Curr Protein Pept Sci. 2025 May 8. doi: 10.2174/0113892037364237250402151440. Online ahead of print.

ABSTRACT

The COVID-19 outbreak, caused by the SARS-CoV-2 coronavirus, has threatened and taken many lives since the end of 2019. Given the importance of COVID-19 worldwide, since its spread, many research groups have been seeking blood markers that could help to understand the disease establishment and prognosis. Usually, those markers are proteins with a differential accumulation only during infection. Based on that, proteomic studies have played a crucial role in elucidating diseases. Mass spectrometry (MS) is a promising technique in COVID-19 studies, allowing the identification and quantification of proteins present in the plasma or serum of affected patients. It helps us to understand pathological mechanisms, predict clinical outcomes, and develop specific therapies. MS proteomics revealed biomarkers associated with infection, disease severity, and immune response. Plasma or blood serum is easy to collect and store; however, its composition and the higher concentration of proteins (e.g., albumins) shadow the identification of less abundant proteins, which usually are essential markers. So, clean-up approaches such as depletion strategies and fractionating are often required to analyze blood samples, allowing the identification of low-abundant proteins. This review will discuss many proteomic approaches to discovering new plasma biomarkers of COVID-19 employed in recently published studies. The challenges inherent to blood samples will also be discussed, such as sample preparation, data processing, and identifying reliable biomarkers.

PMID:40353410 | DOI:10.2174/0113892037364237250402151440

Alzheimers Dement (Amst). 2025 May 9;17(2):e70111. doi: 10.1002/dad2.70111. eCollection 2025 Apr-Jun.

ABSTRACT

INTRODUCTION: The apolipoprotein E (APOE) ɛ4 allele is a well-established risk factor for neurocognitive impairment (NCI), with varying impacts between men and women. This study investigates the distinct roles of sex and gender in modifying APOE ɛ4-related NCI.

METHODS: Biological sex was inferred from sex chromosomes, and a femininity score (FS) was used as a proxy for gender. We analyzed 276,596 UK Biobank participants without prior NCI to assess whether sex and FS modified the effect of APOE ɛ4 on NCI.

RESULTS: NCI risk was higher in APOE ɛ4 carriers compared to non-carriers (hazard ratio [HR] = 2.48 in females; HR = 1.96 in males) with significant interaction by sex (P < 0.0001). FS was associated with an increased NCI risk after accounting for sex (HR = 1.07, 95% confidence interval: 1.04-1.10, P < 0.0001) with no significant differences by sex or APOE ɛ4 carrier status.

DISCUSSION: Our findings show that APOE ɛ4 increases NCI risk more in females, while FS independently elevates risk across sexes.

HIGHLIGHTS: Apolipoprotein E (APOE) ɛ4 increases neurocognitive impairment (NCI) risk, with a greater impact in females (hazard ratio [HR] = 2.48) than males (HR = 1.96).Sex significantly modifies the effect of APOE ɛ4 on NCI (P < 0.0001f).Femininity score increases NCI risk (HR = 1.07) independently of sex and APOE ɛ4.Understanding the distinct sex and gender contributions to APOE ɛ4-related NCI can improve interventions.

PMID:40352685 | PMC:PMC12064333 | DOI:10.1002/dad2.70111

Clin Pharmacol Ther. 2025 May 11. doi: 10.1002/cpt.3691. Online ahead of print.

ABSTRACT

The cytochrome P450 2D6 (CYP2D6) metabolizes around 20% of currently prescribed medications, including the antipsychotic risperidone. Previous studies reported greater odds of switching antipsychotic medication from risperidone among CYP2D6 poor metabolizers (PM) without considering treatment duration up to the switch. Risperidone treatment failure, defined as risperidone treatment duration up to switching medication, was analyzed among 515 patients of the PsyMetab cohort using Kaplan-Meier estimates with log-rank tests and Cox multivariate regression. Risperidone-to-paliperidone ratios were higher among CYP2D6 PMs (median: 2.78) vs. the other phenotypes (median: 0.14, P < 0.001). After 1 year of treatment, the proportion of patients who switched from risperidone was 44%. This proportion was increased to 70% among PMs, vs. 42% among the other CYP2D6 phenotypes (P = 0.026). PMs' risk of switching increased over time (interaction PM*treatment duration: 1.01; P = 0.011), becoming statistically significant after 3 months of treatment, with 1.79 (P = 0.028), 3.7 times (P < 0.001) and 16.3 times higher (P = 0.001) risk of switch at 3, 6, and 12 months, respectively (95% confidence intervals: 1.07-3.01, 1.91-7.17, and 3.13-85.37, respectively). Considering a pharmacogenetic-guided treatment, the number of patients needed to genotype to find one PM and lower the switching proportion from 70% to 42% would be 65. In conclusion, CYP2D6 PM status presented an increased risk of switching from risperidone over 1 year of treatment, the risk increasing over time and becoming statistically significant after the first 3 months of treatment.

PMID:40350722 | DOI:10.1002/cpt.3691

Adv Med Sci. 2025 May 9:S1896-1126(25)00025-2. doi: 10.1016/j.advms.2025.05.001. Online ahead of print.

ABSTRACT

PURPOSE: Ferritin amounts that accumulate in the meconium may provide new postnatal insights into intrauterine iron homeostasis and neonatal preparedness for the postnatal period. The most dynamic increases in fetal iron stores and fetal growth occur during the third trimester.

MATERIALS AND METHODS: This study involved 122 neonates born between 36 and 41 weeks of gestation, with birth weights from 2,650 g to 4,960 g and birth lengths ranging from 50 cm to 60 cm. Ferritin amounts per gram of meconium were determined via ELISA in the first meconium passed after birth.

RESULTS: A significant week-by-week increase in the birth weight and length (p<0.05) was accompanied by decreasing meconium ferritin amounts (p=0.021) across the gestational age range of 36-41 weeks. There were negative correlations (p<0.05) between the systematic decrease in meconium ferritin amounts and the gestational age across the same range (r = -0.18) and between ferritin amounts and the birth weight and length of newborns (r= -0.20 and r= -0.31). Neonates born at 36-37 weeks of gestation had lower birth weight and length, while their meconium ferritin amounts were nearly twice as high as in neonates born at 38-39 weeks or 40-41 weeks (p<0.05).

CONCLUSIONS: Systematic decreases in meconium ferritin amounts from 36 to 41 weeks of gestation may suggest a gradual and gestational age-appropriate maturation of the mechanisms responsible for adaptation of the fetus to postnatal life. Determining a cut-off value for meconium ferritin amounts could aid in optimal management of newborns after birth.

PMID:40349924 | DOI:10.1016/j.advms.2025.05.001

Ann Clin Microbiol Antimicrob. 2025 May 10;24(1):32. doi: 10.1186/s12941-025-00799-3.

ABSTRACT

BACKGROUND: This study examines colistin resistance in Gram-negative bacteria in Egypt, analyzing prevalence, trends, geographic variations, colistin-carbapenem resistance correlation, and mcr-mediated plasmid resistance.

METHODS: We conducted a systematic search of articles published between 2014 and 2024 that reported on colistin or mcr-mediated resistance in Gram-negative bacteria isolated from human infections in Egypt, with clearly defined susceptibility testing methods. A random-effects meta-analysis was conducted to estimate colistin resistance prevalence based on broth microdilution (BMD) findings, the gold standard method. To explore the influence of study-level factors-including alternative susceptibility testing methods-a multivariate meta-regression analysis was performed. The results of the meta-regression are reported as regression coefficients (β), representing the difference in colistin resistance, expressed in percentage points. All statistical analyses were conducted using R software.

RESULTS: This analysis included 55 studies. Based on BMD susceptibility testing, colistin resistance was observed in 9% of all recovered Gram-negative isolates (95% CI: 6-14%) and was significantly higher among carbapenem-resistant isolates (31%, 95% CI: 25-38%), with p < 0.001. Multivariate meta-regression analysis further confirmed that colistin resistance was significantly higher in carbapenem-resistant isolates compared to the total recovered isolates (β = 9.8% points, p = 0.001). Additionally, colistin resistance has significantly increased over time, with a β = 1.8% points per year (p = 0.001). The use of the VITEK 2 system was associated with lower detected colistin resistance compared to BMD (β = -7.0, p = 0.02). Geographically, resistance rates were higher in Upper Egypt (β = 9.3, p = 0.04). Regarding mcr plasmid-mediated resistance, mcr-1 was the most prevalent resistance gene, particularly in E. coli. In contrast, mcr-2 was rare, detected sporadically in K. pneumoniae and P. aeruginosa.

CONCLUSION: In Egypt, BMD testing identified colistin resistance in 9% of Gram-negative bacteria, increasing to 31% in carbapenem-resistant isolates. This higher resistance in carbapenem-resistant strains suggests stronger selective pressure from frequent colistin use. Additionally, colistin resistance has shown a rising trend over time, likely driven by increased usage and the spread of plasmid-mediated resistance. These findings underscore the urgent need for strict antimicrobial stewardship and alternative therapies to curb resistance evolution.

PMID:40349047 | DOI:10.1186/s12941-025-00799-3

Psychiatr Clin North Am. 2025 Jun;48(2):257-264. doi: 10.1016/j.psc.2025.01.004. Epub 2025 Mar 4.

ABSTRACT

Pharmacogenomic (PGx) testing is an evidence-based strategy to optimize the selection and dosing of certain psychotropic medications. An individual's genetics play a role in medication response through pharmacokinetic and pharmacodynamic mechanisms. The current evidence base of psychiatric PGx mainly focuses on the metabolism of psychotropics through the cytochrome P450 (CYP) system. PGx testing and decision support tools are not yet standardized, resulting in variations in interpretation and prescribing recommendations. Clinicians are encouraged to use PGx results as part of the clinical picture, in addition to the patient's overall clinical profile, in determining a personalized treatment plan for their patients.

PMID:40348416 | DOI:10.1016/j.psc.2025.01.004

EBioMedicine. 2025 May 9;116:105745. doi: 10.1016/j.ebiom.2025.105745. Online ahead of print.

ABSTRACT

BACKGROUND: People with schizophrenia differ in the type and severity of symptoms experienced, as well as their response to medication. A better understanding of the factors that influence this heterogeneity is necessary for the development of individualised patient care. Here, we sought to investigate the relationships between phenotypic severity and both medication and pharmacogenomic variables in a cross-sectional sample of people with schizophrenia or schizoaffective disorder depressed type.

METHODS: Confirmatory factor analysis derived five dimensions relating to current symptom severity (positive symptoms, negative symptoms of diminished expressivity, negative symptoms of reduced motivation and pleasure, depression and suicide) and cognitive ability in participants prescribed with antipsychotic medication. Linear models were fit to test for associations between medication and pharmacogenomic variables with dimension scores in the full sample (N = 585), and in a sub-sample of participants prescribed clozapine (N = 215).

FINDINGS: Lower cognitive ability was associated with higher chlorpromazine-equivalent daily antipsychotic dose (β = -0.12; 95% CI, -0.19 to -0.05; p = 0.001) and with the prescription of clozapine (β = -0.498; 95% CI, -0.65 to -0.35; p = 3 × 10-10) and anticholinergic medication (β = -0.345; 95% CI, -0.55 to -0.14; p = 8 × 10-4). We also found associations between pharmacogenomics-inferred cytochrome P450 (CYP) enzyme activity and symptom dimensions. Increased genotype-predicted CYP2C19 and CYP3A5 activity were associated with reduced severity of the positive (β = -0.108; 95% CI, -0.19 to -0.03; p = 0.009) and both negative symptom dimensions (β = -0.113; 95% CI, -0.19 to -0.03; p = 0.007; β = -0.106; 95% CI, -0.19 to -0.02; p = 0.012), respectively. Faster predicted CYP1A2 activity was associated with higher cognitive dimension scores in people taking clozapine (β = 0.17; 95% CI, 0.05-0.29; p = 0.005).

INTERPRETATION: Our results confirm the importance of taking account of medication history (and particularly antipsychotic type and dose) in assessing potential correlates of cognitive impairment or poor functioning in patients with schizophrenia. We also highlight the potential for pharmacogenomic variation to be a useful tool to help guide drug prescription, although these findings require further validation.

FUNDING: Medical Research Council (MR/Y004094/1) and The National Center for Mental Health, funded by the Welsh Government through Health and Care Research Wales. SKL was funded by a PhD studentship from Mental Health Research UK (MHRUK). DBK, JTRW, MCOD and AFP were supported by the European Union's Horizon 2020 research and innovation programme under grant agreement 964874.

PMID:40347835 | DOI:10.1016/j.ebiom.2025.105745

Clin Transl Sci. 2025 May;18(5):e70246. doi: 10.1111/cts.70246.

ABSTRACT

Pharmacogenomics remains underutilized in pediatric oncology, despite the existence of evidence-based guidelines. Implementation of pharmacogenomics-informed prescribing could improve medication safety and efficacy in pediatric oncology patients, who are at high risk of adverse drug reactions. This study examines the prevalence of high-risk pharmacogenomic phenotypes and the prescription of relevant medications in a diverse Australian pediatric oncology cohort, highlighting the potential impact of pharmacogenomic testing in this unique population. Whole genome sequencing data from 180 patients were analyzed to assess 14 genes with evidence-based pharmacogenomic guidelines relevant to pediatric oncology. Over 90% of patients had at least one high-risk phenotype, with 20% presenting four or more. Ondansetron, mercaptopurine, omeprazole, pantoprazole, and voriconazole were commonly prescribed medications that have pharmacogenomic prescribing recommendations, with the latter three showing the highest actionability rates. High-risk phenotypes were most frequently observed for CYP2C19 and CYP2D6, with 30% of patients having a high-risk phenotype for both genes. This study underscores the potential utility of pharmacogenomics in pediatric oncology patients across a range of pharmacogenes and commonly prescribed medications. The findings support advocacy for implementing broad, pre-emptive pharmacogenomic testing in oncology patients to improve treatment safety and efficacy.

PMID:40347484 | DOI:10.1111/cts.70246

Mol Pain. 2025 May 10:17448069251343417. doi: 10.1177/17448069251343417. Online ahead of print.

ABSTRACT

Calcium channels play an essential role in the molecular and physiological mechanisms underlying anesthesia by mediating intracellular calcium ion (Ca²⁺) flux, which regulates key processes such as neurotransmitter release, neuronal excitability, and immune responses. Voltage-gated calcium channels (VGCCs) and ligand-gated calcium channels (LGCCs) are integral to the anesthetic process, with subtypes such as T-type VGCCs and NMDA receptors influencing consciousness and pain perception. This review emphasizes current evidence to highlight how anesthetic agents interact with calcium channels via direct inhibition and modulation of intracellular signaling pathways, such as phosphatidylinositol metabolism.Additionally, calcium channelopathies-genetic or acquired dysfunctions affecting VGCCs and LGCCs-pose challenges in anesthetic management, including arrhythmias, malignant hyperthermia, and altered anesthetic sensitivity. These findings underscore the critical need for precision medicine approaches tailored to patients with these conditions. While significant progress has been made in understanding the roles of calcium channels in anesthesia, knowledge gaps remain regarding the long-term implications of anesthetic interactions on calcium signaling and clinical outcomes.This review bridges foundational science with clinical practice, emphasizing the translational potential of calcium channel research for optimizing anesthetic strategies. By integrating molecular insights with emerging pharmacogenomic approaches, it provides a pathway for developing safer and more effective anesthesia protocols that enhance patient outcomes.

PMID:40346957 | DOI:10.1177/17448069251343417

Fundam Clin Pharmacol. 2025 Jun;39(3):e70013. doi: 10.1111/fcp.70013.

ABSTRACT

BACKGROUND: Opioid use disorder (OUD) is an emerging and global public health concern, and its management remains inadequate, notably due to a lack of biomarkers, except for the CYP2B6 genetic polymorphisms.

OBJECTIVES: Hence, the aim of this study was to assess the influence of genetic polymorphisms of ABCB1, SLC22A1, COMT, and OPRM1 on biological parameters and clinical response in patients receiving methadone maintenance treatment (MMT).

METHODS: A subgroup of 72 patients treated by MMT was genotyped for ABCB1 (rs1045642; rs2032582), SLC22A1 (rs12208357; rs72552763; rs113569197), COMT (rs4680), and OPRM1 (rs1799971) from Opioid PhArmacoLogy (OPAL), a clinical survey of patients suffering from OUD. Associations of these polymorphisms and both clinical and pharmacological (plasma methadone levels) responses were investigated.

RESULTS: All polymorphisms tested were not associated with (R,S)-methadone concentrations/doses (concentrations relative to doses), (R)-methadone concentrations/doses nor (S)-methadone concentrations/doses in bivariate analyses with codominant and recessive models. Also, polymorphisms tested were not related to clinical response (opiate cessation) during MMT in treated patients. The main limitations of our study were the sample size and the absence of polygenic analyses.

CONCLUSION: This study found no evidence to support the use of genotyping for polymorphisms in the ABCB1, SLC22A1, COMT, and OPRM1 genes in a clinical setting for the management of MMT in OUD.

PMID:40346879 | DOI:10.1111/fcp.70013

BMC Genomics. 2025 May 9;26(1):462. doi: 10.1186/s12864-025-11676-w.

ABSTRACT

Glucocorticoids, acting through the glucocorticoid receptor (GR), control metabolism, maintain homeostasis, and enable adaptive responses to environmental challenges. Their function has been comprehensively studied, leading to identification of numerous tissue-specific GR-dependent mechanisms. Abundant evidence shows that GR-triggered responses differ across tissues, however, the extent of this specificity was not comprehensively explored. It is also unknown how particular GR-induced molecular patterns are translated into profile of higher-level human traits. Here, we examine cross-tissue effects of GR activation on gene expression. We assessed changes induced by stimulation with GR agonist, dexamethasone in nine tissues (adrenal cortex, perigonadal adipose tissue, hypothalamus, liver, kidney, anterior thigh muscle, pituitary gland, spleen, and lungs) in adult male C57BL/6 mice, using whole-genome microarrays. Dexamethasone induced balanced transcriptional responses across all examined tissues with 585 identified dexamethasone-regulated transcripts, including 446 with significant treatment-tissue interaction effects. Clustering analysis revealed sixteen GR-dependent patterns, including those universal across tissues and tissue-specific. We leveraged existing gene annotations and created new annotation sets based on chromatin immunoprecipitation sequencing, recent large-scale genome-wide association studies, and human transcriptome collections. As expected, GR-dependent transcripts were associated with essential metabolic processes (glycolysis/gluconeogenesis, lipid-metabolism) and inflammation-related pathways. Beyond these, we found novel links between regulated gene patterns and human phenotypic traits, like reticulocyte count or blood triglyceride levels. Overall effects of GR stimulation are well coordinated and closely linked to biological roles of tissues and organs. Our findings provide novel insights into complex systemic and tissue-specific actions of glucocorticoids and their potential impacts on human physiology and pathology.

PMID:40346507 | DOI:10.1186/s12864-025-11676-w

Nurs Clin North Am. 2025 Jun;60(2):321-332. doi: 10.1016/j.cnur.2024.12.009. Epub 2025 Feb 6.

ABSTRACT

Antibiotics have revolutionized medicine, but their use is not without challenges. The efficacy and safety of antibiotics can vary significantly among individuals due to genetic differences. Genetic variation can influence the risk of antibiotic-related adverse effects, and understanding genetics can improve our ability to identify and manage these risks. Pharmacogenomics, the study of how genes affect a person's response to drugs, is emerging as a crucial field in optimizing antibiotic therapy. Pharmacogenomic elements may have a potential role in optimizing drug therapy and reducing adverse drug reactions.

PMID:40345763 | DOI:10.1016/j.cnur.2024.12.009

Nurs Clin North Am. 2025 Jun;60(2):305-320. doi: 10.1016/j.cnur.2024.12.007. Epub 2025 Feb 20.

ABSTRACT

Pharmacogenomics (PGx)-the study of how one's genes affect their response to drugs-has implications for every medical subspecialty, including cardiology. This article discusses evidence-based resources that provide guidance for interpreting and applying PGx results in patient care. All health care providers, including frontline nurses, should understand this important tool for patient care.

PMID:40345762 | DOI:10.1016/j.cnur.2024.12.007

Nurs Clin North Am. 2025 Jun;60(2):293-304. doi: 10.1016/j.cnur.2024.12.006. Epub 2025 Jan 18.

ABSTRACT

Pharmacogenomics (PGx) offers a personalized approach to treating mental health disorders, like depression, by using an individual's genetic profile to guide medication selection and dosage. This approach can reduce trial-and-error prescribing, shorten time to remission, and decrease adverse side effects. Nurses, as frontline healthcare providers, play a crucial role in educating patients about PGx testing and incorporating it into care. There are many clinical resources available to assist with decision making when integrating PGx into routine care. As PGx testing advances, nurses must stay updated on emerging practices to optimize treatment strategies, improving patient outcomes and quality of life in mental health care.

PMID:40345761 | DOI:10.1016/j.cnur.2024.12.006

Nurs Clin North Am. 2025 Jun;60(2):283-292. doi: 10.1016/j.cnur.2025.01.006. Epub 2025 Feb 15.

ABSTRACT

In the new and evolving area of precision medicine, the nurse will not only have to rely on the 5 rights for medication administration but may also have to take into account the patient's genetic makeup. The 5 rights of medication administration have been incorporated into precision medicine, which includes pharmacogenetics-the specific gene and drug interaction- or more broadly, pharmacogenomics, which encompasses specific gene and drug interactions and other genetic and environmental factors. Pharmacogenomic testing is now available with specific guidelines to assist the prescriber with drug and dose selection to improve drug efficacy and reduce adverse drug reactions.

PMID:40345760 | DOI:10.1016/j.cnur.2025.01.006

Nurs Clin North Am. 2025 Jun;60(2):243-255. doi: 10.1016/j.cnur.2024.12.003. Epub 2025 Mar 12.

ABSTRACT

Evidence-based genomic applications improve the quality and safety of health care. Nurses irrespective of their role, level of training, clinical specialty, need to achieve genomic competency as defined by competencies internationally. This includes nursing educators who teach nurses in training as well as nursing leadership who guide policy and support infrastructures. Genomic resources are abundant to help achieve competency, which is aimed at further improving the quality, safety, and outcomes of nursing care.

PMID:40345757 | DOI:10.1016/j.cnur.2024.12.003

Nurs Clin North Am. 2025 Jun;60(2):217-228. doi: 10.1016/j.cnur.2024.12.001. Epub 2025 Mar 4.

ABSTRACT

Evidence based genomic applications improve the quality and safety of healthcare. Nurses, irrespective of their role, level of training, or clinical specialty, need to achieve genomic competency as defined internationally. This includes nursing educators who teach nurses in training as well as nursing leadership who guide policy and support infrastructure. Genomic resources are abundant to help achieve competency which in turn improves quality, safety, and outcomes of nursing care.

PMID:40345755 | DOI:10.1016/j.cnur.2024.12.001

Clin Nutr ESPEN. 2025 May 7:S2405-4577(25)00310-9. doi: 10.1016/j.clnesp.2025.05.013. Online ahead of print.

ABSTRACT

BACKGROUND: Type 2 diabetes presents significant public health challenges. The gut microbiome has emerged as a potential factor influencing glucose metabolism.

METHODS: We performed a randomized, double-blind, single-center trial involving patients with type 2 diabetes and glycated hemoglobin (HbA1c) concentration of 7% or greater. Patients were randomly assigned to receive 100 billion colony-forming units (CFUs) of probiotic supplementation daily or placebo. The primary efficacy endpoint was the change in HbA1c from baseline to 12 weeks, and secondary endpoints included lipid and inflammatory markers.

RESULTS: A total of 130 patients were included. HbA1c was 7.63 ± 0.54% at baseline and 7.63 ± 0.63% at 12 weeks in the probiotic group and 7.71 ± 0.74% and 7.81 ± 0.84% in the placebo group (p = 0.29 between treatment groups). There were also no significant differences between treatment groups in plasma glucose (p = 0.60) and insulin (p = 0.41), as well as in LDL-cholesterol (p = 0.90) and triglycerides (p = 0.32). The adjusted geometric mean percent change (95% confidence interval) in high-sensitivity C-reactive protein was 1.59% (-15.71, 22.44) in the probiotic group and -1.37% (-18.04, 18.70) in the placebo group (p = 0.82). Gastrointestinal adverse events occurred in 38.5% and 46.2% of patients in the probiotic group and placebo group respectively (p = 0.48).

CONCLUSIONS: Probiotic supplementation for 12 weeks did not improve glycemic control, lipid or inflammatory markers in patients with type 2 diabetes. Further research is needed to determine the potential benefits and underlying mechanisms of probiotics in subsets of patients.

CLINICALTRIALS: gov Identifier no. NCT03239366.

PMID:40345656 | DOI:10.1016/j.clnesp.2025.05.013

J Biol Chem. 2025 May 8:110216. doi: 10.1016/j.jbc.2025.110216. Online ahead of print.

ABSTRACT

Colorectal cancer (CRC) is the third-most common cancer and the second-leading cause of mortality due to cancer worldwide. The underlying regulatory mechanism of CCNA2 in CRC was explored through multiomics and experimental analyses, thus facilitating diagnosis, therapy and prognosis. Two gene expression datasets (i.e., GSE9348 and GSE110223) were extracted from GEO. Differentially expressed genes (DEGs) were identified via GEO2R, which were used for enrichment analyses through DAVID. PPI network of DEGs was constructed by STRING, and the core genes were identified. CCNA2, a prognostic core gene for CRC, was validated in TCGA and HPA via transcriptomics and proteomics. ROC analysis was performed to evaluate the diagnostic value of CCNA2 in CRC. The therapeutic value of CCNA2 was evaluated in DGIdb through pharmacogenomics. The correlation between CCNA2 and immune infiltration was determined in TIMER by immunomics. TF-mRNA and miRNA-mRNA networks for CCNA2 were constructed in miRnet and miRDB via transcriptomics. The role and mechanism of CCNA2 in CRC were investigated both in vitro and in vivo. The miR-548x-3p/CCNA2 regulatory axis in CRC was investigated in vitro. CCNA2 showed excellent diagnostic, therapeutic, and prognostic value in CRC. CCNA2 was closely associated with tumor-infiltrating immunocytes, TFs, and miRNAs. The upregulation of CCNA2 was observed in CRC, and the knockdown of CCNA2 inhibited the proliferation, migration, and invasion while inducing apoptosis of CRC cells. The knockdown of CCNA2 could inhibit epithelial-mesenchymal transition (EMT) pathway. CCNA2 acted as a target of miR-548x-3p in regulating the biological behavior of CRC cells via the EMT-signaling pathway. CCNA2 is a potential biomarker for the diagnosis, treatment, and prognosis of CRC and is associated with immune infiltration, TF, and miRNA. The miR-548x-3p/CCNA2 axis plays a pivotal role in regulating the tumorigenesis of CRC through the EMT-signaling pathway.

PMID:40345591 | DOI:10.1016/j.jbc.2025.110216

Genetics. 2025 May 9:iyaf088. doi: 10.1093/genetics/iyaf088. Online ahead of print.

ABSTRACT

Biobanks linking genetic data with clinical health records provide exciting opportunities for pharmacogenomic (PGx) research on genetic variation and drug response. Designed as central and multi-use resources, biobanks can facilitate diverse PGx research efforts, including the study of drug efficacy and adverse effects. Specialized PGx alleles and phenotypes are critical for such studies and can be conveniently called from existing array-based genotypes routinely collected in most biobanks. We describe a central callset of PGx alleles and phenotypes in over 80,000 participants of the Michigan Genomics Initiative (MGI) biobank, created using the PyPGx software on TOPMed imputed genotypes. The array-based PGx allele calls demonstrate concordance (>92%) with a set of PCR-validated alleles collected during clinical care, but do not identify PGx alleles dependent on structural variation, including the clinically important CYP2D6*5 deletion. To address this, we developed a support vector machine trained on genotype array SNV probe intensities to classify CYP2D6*5 carriers. This method had >99% accuracy and reclassified ∼7% of African American and ∼4% of White MGI participants to lower activity metabolizer phenotypes, predicting higher risks of adverse drug reactions. We demonstrate that central PGx callsets created with existing tools and genetic data can be augmented by customized calls for challenging alleles based on structural variants to broaden the research potential and clinical utility of biobanks. These PGx callsets can be created in biobanks with existing array-based genotype data and highlight the utility of advanced computational methods in PGx allele identification.

PMID:40344017 | DOI:10.1093/genetics/iyaf088