal or fetal HRV at rest. However, leisure-time physical activity, unlike work-related activity, is associated with improved maternal insulin sensitivity. Additionally, our exploratory analyses revealed that lower HRV in both the mother and the fetus is associated with poorer maternal metabolic health quantified through higher fasting insulin levels, triglycerides, and adiposity. Finally, male fetuses showed higher HRV compared to females, highlighting the difference in cardiac development between the two biological sexes.

PMID:40339304 | DOI:10.1016/j.earlhumdev.2025.106272

Br J Occup Ther. 2023 Apr;86(4):257-264. doi: 10.1177/03080226221135366. Epub 2023 Mar 21.

ABSTRACT

INTRODUCTION: Medication management is an essential instrumental activity of daily living for older adults; however, 40-70% of older adults fail to take their medications correctly. Addressing medication management falls under the scope of occupational therapy, but there is a lack of evidence supporting occupational therapy interventions to improving medication management. This study's primary aims are to examine the feasibility, acceptability, and preliminary efficacy of a Tailored Intervention for Medication Management delivered by occupational therapists to improve medication management.

METHOD/DESIGN: Single-blind, parallel-group randomized controlled equivalency trial, with two phases. Thirty community-dwelling older adults will be enrolled in this study. In Phase 1, participants in the treatment group will receive Tailored Intervention for Medication Management delivered remotely; those in the waitlist control will receive attention visits. In Phase 2, waitlist control participants will receive Tailored Intervention for Medication Management in person. The primary outcomes are feasibility and acceptability; secondary outcomes include preliminary efficacy of the intervention delivered by an occupational therapist remotely and in person. Additionally, the remote and in-person delivery methods will be compared to each other for equivalency.

DISCUSSION: Inability to manage medication and inappropriate polypharmacy are significant and prevalent problems that must be addressed so older adults can safely perform this essential instrumental activity of daily living.

TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04717297.

PMID:40337485 | PMC:PMC12033853 | DOI:10.1177/03080226221135366

BMC Cardiovasc Disord. 2025 May 7;25(1):353. doi: 10.1186/s12872-025-04753-1.

ABSTRACT

BACKGROUND: Human genetics is an important tool for identifying genes as potential drug targets, and the extensive genetic study of cardiovascular disease provides an opportunity to leverage genetics to match specific patient populations to specific drug targets to improve prioritization of patient selection for clinical studies.

METHODS: We selected well described genetic variants in the region of PCSK9 (rs11591147 and rs562556), ADRB1 (rs7076938), ACE (rs4968782 and rs4363), GLP1R (rs10305492) and ABCC8 (rs757110) for use as proxies for the effects of drugs. Time-to-event analyses were utilized to evaluate their effects on atrial fibrillation (AF) and heart failure (HF) death and/or re-hospitalization using real-world longitudinal dataset. To mitigate the effect of confounding factors for cardiovascular (CV) outcomes, we employed propensity score matching.

RESULTS: After matching, a genetic proxy for PCSK9 inhibition (rs11591147) improved survival from CV death/heart transplant in individuals following a diagnosis of ischemic heart disease (Hazard Ratio (HR) 0.78, P = 0.03). A genetic proxy for beta-blockade (rs7076938) improved freedom from rehospitalization or death in individuals with AF (HR 0.92, P = 0.001), and a genetic proxy of ACE inhibition (rs7076938) improved freedom from rehospitalization for HF or death (HR 0.8, P = 0.017) and AF (HR 0.85, P = 0.0014). A protective variant in GLP1R (rs10305492) showed decreased risk of developing HF or CV death after diagnosis of ischemic heart disease (HR = 0.82, P = 0.031) and a protective variant in ABCC8 (rs757110) showed decreased risk of CV mortality since ischemic disease diagnosis (HR = 0.88, P = 0.04) and decreased risk of AF in diabetic patients with ischemic heart disease (HR = 0.68, P = 0.001). Notably, despite smaller cohort sizes after matching, we often observed numerically smaller HRs and reduced P, indicating more pronounced effects and increased statistical association. However, not all genetic proxies replicated known treatment effects.

CONCLUSIONS: Genetic proxies for well-known drugs corroborate findings from clinical trials in cardiovascular disease. Our results demonstrate a useful analytical approach that leverages genetic evidence from a large cohort with longitudinal outcomes data to effectively select patient populations where specific drug targets may be most effective.

PMID:40335923 | DOI:10.1186/s12872-025-04753-1

Pharmacogenomics J. 2025 May 7;25(3):13. doi: 10.1038/s41397-025-00370-5.

ABSTRACT

The serotonin transporter (SLC6A4) and the serotonin autoreceptor (HTR1A) are two of the most extensively studied genes in the field of psychiatry, and their variants have been implicated in antidepressant response, specifically with selective serotonin reuptake inhibitors (SSRIs) which are widely regarded as the first-line medications for depression and anxiety. Variants of SLC6A4 and HTR1A have also been studied as risk factors for depression. In this retrospective study, we aim to investigate the relationship between all possible serotonin transporter (SLC6A4) and autoreceptor (HTR1A) variant expression combinations that may have contributed to the therapeutic failure of an SSRI and subsequent disability. In this study, we utilize data from a cohort of 302 European patients diagnosed with depression and/or anxiety who were referred to Personalized Prescribing Inc. (PPI) in 2022 as result of a mental health disability claim to determine whether statistical differences are present in this cohort as compared to general European population allele frequencies. Our data reveals the presence and relevance of significant differences in the presentation of SLC6A4 and HTR1A, specifically in a disability cohort, relative to the average European population. The SLC6A4 gene codes for the serotonin transporter; the SSRI drug target that aims to be blocked to prevent the recycling of serotonin, whereas the HTR1A plays an indirect role as an autoreceptor allowing serotonin levels to be maintained by the SSRI, as well as a direct role in modulating mood through post-synaptic serotonin interaction. This study has revealed statistically significant differences in the expression of these two genes together in increasing the likelihood of drug failure, specifically the presence of one or more G alleles at HTR1A rs6295 in combination with the SLC6A4 SS variant. The most significantly overrepresented combination in this cohort of patients suffering from depression and anxiety that have failed to achieve adequate symptom remission on previous SSRI trials is HTR1A rs6295 GG-SLC6A4 SS which is overrepresented in this study by over 74% at a p-value well below 0.01. Genotyping anti-depressant drug targets may play an important role in optimizing anti-depressant drug response and research developments for future therapies.

PMID:40335484 | DOI:10.1038/s41397-025-00370-5

Nat Commun. 2025 May 7;16(1):4235. doi: 10.1038/s41467-025-56910-x.

ABSTRACT

Chronic care manages long-term, progressive conditions, while acute care addresses short-term conditions. Chronic conditions increasingly strain health systems, which are often unprepared for these demands. This study examines the burden of conditions requiring acute versus chronic care, including sequelae. Conditions and sequelae from the Global Burden of Diseases Study 2019 were classified into acute or chronic care categories. Data were analysed by age, sex, and socio-demographic index, presenting total numbers and contributions to burden metrics such as Disability-Adjusted Life Years (DALYs), Years Lived with Disability (YLD), and Years of Life Lost (YLL). Approximately 68% of DALYs were attributed to chronic care, while 27% were due to acute care. Chronic care needs increased with age, representing 86% of YLDs and 71% of YLLs, and accounting for 93% of YLDs from sequelae. These findings highlight that chronic care needs far exceed acute care needs globally, necessitating health systems to adapt accordingly.

PMID:40335470 | DOI:10.1038/s41467-025-56910-x

BMJ Open. 2025 May 6;15(5):e088456. doi: 10.1136/bmjopen-2024-088456.

ABSTRACT

INTRODUCTION: Patients with chronic limb-threatening ischaemia (CLTI) are often prescribed clopidogrel in order to reduce their risk of major adverse limb and cardiovascular events. Clopidogrel is metabolised by the CYP2C19 enzyme and genetic variations in CYP2C19 are common. These variants can influence an individual's ability to metabolise clopidogrel to its active metabolite. Few studies have investigated the relationship between patient genotype and outcomes in vascular surgery. This work aims to establish the relationship between patient genotype and outcomes after revascularisation in patients with CLTI who are prescribed clopidogrel. It will consider whether pharmacogenetics can be used to ensure patients are prescribed effective medications to optimise their outcomes.

METHODS AND ANALYSIS: This is an observational cohort study of patients undergoing lower limb surgical, endovascular or hybrid revascularisation for CLTI at Manchester University NHS Foundation Trust. Patients taking clopidogrel post-procedure, as well as those prescribed a non-clopidogrel based medication regimen, will be recruited prior to or shortly after revascularisation. Patients will undergo CYP2C19 genotyping and will be followed up using online records. The study has 90% power to detect 114 amputations with a target sample size of 483 participants. The primary outcomes are risk of amputation at 1 year and a composite endpoint for the risk of major adverse limb events (MALE) or death from any cause at 1 year. Secondary outcomes are risk of MALE at 1 year, risk of major adverse cardiovascular events (MACE) or death from any cause at 1 year, death within 30 days of revascularisation, minor re-interventions at 1 year, total number of re-interventions at 1 year and rate of systemic or gastrointestinal bleed at 1 year.Risk of amputation, MALE and MACE will be analysed using Cox models. All remaining outcomes will be analysed using negative binomial models. Potential competing events for the risk of amputation will be investigated as part of a sensitivity analysis. Patients given a non-clopidogrel-based medication will be compared as an additional analysis.

ETHICS AND DISSEMINATION: Manchester University Research Ethics Committee approval obtained as part of the Implementing Pharmacogenetics to Improve Prescribing (IPTIP) trial process (IRAS 305751). The results of the study will be published in a peer-reviewed journal and presented at international conferences.

REGISTRATION: This work is a sub-protocol for the IPTIP study which is registered as ISRCTN14050335.

PMID:40335138 | DOI:10.1136/bmjopen-2024-088456

Int J Mol Sci. 2025 Apr 19;26(8):3881. doi: 10.3390/ijms26083881.

ABSTRACT

Antituberculosis drug-induced hepatotoxicity (ATDH) is a common adverse drug reaction often requiring treatment interruption, complicating tuberculosis management. The slow acetylator phenotype, characterized by reduced N-acetyltransferase 2 (NAT2) enzyme activity, is associated with increased hepatotoxicity risk, while rapid acetylators are associated with a higher risk of therapeutic failure. This study investigates the association between the NAT2 acetylation phenotype and ATDH occurrence, with an emphasis on its predictive value in regard to a multiethnic population and its impact on the timing of ATDH onset. A retrospective observational study was conducted on tuberculosis patients treated at Luigi Sacco Hospital, Milan, Italy (July 2020-September 2023). The NAT2 genotyping identified slow and rapid/intermediate acetylators. Cumulative incidence analysis and Fine-Gray competing risks regression models were used to assess ATDH risk and onset timing. Among 102 patients, 21.6% developed ATDH, including 16.7% with slow and 4.9% with rapid/intermediate acetylators. ATDH onset was significantly earlier in regard to slow acetylators (median 0.5 vs. 2 months, interquartile range-IQR: 0.5-3 vs. 1.7-5.5). Slow acetylators were associated with a higher risk of developing ATDH (Sub-distribution hazard ratio, SHR = 3.05; 95% confidence interval-CI: 1.17-7.95; p = 0.02), even after adjusting for confounders. The NAT2 acetylation phenotype strongly influences ATDH risk and timing. Early acetylator status identification may enable dose adjustments, enhancing treatment safety. These findings highlight the role of pharmacogenetics in optimizing antituberculosis therapy by improving efficacy and minimizing toxicity.

PMID:40332508 | DOI:10.3390/ijms26083881

Int J Mol Sci. 2025 Apr 12;26(8):3668. doi: 10.3390/ijms26083668.

ABSTRACT

Osteoarthritis (OA) of the temporomandibular joint (TMJ) is a progressive disease characterized by the progressive destruction of the internal surfaces of the joint. Certain epigenetic biomarkers have been detected in TMJ-OA. We summarized the available evidence on the epigenetic biomarkers in TMJ-OA. There is an increase in the expression of non-coding RNAs related to the degradation of the extracellular matrix, chondrocyte apoptosis, and proinflammatory cytokines, while there is a decrease in the expression of those related to COL2A1, as well as the osteogenic and chondrogenic differentiation of mesenchymal stem cells. Certain methylated genes and histone modifications in TMJ-OA were also identified. In the early stage, DNA methylation was significantly decreased; that is, the expression of inflammation-related genes such as TNF and genes associated with extracellular matrix degradation, such as Adamts, were increased. While in the late stage, there was an increase in the expression of genes associated with the TGF-β and MAPK signaling pathway and angiogenesis-related genes. Although research on the role of epigenetic markers in TMJ-OA is still ongoing, the results here contribute to improving the basis for the identification of accurate diagnostic and prognostic markers and the development of new therapeutic molecules for the prevention and management of TMJ-OA. It also represents a significant advancement in elucidating its pathogenesis.

PMID:40332184 | DOI:10.3390/ijms26083668

Int J Mol Sci. 2025 Apr 10;26(8):3582. doi: 10.3390/ijms26083582.

ABSTRACT

The N-Myc Downstream Regulated Gene 1 (NDRG1) protein, a member of a family of four, has emerged as a key regulator of various physiological and pathological processes. Extensive knowledge has been gained on the modulation of NDRG1 expression during endoplasmic reticulum stress, autophagy, and hypoxia. Moreover, new functions have emerged in recent years. Notably, NDRG1 regulates cell differentiation, metabolism, autophagy and vesicular transport. This has raised interest in the molecular mechanisms that control the cellular levels and activity of NDRG1. A series of studies have shown that NDRG1 can be finely regulated at the transcriptional, post-transcriptional, and translational levels. In addition, processes that mediate protein degradation and clearance also play key roles. Furthermore, three different NDRG1 proteoforms with distinct functions have been identified. An important question is the extent to which these proteoforms contribute to the regulation of cellular functions. Given the growing clinical interest in NDRG1, this review provides an overview of the regulatory mechanisms that control NDRG1 abundance, helping to deepen our understanding of the complex mechanisms underlying protein regulation.

PMID:40332138 | DOI:10.3390/ijms26083582

Clin Pharmacol Ther. 2025 May 7. doi: 10.1002/cpt.3685. Online ahead of print.

ABSTRACT

In pediatric oncology, pharmacogenetic guidelines are underutilized and the potential impact of pre-emptive pharmacogenetic screening remains largely unexplored despite this field's need for individualized approaches. While comprehensive pharmacogenetic guidelines are not yet available for all anticancer drugs, evidence-based recommendations exist for a subset of supportive care drugs and anticancer drugs, including thiopurines, irinotecan, capecitabine, and 5-fluorouracil. In this study, we evaluate the potential impact of pre-emptive pharmacogenetic screening by retrospectively identifying opportunities for dose or treatment adjustments within a national pediatric oncology cohort. Our analysis focused on ten genes and 28 drugs relevant to pediatric oncology, which are included in the Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenetics Working Group guidelines. In a cohort of 1,151 pediatric oncology subjects, we identified that 16% of individuals could have benefited from altered drug dosing or treatment. These include dose and treatment recommendations for allopurinol, nonsteroidal anti-inflammatory drugs, phenytoin, amitriptyline, proton pump inhibitors, voriconazole, tramadol, codeine, paroxetine, tacrolimus, rasburicase, and 6-mercaptopurine. As genetic data increasingly becomes available through molecular diagnostics in pediatric oncology, there is a unique opportunity to re-utilize this data for pre-emptive pharmacogenetic screening. Leveraging genetic profiles to guide clinicians in drug selection and dose optimization can improve patient outcomes by enhancing the safety and efficacy of treatments. We therefore recommend incorporating pharmacogenetic screening into clinical workflows to advance personalized medicine in pediatric oncology.

PMID:40331624 | DOI:10.1002/cpt.3685

Circ Res. 2025 May 7. doi: 10.1161/CIRCRESAHA.124.325699. Online ahead of print.

ABSTRACT

BACKGROUND: It has become evident that some women develop preeclampsia despite aspirin. This study aimed to examine how such aspirin nonresponsiveness develops in high-risk preeclampsia pregnancies by exploring the role of genetic polymorphisms and aspirin metabolism.

METHODS: The study involved pregnant women who developed preeclampsia despite low-dose aspirin and those who did not. First, we conducted a pharmacogenomic association study exploring the association of potential genetic variants with aspirin nonresponsiveness. Next, we analyzed the rate of enzymatic aspirin hydrolysis in maternal plasma. The extent of placental exposure to acetylsalicylic acid and its bioactive metabolites, that is, salicylic acid and gentisic acid, was determined by liquid chromatography-mass spectrometry. The expressions of AMEs (aspirin metabolizing enzymes), that is, GLYAT (glycine-N-acyltransferase), UGT1A6, CYP2E1, and NAT2 in the placenta, were analyzed by quantitative reverse transcription polymerase chain reaction, immunohistochemistry staining, and ELISA. Finally, the effects of AMEs were further examined on HTR-8/SVneo and human primary cytotrophoblast cells.

RESULT: Our genetic study showed that single-nucleotide polymorphisms (SNPs) of genes involved in aspirin pharmacokinetics and pharmacodynamics were not associated with aspirin nonresponsiveness in preeclampsia. Rates of aspirin hydrolysis in maternal plasma and the concentrations of acetylsalicylic acid, salicylic acid, and gentisic acid in the placenta did not differ between aspirin-responsive and aspirin-nonresponsive women. Intriguingly, GLYAT was significantly upregulated in the aspirin-nonresponsive placenta and associated with aspirin nonresponsiveness. This overexpression of GLYAT was found to diminish the proangiogenic, anti-inflammatory, and antisenescence effects of salicylic acid in HTR-8/SVneo and human primary cytotrophoblast cells.

CONCLUSIONS: Our study revealed that maternal genetic factors and plasma aspirin hydrolysis are not among the decisive factors in determining the effectiveness of low-dose aspirin in preventing preeclampsia among high-risk women. Instead, placental GLYAT appears to play a key role by limiting the effect of salicylic acid in the placenta.

PMID:40329906 | DOI:10.1161/CIRCRESAHA.124.325699

Acta Biochim Biophys Sin (Shanghai). 2025 May 6. doi: 10.3724/abbs.2025052. Online ahead of print.

ABSTRACT

Platinum drugs are widely used in lung cancer chemotherapy, but the immune characteristics of different individuals have different effects on the sensitivity and side effects of platinum drugs. In this study, we use 731 kinds of immune cell traits of 3757 healthy individuals and 429 patients with non-small cell lung cancer (NSCLC) in Xiangya Hospital of Central South University to conduct a Mendel randomized analysis in order to find out the causal relationship between some immune cell traits and the efficacy and adverse reactions of platinum drugs. We find that CD19 on CD24 +CD27 + B cell (OR = 0.598, P = 0.004) is the most significant immune cell trait as the protective factor of efficacy. HLA-DR +CD8 + T cell % lymphocyte (OR = 0.427, P = 7.55 × 10 -4) and HLA-DR +CD8 + T cell % T cell (OR = 0.471, P = 0.003) are the protective factors of liver injury. CD39 on CD39 + secreting CD4 + regulatory T cell (OR = 28.729, P = 0.009) and CD3 on CD39 + resting CD4 regulatory T cell (OR = 3.024, P = 0.009) are the risk factors of renal injury. Meanwhile, B cell-related traits mainly affect gastrointestinal upset and cutaneous toxicity, while T cell-related traits mainly affect other outcome variables. These findings may promote our understanding of the relationship between the efficacy and adverse reactions of platinum drugs and the immune system, and promote future development of biomarkers for predicting the efficacy and adverse reactions of platinum drugs.

PMID:40329806 | DOI:10.3724/abbs.2025052

Cell Death Differ. 2025 May 6. doi: 10.1038/s41418-025-01521-8. Online ahead of print.

ABSTRACT

Oxysterol-binding proteins (OSBPs), lipid transfer proteins functioning at intracellular membrane contact sites, are recently found to be dysregulated in cancer and promote cancer cell survival. However, their role as potential targets in cancer therapy remains largely unexplored. In this study, we found OSW-1, a natural compound and OSBP inhibitor, potently and selectively kills colon cancer cells by activating a previously unknown necroptosis pathway that is independent of receptor-interacting protein 1 (RIP1) and RIP3. OSW-1 stabilizes p53 and degrades OSBPs to promote endoplasmic reticulum (ER) stress and glycogen synthase kinase 3β (GSK3β)/Tip60-mediated p53 acetylation at Lysine 120, which selectively induces its target PUMA. PUMA-mediated mitochondrial calcium influx activates calcium/calmodulin-dependent protein kinase IIδ (CamKIIδ) to promote mixed lineage kinase domain-like (MLKL) phosphorylation and necroptotic cell death. Furthermore, OSW-1-induced necroptosis is highly immunogenic and sensitizes syngeneic colorectal tumors to anti-PD-1 immunotherapy. Together, our results identified a novel RIP1/RIP3-independent necroptosis pathway underlying the extremely potent anticancer activity of OSW-1, which can be harnessed to develop new anticancer therapies by selectively stimulating antitumor immunity.

PMID:40329104 | DOI:10.1038/s41418-025-01521-8

Pharmacogenet Genomics. 2025 May 6. doi: 10.1097/FPC.0000000000000568. Online ahead of print.

ABSTRACT

OBJECTIVES: Evaluate the feasibility of implementing a multigene pharmacogenetic (PGx) test and genotype-guided pharmacist recommendations into gynecologic perioperative workflows and fidelity to pharmacist genotype-guided postoperative analgesic recommendations.

METHODS: A randomized, prospective, open-label pilot study was conducted in gynecologic patients undergoing abdominal surgery. Participants received multigene PGx testing and were randomized to the PGx-guided group where results were returned to the electronic health record with pharmacist genotype-guided postoperative analgesic recommendations or usual care. Primary outcomes included the proportion of PGx results and pharmacist recommendations completed before surgery, the number of prescriptions in alignment with pharmacist recommendations, and the proportion of analgesics prescribed differing from usual care.

RESULTS: Of the 101 participants analyzed, all were female, 50 ± 14 years old, 49% were Black, 48% were White, 60% were treated by gynecologic oncology, and 76% underwent minimally invasive surgery. PGx results were returned to the genomics results portal a median of 7 (interquartile range: 6-9) business days after ordering the test. A majority (85%) of results were returned before the participant's surgery. Pharmacist genotype-guided analgesic recommendations were completed for 35 (73%) of the 48 participants in the PGx-guided group. And, 32 (91%) of the prescribed nonsteroidal anti-inflammatory drugs and 23 (66%) of the prescribed opioids matched the pharmacist's recommendations. Barriers included missed pharmacist notes when surgery dates were moved and low use of study-specific order set.

CONCLUSION: PGx test results were available before most surgeries, but the pharmacist recommendations were not always followed. Enhanced implementation strategies will need to be developed in future genotype-guided protocols.

PMID:40327052 | DOI:10.1097/FPC.0000000000000568

Clin Pharmacol Ther. 2025 May 5. doi: 10.1002/cpt.3704. Online ahead of print.

ABSTRACT

There is increasing attention on the clinical utility and value of pharmacogenetic (PGx) testing to individualize medication management. Most clinical practice guidelines from medical professional societies do not recommend routine PGx testing, with a few key exceptions. Inconsistent recommendations across clinical practice guidelines, FDA product labeling, and payer reimbursement policies have hampered widespread adoption of testing. Multiple resources exist to aid in the adoption and use of actionable PGx test results in clinical practice; however, most of these resources do not provide guidance on who should receive PGx testing and when-a critical question the clinical community continues to struggle with. There are multiple considerations when answering this question beyond the clinical validity of the drug-gene interaction itself, such as the actionable result frequency, severity of the adverse clinical outcome, predictive power of the PGx test, suitability of alternative treatments, cost, and turnaround time of test results. This perspective discusses these considerations and models for testing including preemptive screening, pretreatment testing, and reactive testing, highlighting advantages and disadvantages of each approach. The authors provide their perspectives on identifying candidates for PGx testing in the current real-world environment and how that differs from a clinically ideal scenario.

PMID:40325943 | DOI:10.1002/cpt.3704

Nat Commun. 2025 May 5;16(1):4176. doi: 10.1038/s41467-025-59490-y.

ABSTRACT

SERPINB9, an endogenous inhibitor of granzyme B (GzmB), has emerged as a critical factor in the resistance to immunotherapy by protecting cancer cells from GzmB-induced cytotoxicity. However, its role in chemosensitivity remains unknown. In this study, we show that gemcitabine (GEM) treatment upregulates SERPINB9 through transcription factor ATF-3. Interestingly, GEM also induces the expression of GzmB and knockout or knockdown of SERPINB9 results in enhanced response of tumor cells to GEM, suggesting a role of GzmB/SERPINB9 axis in regulating chemosensitivity. To facilitate the therapeutic translation of these findings, we engineer POEM nanocarrier (consisting of lipid-derivatized polylysine (PEG-PLL-Oleic acid, PPO), and GEM-conjugated polylysine (PEG-PLL-OA-GEM, PPOGEM), PPO/PPOGEM (POEM)) that is highly effective in codelivery of built-in GEM and loaded SERPINB9 short interfering RNA (siSPB9). GEM conjugation introduces an additional mechanism of carrier/siRNA interaction in addition to charge-mediated interaction and enables efficient i.v. delivery at lower N/P ratios. Here, we show that co-delivery of GEM and siSPB9 significantly improves antitumor efficacy and remodels the tumor immune microenvironment in pancreatic cancer models, supporting a promising therapeutic strategy.

PMID:40325025 | DOI:10.1038/s41467-025-59490-y