Pharmacogenet Genomics. 2025 Feb 12. doi: 10.1097/FPC.0000000000000562. Online ahead of print.

ABSTRACT

In Advancing Clinical Therapeutics Globally protocol A5372, a pharmacokinetic study of dolutegravir with 1-month of daily rifapentine/isoniazid, twice-daily dolutegravir offset the induction effects of rifapentine on plasma dolutegravir trough concentrations (Ctrough). Here, we characterize the impact on dolutegravir Ctrough of UGT1A1, AADAC, and NAT2 polymorphisms that affect dolutegravir, rifapentine, and isoniazid, respectively. People with HIV receiving dolutegravir-based antiretroviral therapy with an indication to treat latent tuberculosis underwent pharmacokinetic sampling during dolutegravir 50 mg once daily alone, and on day 28 of dolutegravir 50 mg twice daily with rifapentine/isoniazid. Multivariable linear regression models characterized genetic associations with dolutegravir Ctrough. Among 30 participants evaluable for genetic associations, median (Q1, Q3) day 0 dolutegravir Ctrough was 1745 (1099, 2694) ng/ml, and day 28 was 2146 (1412, 2484) ng/ml. Day 28 Ctrough was higher with UGT1A1 rs887829 TT [geometric mean ratio (GMR) = 1.65; 90% confidence interval (CI): 0.97-2.78] and CT (GMR = 1.38; 90% CI: 1.02-1.86) than with CC, and was higher with AADAC rs1803155 GG (GMR = 1.79; 90% CI: 1.09-2.93) and AG (GMR = 1.48; 90% CI: 1.14-1.90) than with AA. Median day 28 Ctrough ranged from 1205 (1063, 1897) ng/ml with 4 total UGT1A1 and AADAC risk alleles, to 3882 and 3717 ng/ml with only one risk allele. Individuals with concomitant AADAC slow metabolizer and UGT1A1 normal metabolizer genotypes may be at greater risk for clinically significant drug-drug interactions between rifapentine/isoniazid and dolutegravir.

PMID:39960813 | DOI:10.1097/FPC.0000000000000562

Clin Pharmacol Ther. 2025 Feb 17. doi: 10.1002/cpt.3599. Online ahead of print.

ABSTRACT

In the past decade, pharmacogenomic (PGx) testing to predict drug response have emerged into clinical care. Clinical decision support (CDS) has and continues to play a key role in educating prescribers and facilitating the integration of pharmacogenomic results into routine clinical practice. The Epic Genomics module, an add-on to Epic's base clinical software, allows for storage of structured genomic data and provides electronic heath record tools designed with PGx CDS implementation in mind. In early 2022, the University of Florida Health deployed the Genomics module. This tutorial outlines the steps taken by the University of Florida Health Precision Medicine Program to implement Epic's Genomic Module at University of Florida Health and identifies key factors for a successful implementation.

PMID:39960348 | DOI:10.1002/cpt.3599

Pharmacogenomics. 2025 Feb 16:1-10. doi: 10.1080/14622416.2025.2463866. Online ahead of print.

ABSTRACT

AIM: To share the experience of a US national reference laboratory, offering genotyping for TPMT and NUDT15, TPMT enzyme phenotyping and detection of thiopurine metabolites.

METHODS: Retrospective review of archived datasets related to thiopurines drug therapy including patients' data that underwent TPMT and NUDT15 genotyping, and smaller data sets where genotyping was performed with TPMT enzyme levels (phenotyping) +/- therapeutic drug monitoring (TDM).

RESULTS: Thirteen percent of patients had variants in one or both genes tested. Testing for NUDT15 revealed 3.9% additional patients requiring thiopurines dosing recommendations. A correlation between TPMT enzyme activity and TPMT polymorphisms (odds ratio OD = 71.41, p-value <0.001) and between older age and higher enzyme levels (OD = 0.98, p-value = 0.002) was identified. No correlation between sex and TPMT enzyme levels, nor between TPMT genotyping and the level of thiopurine metabolites was found.

CONCLUSION: Adding NUDT15 to TPMT genotyping, identified additional 3.9% patients to benefit from thiopurine dose modifications. A significant correlation between genetic variants in TPMT and TPMT enzyme levels and between age and enzyme levels was established, while no correlation was identified between sex and enzyme levels nor between TPMT variation and thiopurine metabolites. Providers rely more significantly on genotyping only approach, rather than genotyping and phenotyping.

PMID:39957149 | DOI:10.1080/14622416.2025.2463866

Br J Clin Pharmacol. 2025 Feb 16. doi: 10.1002/bcp.70004. Online ahead of print.

ABSTRACT

AIMS: Phenoconversion, a genotype-phenotype mismatch, challenges a successful implementation of personalized medicine. The aim of this study was to detect and determine phenoconversion using the solanidine metabolites 3,4-seco-solanidine-3,4-dioic acid (SSDA) and 4-OH-solanidine as diet-derived cytochrome P450 2D6 (CYP2D6) biomarkers in a geriatric, multimorbid cohort with high levels of polypharmacy.

METHODS: Blood samples and data of geriatric, multimedicated patients were collected during physician counsel (CT: NCT05247814). Solanidine and its metabolites were determined via liquid chromatography/tandem mass spectrometry and used for CYP2D6 phenotyping. CYP2D6 genotyping was performed and activity scores (AS) were assigned. Complete medication intake was assessed. A shift of the AS predicted via genotyping as measured by phenotyping was calculated.

RESULTS: Solanidine and its metabolites were measured in 88 patients with complete documentation of drug use. Patients had a median age of 83 years (interquartile range [IQR] 77-87) and the majority (70.5%, n = 62) were female. Patients took a median of 15 (IQR 12-17) medications. The SSDA/solanidine metabolic ratio correlated significantly with the genotyping-derived AS (P < .001) and clearly detected poor metabolizers. In the model adjusted for age, sex, Charlson Comorbidity Index and estimated glomerular filtration rate each additional CYP2D6 substrate/inhibitor significantly lowered the expected AS by 0.53 (95% confidence interval 0.85-0.21) points in patients encoding functional CYP2D6 variants (R2 = 0.242).

CONCLUSIONS: Phenotyping of CYP2D6 activity by measurement of diet-derived biomarkers elucidates phenoconversion in geriatric patients. These results might serve as a prerequisite for the validation and establishment of a bedside method to measure CYP2D6 activity in multimorbid patients for successful application of personalized drug prescribing.

PMID:39957076 | DOI:10.1002/bcp.70004

Ultrason Sonochem. 2025 Feb 12;114:107271. doi: 10.1016/j.ultsonch.2025.107271. Online ahead of print.

ABSTRACT

Javanese turmeric (Curcuma xanthorrhiza Roxb.) is known for its diverse pharmacological activities due to its rich phytoconstituents, including curcuminoids and xanthorrhizol. Typically, these compounds are extracted using organic solvents, which pose health and environmental risks. Therefore, safer and more environmentally friendly green extraction methods are being developed. This study investigated the effect of ultrasound-assisted extraction (UAE) combined with natural deep eutectic solvents (NADES) based on choline chloride and organic acids (lactic, malic, and citric acid) to find the best combination for extracting curcuminoids and xanthorrhizol from Javanese turmeric. Results showed that UAE using choline chloride and malic acid (1:1) (ChCl-MA) yielded the best results. The Box-Behnken Design optimized water addition, solvent-to-powder ratio, and extraction time, with optimal conditions being 25 % water addition, a 20 mL/g ratio, and a 15-minute extraction time. This method yielded 4.58 mg/g of curcuminoids and 12.93 mg/g of xanthorrhizol. Furthermore, the ChCl-MA NADES with UAE extraction showed more cytoselective activity towards the HeLa cancer cell line compared to the non-cancer HaCaT cell line. In contrast, traditional ethanol extraction was non-selective, as indicated by similar cell viability reductions in both HeLa and HaCaT cells at 6.25 ppm. Collectively, this study is the first to report the optimal NADES combination with UAE, based on salts and organic acids, for the extraction of Javanese turmeric rhizomes with selective cytotoxic effects against cancer cells. These findings may contribute to the development of novel, naturally derived anticancer agents using green extraction techniques.

PMID:39955874 | DOI:10.1016/j.ultsonch.2025.107271

Cancer Chemother Pharmacol. 2025 Feb 15;95(1):34. doi: 10.1007/s00280-025-04759-8.

ABSTRACT

PURPOSE: In 20-30% of the patients, fluoropyrimidines (5-FU) based chemotherapy leads to severe toxicity, which is associated with dihydropyridine dehydrogenase (DPD) deficiency. Therefore, DPYD genotyping became standard practice before treatment with fluoropyrimidines. Nevertheless, only 17% of the patients with severe toxicity have a DPYD variant. Therefore, an urgent need persists to investigate other strategies contributing to prediction and prevention of toxicity. Endogenous DPD substrates are considered as potential biomarkers to predict toxicity, yet contradictional data exist on demonstrating uracil as a reliable biomarker. Thymine as biomarker for toxicity has been investigated less. The aim of this study was to determine the association between the concentrations of uracil, thymine dihydrouracil (DHU) and dihydrothymine (DHT), with the systemic drug exposure of 5-FU and DPD enzyme activity in patients treated with 5-FU.

METHODS: We included 36 patients with gastrointestinal malignancy who received 5-FU infusion. DPYD genotyping was conducted before start of treatment. Blood samples for determining 5-FU, uracil and thymine concentrations during infusion and DPD enzyme activity were taken.

RESULTS: We found a significant correlation between the 5-FU systematic exposure and baseline thymine concentrations (R2 = 0.1468; p = 0.0402). DPD enzyme activity was significantly correlated with baseline thymine concentrations but no correlation was found between DPD enzyme activity and 5-FU systemic drug exposure.

CONCLUSION: 5-FU dose individualization based on thymine concentrations could be a promising addition to DPYD genotyping to predict 5-FU-induced toxicity. Larger prospective trials are needed to examine thymine as predictor for toxicity in daily practice.

TRIAL REGISTRATION: Trial NL7539 at 'Overview of Medical Research in the Netherlands' (ID NL-OMON21471). Date of registration 19-02-2019.

PMID:39955449 | DOI:10.1007/s00280-025-04759-8

J Genet Genomics. 2025 Feb 13:S1673-8527(25)00038-4. doi: 10.1016/j.jgg.2025.02.001. Online ahead of print.

ABSTRACT

Founder events influence recessive diseases in highly endogamous populations. Several Indian populations have experienced significant founder events due to strict endogamy. However, the clinical implications of it remain underexplored. Therefore, we perform whole-exome sequencing of 281 individuals from four South Indian populations, characterized by high IBD scores. Our study reveals a high inbreeding rate of 59% across the populations. We identify ∼29.2% of the variants that are exclusively present in a single population and uncovered 1284 unreported exonic variants, underscoring the underrepresentation of Indian populations in global databases. Among these, 23 are predicted to be deleterious, all present in heterozygous state may be pathogenic when homozygous, an expected phenomenon in endogamous populations. Approximately 16%-33% of the identified pathogenic variants showed significantly higher occurrence rates compared to the South Asian populations from 1000 Genomes dataset. Pharmacogenomic analysis revealed distinct allele frequencies of variants in CYP450 and non-CYP450 genes, highlighting heterogeneous drug responses and associated risks. We report a high prevalence of ankylosing spondylitis in Reddy population, linked to HLA-B*27:04 allele and strong founder effect. Our findings highlight the need for extensive genomic research in understudied Indian populations for better understanding of disease risk and evolving strategies for precision and preventive medicine.

PMID:39955025 | DOI:10.1016/j.jgg.2025.02.001

J Psychiatr Res. 2025 Feb 6;183:106-111. doi: 10.1016/j.jpsychires.2025.02.005. Online ahead of print.

ABSTRACT

INTRODUCTION: Although post-COVID major depressive disorder (MDD) is frequent, the physiological mechanisms associated with it remain unclear. This study aimed to assess the association between 10 residual blood markers of inflammation and the presence of MDD 4 months after the acute phase of COVID-19.

METHODS: This is a cross-sectional study of the COMEBAC cohort that followed patients 4 months after hospitalization for COVID-19 at Bicêtre Hospital. Patients with lingering symptoms or who had been in critical care (n = 177) were invited to a day hospital for assessment of MDD and peripheral inflammation. Ten peripheral inflammatory markers were examined: plasmatic C-reactive protein; leukocyte, monocyte, neutrophil, and lymphocyte counts; the neutrophil to lymphocyte ratio; the systemic inflammatory index (i.e., the (platelet x neutrophil) to lymphocyte ratio); cortisol, ferritin, and hemoglobin levels. Current MDD was assessed through structured interviews with a psychiatrist, depressive symptoms through self-questionnaires. Peripheral inflammatory markers were compared between patients with post-COVID MDD and patients without a lifetime history of psychiatric disorders (controls).

RESULTS: Out of 177 patients, 24 (13.6%) had MDD. No significant differences in peripheral inflammatory markers were observed between patients with post-COVID MDD and controls. Furthermore, peripheral inflammatory markers were not correlated with symptoms of depression.

CONCLUSION: We found no association between post-COVID MDD and 10 peripheral inflammatory markers 4 months after COVID-19 infection. Other potential mechanisms warrant investigation.

PMID:39954540 | DOI:10.1016/j.jpsychires.2025.02.005

Clin Transl Sci. 2025 Feb;18(2):e70080. doi: 10.1111/cts.70080.

ABSTRACT

Selection of rational antagonists of P2Y12 receptor for CAD patients who inherit CYP2C19 LoF alleles remains still conflicting. This study compared the clinical outcomes in CAD patients inheriting CYP2C19 LoF alleles undergoing PCI and treated with clopidogrel against alternative antagonists of P2Y12 receptor. A thorough literature search was performed across multiple scientific databases following the PRISMA guidelines and PICO model. Setting the statistical significance at p < 0.05 and RevMan software was used to calculate the risk ratios (RRs). Estimation of the pooled analysis revealed a significant 62% increased risk of major adverse cardiovascular events (MACE) in CAD patients inheriting CYP2C19 LoF alleles and treated with clopidogrel against those treated with alternative P2Y12 receptor antagonists such as prasugrel or ticagrelor (RR 1.62; 95% CI 1.42-1.86; p < 0.00001). In addition, Asian CAD patients were found at a significantly higher risk of MACE (RR 1.93; 95% CI: 1.49-2.49; p < 0.00001) juxtaposed to CAD patients of other ethnicities (RR 1.51; 95% CI: 1.29-1.78; p < 0.00001). Conversely, between these two treatment groups, taking clopidogrel against prasugrel/ticagrelor, who possess CYP2C19 LoF alleles, no significant differences in bleeding events were observed (RR 0.94; 95% CI 0.79-1.11; p = 0.47). CAD patients undergoing PCI who inherited CYP2C19 LoF alleles and treated with clopidogrel were associated with significantly higher risk of MACE against those treated with alternative antagonists of P2Y12 receptor, that is, prasugrel or ticagrelor.

PMID:39953666 | DOI:10.1111/cts.70080

Mol Med. 2025 Feb 14;31(1):59. doi: 10.1186/s10020-025-01123-7.

ABSTRACT

BACKGROUND: Patients with higher-risk (HR) myelodysplastic syndrome (MDS), ineligible for allogeneic hematopoietic stem cell transplantation (alloHSCT), require prompt therapeutic interventions, such as treatment with hypomethylating agents (HMAs) to restore normal DNA methylation patterns, mainly of oncosuppressor genes, and consequently to delay disease progression and increase overall survival (OS). However, response assessment to HMA treatment relies on conventional methods with limited capacity to uncover a wide spectrum of underlying molecular events.

METHODS: We implemented liquid chromatography-tandem mass spectrometry (LC-MS/MS) to assess 5' methyl-2' deoxycytidine (5mdC), 5' hydroxy-methyl-2'-deoxycytidine (5hmdC) levels and global adenosine/thymidine ([dA]/[T]) ratio in bone marrow aspirates from twenty-one HR MDS patients, pre- and post-HMA treatment. Additionally, targeted methylation analysis was performed by interpretation of NGS-methylation (MeD-seq) data obtained from the same patient cohort.

RESULTS: LC/MS-MS analysis revealed a significant hypomethylation status in responders (Rs), already established at baseline and a trend for further DNA methylation reduction post-HMA treatment. Non-responders (NRs) reached statistical significance for DNA hypomethylation only post-HMA treatment. The 5hmdC epigenetic mark was approximately detected at 37.5-40% among NRs and Rs, implying the impairment of the natural active demethylation pathway, mediated by the ten-eleven (TET) 5mdC dioxygenases. R and NR subgroups displayed a [dA]/[T] ratio < 1 (0.727 - 0.633), supporting high frequences of 5mdC transition to thymidine. Response to treatment, according to whole genome MeD-seq data analysis, was associated with specific, scattered hypomethylated DMRs, rather than presenting a global effect across genome. MeD-seq analysis identified divergent epigenetic effects along chromosomes 7, 9, 12, 16, 18, 21, 22, X and Y. Within statistically significant selected chromosomal bins, genes encoding for proteins and non-coding RNAs with reversed methylation profiles between Rs and NRs, were highlighted.

CONCLUSIONS: Implementation of powerful analytical tools to identify the dynamic DNA methylation changes in HR MDS patients undergoing HMA therapy demonstrated that LC-MS/MS exerts high efficiency as a broad-based but rapid and cost-effective methodology (compared to MeD-seq) to decode different perspectives of the epigenetic background of HR MDS patients and possess discriminative efficacy of the response phenotype to HMA treatment.

PMID:39953389 | DOI:10.1186/s10020-025-01123-7

Sci Rep. 2025 Feb 14;15(1):5458. doi: 10.1038/s41598-025-89160-4.

ABSTRACT

Glucuronidation is a crucial pathway for the metabolism and detoxification of drugs and endobiotics, and primarily occurs in the liver. UGT2B17 is one of the 22 glycosyltransferases (UGT) that catalyze this reaction. In a large proportion of the population, UGT2B17 is absent due to complete gene deletion. We hypothesized that a UGT2B17 human deficiency affects the composition and function of the liver proteome, potentially provoking compensatory responses, and altering interconnected pathways and regulatory networks. The objective was to elucidate the liver proteome of UGT2B17-deficient individuals. Liver specimens from UGT2B17-deficient and proficient individuals were compared by mass spectrometry-based proteomics using data-independent acquisition. In UGT2B17-deficient livers, 80% of altered proteins showed increased abundance with a notable enrichment in various metabolic and chemical defense pathways, cellular stress and immune-related responses. Enzymes involved in the homeostasis of steroids, nicotinamide, carbohydrate and energy metabolism, and sugar pathways were also more abundant. Some of these changes support compensatory mechanisms, but do not involve other UGTs. An increased abundance of non-metabolic proteins suggests an adaptation to endoplasmic reticulum stress, and activation of immune responses. Data implies a disrupted hepatocellular homeostasis in UGT2B17-deficient individuals and offers new perspectives on functions and phenotypes associated with a complete UGT2B17 deficiency.

PMID:39953065 | DOI:10.1038/s41598-025-89160-4

Pharmacol Rev. 2025 Jan;77(1):100014. doi: 10.1124/pharmrev.124.001049. Epub 2024 Nov 22.

ABSTRACT

Precision cancer medicine is widely established, and numerous molecularly targeted drugs for various tumor entities are approved or are in development. Personalized pharmacotherapy in oncology has so far been based primarily on tumor characteristics, for example, somatic mutations. However, the response to drug treatment also depends on pharmacological processes summarized under the term ADME (absorption, distribution, metabolism, and excretion). Variations in ADME genes have been the subject of intensive research for >5 decades, considering individual patients' genetic makeup, referred to as pharmacogenomics (PGx). The combined impact of a patient's tumor and germline genome is only partially understood and often not adequately considered in cancer therapy. This may be attributed, in part, to the lack of methods for combined analysis of both data layers. Optimized personalized cancer therapies should, therefore, aim to integrate molecular information, which derives from both the tumor and the germline genome, and taking into account existing PGx guidelines for drug therapy. Moreover, such strategies should provide the opportunity to consider genetic variants of previously unknown functional significance. Bioinformatic analysis methods and corresponding algorithms for data interpretation need to be developed to integrate PGx data in cancer therapy with a special meaning for interdisciplinary molecular tumor boards, in which cancer patients are discussed to provide evidence-based recommendations for clinical management based on individual tumor profiles. SIGNIFICANCE STATEMENT: The era of personalized oncology has seen the emergence of drugs tailored to genetic variants associated with cancer biology. However, the full potential of targeted therapy remains untapped owing to the predominant focus on acquired tumor-specific alterations. Optimized cancer care must integrate tumor and patient genomes, guided by pharmacogenomic principles. An essential prerequisite for realizing truly personalized drug treatment of cancer patients is the development of bioinformatic tools for comprehensive analysis of all data layers generated in modern precision oncology programs.

PMID:39952686 | DOI:10.1124/pharmrev.124.001049

Expert Rev Clin Pharmacol. 2025 Feb 14. doi: 10.1080/17512433.2025.2465426. Online ahead of print.

ABSTRACT

INTRODUCTION: Therapeutic drug monitoring (TDM) is important to optimize drug exposure and minimize toxicity for the individual patient.

AREAS COVERED: This narrative review covers the pharmacokinetics (PK), -dynamics (PD) and-genetics of classic chemotherapeutic drugs used in frontline therapy for acute lymphoblastic leukemia (ALL), including anthracyclines, asparaginase, busulfan, cyclophosphamide, cytarabine, glucocorticoids, methotrexate, nelarabine, thiopurines, tyrosine kinase inhibitors, and vincristine. Furthermore, novel immunotherapies including blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor T-cells that are rapidly moving into frontline therapy are addressed. This review focuses on TDM already used in clinical practice as well as the unused potential and feasibility of TDM. Finally, important factors affecting PK/PD such as obesity and transition to adolescence and young adulthood are discussed.

EXPERT OPINION: Investigation of TDM as standard of care for antileukemic agents is highly warranted to personalize curative yet toxic anticancer regimens within frontline ALL treatment. Some of the drugs have been used in ALL treatment regimens for decades, but a wide range of new compounds are being introduced, some like blinatumomab reaching standard-of-care designation. Not least, optimized drug efficacy and reduction of the risk of serious toxicities may render TDM implementation cost-effective.

PMID:39949259 | DOI:10.1080/17512433.2025.2465426

BMC Genomics. 2025 Feb 13;26(1):140. doi: 10.1186/s12864-025-11310-9.

ABSTRACT

BACKGROUND: The cytochrome P450 family 2 subfamily C member 9 (CYP2C9) exhibits extensive genetic variability that may influence the metabolism of approximately 16-20% of all drugs. Understanding the frequency and functional impact of the CYP2C9 variants is crucial for the implementation of pharmacogenetics. Our study aims to determine the frequencies of CYP2C9 variants in the Syrian population, contributing to the limited information available for Middle Eastern populations.

METHODS: One hundred thirty-eight unrelated individuals from two major Syrian cities (Damascus and Homs) enrolled in this cross-sectional study. Genomic DNA was extracted from peripheral blood and specific PCR amplification products were purified and sequenced. The length of the amplicons allowed for the detection of 17 star alleles (i.e. *2, *8, *14, *20, *26, *33, *40, *41, *42, *43, *45, *46, *62, *63, *72, *73, and *78) in exon three, and seven star alleles (i.e., *3, *4, *5, *24, *55, *66, *68) in exon seven, in addition to two intronic variants. The frequencies of the functionally compromised CYP2C9*2rs1799853 and CYP2C9*3rs1057910 alleles were compared to same variants in other populations.

RESULTS: Of the 24 exonic alleles investigated, only the *2, *3, *41, and *46 alleles were detected at frequencies of 14.8%, 8.3%, 1.45%, and 0.72%, respectively, with 43.5% of the study subjects carrying at least one dysfunctional variant. The genotype frequencies observed were as follows: *1/*1 (56.5%), *1/*2 (23.9%), *2/*2 (0.7%), *3/*1 (12.3%), *2/*3 (4.3%), *3/*3 (0%), *1/*41 (0.7%), *2/*41 (0%), *3/*41 (0.7%), *1/*46 (0.7%), *46/*2 (0%), and *46/*3 (0%). Moreover, frequencies of the rs933120 and rs933119 intronic alleles were 12.3% and 6.1%, respectively. A high linkage disequilibrium (LD) was found (D'=0.78) between the intronic rs933119 and exonic rs1799853 (*2 allele).

CONCLUSIONS: This study provides evidence for high prevalence of the CYP2C9 *2 and *3 alleles, and consequently the intermediate and poor metabolizer phenotypes in Syrians. Two rare putative function-relevant variants (*41 and *46) were detected in three individuals. These findings pave the path to the efforts for implementing CYP2C9 pharmacogenetics-based personalized pharmacotherapy in this Middle Eastern population.

PMID:39948503 | DOI:10.1186/s12864-025-11310-9

J Endocrinol Invest. 2025 Feb 13. doi: 10.1007/s40618-025-02550-3. Online ahead of print.

ABSTRACT

PURPOSE: To detect the expression of miR-27a-5p in differentiated thyroid cancer (DTC) and to explore its correlation with SREBP1 expression, DTC malignant progression, and TSH suppression therapy.

METHODS: The expression levels of SREBP1 and miR-27a-5p in DTC tissues (n = 75) were detected by qRT-PCR. The expression of miR-27a-5p and SREBP1 was statistically analyzed for correlation with patients' postoperative TSH inhibition therapy. Dual luciferase reporter gene assay was performed to verify the target-regulatory relationship between miR-27a-5p and SREBP1. qRT-PCR and Western blots were performed to detect the effect of miR-27a-5p on the expression level of SREBP1. MTS, plate clone formation assay was performed to detect the effect of miR-27a-5p on the proliferative capacity of cells. Flow cytometry was performed to detect the effect of miR-27a-5p on cell cycle and apoptosis. Scratch assay and Transwell assay was performed to detect the effect of miR-27a-5p on cell migration invasion ability.

RESULTS: MiR-27a-5p expression was significantly downregulated in DTC cancer tissues and significantly negatively correlated with SREBP1 expression. It correlated with the outcome of postoperative TSH suppression therapy in DTC patients. The results of dual luciferase reporter gene assay showed that the 3'-UTR region of SREBP1 mRNA was the target site of action of miR-27a-5p. Overexpression of miR-27a-5p was associated with a significant reduction in cell proliferation, cell cycle arrest, increased apoptosis, and diminished cell invasive migration.

CONCLUSION: The miR-27a-5p expression level was negatively correlated with the progression of DTC, which may be inhibited by targeting SREBP1 and correlated with the outcome of TSH inhibitory therapy.

PMID:39946050 | DOI:10.1007/s40618-025-02550-3

Curr Gene Ther. 2025 Feb 12. doi: 10.2174/0115665232342211250207064205. Online ahead of print.

ABSTRACT

This article provides a detailed look at Parkinson's disease (PD), a neurodegenerative ailment mostly known for movement difficulties such tremor, stiffness, and bradykinesia, which affects approximately 1% of persons over the age of 60. Although the precise cause of PD is still unknown, various factors such as pesticide exposure, genetics, and lifestyle choices like smoking and caffeine consumption are thought to play a role in its development. The presence of Lewy bodies characterizes the disease, the aggregation of alpha-synuclein, the loss of dopaminergic neurons in the substantia nigra, and disruptions in basal ganglia circuitry, resulting in both motor and nonmotor symptoms. This review is structured into several key sections, beginning with an exploration of the pathophysiological mechanisms behind PD, including how genetic mutations can lead to deficits in the Ubiquitin Proteasome System and mitochondrial function, which are linked to familial cases of the disease. Following this, the article explores diagnostic methods, such as the UK Brain Bank Criteria, advanced imaging techniques, olfactory testing, and innovative technologies like machine learning, all of which support early detection and accurate diagnosis of PD. Treatment strategies are also comprehensively reviewed, focusing on traditional pharmacological options like levodopa and dopamine agonists, as well as surgical interventions such as deep brain stimulation. Additionally, the review discusses promising new therapies, including immunotherapy aimed at neuroinflammation and gene therapy for disease modification. The impact of lifestyle changes such as exercise and diet on reducing PD risk and enhancing symptom management are also considered. In conclusion, this review highlights the complex nature of Parkinson's disease and underscores the need for a holistic approach that combines pharmacotherapy, advanced treatments, and lifestyle adjustments. By addressing both symptom management and disease modification, these strategies provide hope for improving quality of life.

PMID:39945257 | DOI:10.2174/0115665232342211250207064205

Front Nephrol. 2025 Jan 29;4:1465380. doi: 10.3389/fneph.2024.1465380. eCollection 2024.

ABSTRACT

BACKGROUND: Homocysteine (Hcy) is a risk factor for stroke. In this study, we investigated the relationship between gene polymorphisms, particularly SLCO1B1 and homocysteine (Hcy) concentrations in ischemic stroke patients, with a focus on identifying potential risk factors for elevated Hcy levels.

METHODS: A total of 177 ischemic stroke patients, including 99 with single nucleotide polymorphisms (SNPs), underwent pharmacogenomics (PGx) sequencing tests, from September 2022 to November 2023 at the hospital. Logistic regression analysis was used to analyze the relationship between clinical characteristics, SNPs, and Hcy concentrations. In the sub-study, 207 ischemic stroke and 244 non-stroke patients underwent SLCO1B1c.521T>C polymorphism to further demonstrate the role of SLCO1B1c.521T>C polymorphism and homocysteine.

RESULTS: Higher Hcy concentrations were observed in men compared to women. Univariate logistic analysis identified gender, GGT concentrations, B12 concentrations, folic acid concentrations, and SLCO1B1 c.521 CC+CT polymorphism as risk factors for elevated Hcy. Multivariate logistic analysis confirmed that B12 concentrations, folic acid concentrations, and SLCO1B1 CT + CC polymorphism were significant dependent risk factors. In the sub-study, SLCO1B1 CT + CC polymorphism and the male sex were identified as risk factors for Hcy, with the effect of SLCO1B1 polymorphism being more pronounced in men.

CONCLUSION: Folic acid and vitamin B12 reduce Hcy concentrations, while the SLCO1B1 CT and CC polymorphisms are associated with higher Hcy levels. The impact of SLCO1B1 gene polymorphism on Hcy is notably stronger in the male population, suggesting that genetic factors play a significant role in determining Hcy levels.

PMID:39944478 | PMC:PMC11815283 | DOI:10.3389/fneph.2024.1465380

Int J Mol Sci. 2025 Feb 6;26(3):1362. doi: 10.3390/ijms26031362.

ABSTRACT

Hypoxia, a common feature in many malignancies, is particularly prominent in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). Investigating the mechanisms underlying hypoxia is essential for understanding the heterogeneity of CESC and developing personalized therapeutic regimens. Firstly, the CESC-specific hypoxia gene sets shared between single-cell RNA sequencing (scRNA-seq) and bulk data were identified through Weighted Gene Correlation Network Analysis (WGCNA)and FindMarkers analyses. A CESC-specific hypoxia-related score (CSHRS) risk model was constructed using the least absolute shrinkage and selection operator (LASSO)and Cox regression analyses based on these genes. The prognostic differences were analyzed in terms of immune infiltration, mutations, and drug resistance. Finally, a nomogram model was constructed by integrating clinicopathological features to facilitate precision treatment for CESC. This study constructed a CSHRS risk model that divides patients into two groups, and this model can comprehensively evaluate the tumor microenvironment characteristics of CESC, provide accurate prognostic predictions, and offer rational treatment options for patients.

PMID:39941131 | DOI:10.3390/ijms26031362

Int J Mol Sci. 2025 Jan 31;26(3):1269. doi: 10.3390/ijms26031269.

ABSTRACT

This study investigated the diagnostic, prognostic, and therapeutic significance of Fc receptor-like 1 (FCRL1) and B-cell activating factor (BAFF) mRNA expression in Egyptian patients with diffuse large B-cell lymphoma (DLBCL) undergoing the standard R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) using quantitative real-time PCR (RT-qPCR). The results demonstrated that FCRL1 and BAFF mRNA expression were significantly elevated in DLBCL patients compared to healthy controls. A strong positive correlation existed between BAFF and FCRL1 expression levels. Diagnostic performance assessed through combined ROC curve analysis revealed that BAFF, FCRL1, and lactate dehydrogenase (LDH) achieved perfect diagnostic accuracy (AUC = 1.0), demonstrating 100% sensitivity, specificity, and predictive values. Further prognostic analysis using COX regression identified elevated FCRL1 expression as the most significant predictor of poor clinical outcomes. Kaplan-Meier survival analysis reinforced this finding, with high FCRL1 expression showing significant associations with reduced overall survival (OS, p = 0.031) and progression-free survival (PFS, p = 0.038). The study underscores the potential utility of BAFF and FCRL1 mRNA as diagnostic markers for DLBCL, with FCRL1 emerging as a promising prognostic marker and potential therapeutic target enabling more tailored treatment approaches for DLBCL, the most common type of B-cell non-Hodgkin lymphoma, and patients receiving R-CHOP therapy.

PMID:39941037 | DOI:10.3390/ijms26031269

Int J Mol Sci. 2025 Jan 26;26(3):1082. doi: 10.3390/ijms26031082.

ABSTRACT

The landscape of psychiatric care is poised for transformation through the integration of pharmaco-multiomics, encompassing genomics, proteomics, metabolomics, transcriptomics, epigenomics, and microbiomics. This review discusses how these approaches can revolutionize personalized treatment strategies in psychiatry by providing a nuanced understanding of the molecular bases of psychiatric disorders and individual pharmacotherapy responses. With nearly one billion affected individuals globally, the shortcomings of traditional treatments, characterized by inconsistent efficacy and frequent adverse effects, are increasingly evident. Advanced computational technologies such as artificial intelligence (AI) and machine learning (ML) play crucial roles in processing and integrating complex omics data, enhancing predictive accuracy, and creating tailored therapeutic strategies. To effectively harness the potential of pharmaco-multiomics approaches in psychiatry, it is crucial to address challenges such as high costs, technological demands, and disparate healthcare systems. Additionally, navigating stringent ethical considerations, including data security, potential discrimination, and ensuring equitable access, is essential for the full realization of this approach. This process requires ongoing validation and comprehensive integration efforts. By analyzing recent advances and elucidating how different omic dimensions contribute to therapeutic customization, this review aims to highlight the promising role of pharmaco-multiomics in enhancing patient outcomes and shifting psychiatric treatments from a one-size-fits-all approach towards a more precise and patient-centered model of care.

PMID:39940850 | DOI:10.3390/ijms26031082