Clin Exp Med. 2025 Jul 16;25(1):251. doi: 10.1007/s10238-025-01735-7.

ABSTRACT

Smooth muscle cells (SMCs) play a crucial role in atherosclerosis, undergoing proliferation, migration, and transdifferentiation into other cell types. Multiple SMC subsets exist, each with distinct roles that are increasingly being elucidated. To investigate the heterogeneity of SMC subsets in lesion, we integrated three single-cell RNA sequencing datasets. Bioinformatics analysis was conducted to evaluate the effects of the immune microenvironment, biological function, metabolic interactions, and differentiation potential of different SMC subsets. Atherosclerotic plaques from ApoE-/- mice were used for validation. We employed pySCENIC to predict the transcription factors associated with different SMC subsets and used bulk RNA sequencing data to identify the function of the_C5 marker gene (ALDOA). We identified a unique smooth muscle cell cluster 5 (SMC_C5) in human coronary plaques and confirmed its presence in aortic plaques of ApoE-/- mice. SMC_C5 interacts with macrophages and monocytes, influencing the microenvironment and participating in various pathways and metabolic processes. Additionally, SMC_C5 cells exhibit pluripotent differentiation potential. Mechanistically, we found a strong association of SMC_C5 and the transcription factor GA binding protein 1 (GABP1). The SMC_C5 marker gene (ALDOA) was involved in regulating metabolism, hypoxia response, and the immune microenvironment. This investigation provides novel insights into the complex biology of SMCs and reveals novel functions of SMC_C5 in atherogenesis.

PMID:40668312 | DOI:10.1007/s10238-025-01735-7

Clin Transl Sci. 2025 Jul;18(7):e70301. doi: 10.1111/cts.70301.

ABSTRACT

Cyclophosphamide (CTX) is one of the most widely used drugs in the clinical treatment of tumors and autoimmune diseases. The correlation between CYP, GST, and ABC gene polymorphisms and CTX activity and its induced toxicity has been extensively studied, but with inconsistent conclusions. In this study, a meta-analysis protocol was employed to comprehensively evaluate the relationship between the gene polymorphisms, including CYP2C9, CYP2C19, CYP2B6, CYP3A5, GSTA1, GSTM1, GSTT1, GSTP1, ABCB1, ABCC4, and ABCG2, and the safety and efficacy of CTX. Forty-five eligible literatures were retrieved from PubMed, Web of Science, Embase, and China National Knowledge Infrastructure (CNKI) databases. The results showed that CYP, GST, and ABC gene polymorphisms analyzed in the study were not associated with the efficacy but related to the safety of CTX. CYP2C19*2 polymorphism showed low risk with CTX-induced gastrointestinal toxicity (RR, 3.70; 95% CI, 1.60-8.55; p = 0.002). The GSTT1-present genotype showed low risk with hematological (RR, 0.63; 95% CI, 0.42-0.96; p = 0.03), gastrointestinal toxicity (RR, 0.62; 95% CI, 0.41-0.94; p = 0.02) and other toxicities (RR, 0.60; 95% CI, 0.38-0.97; p = 0.04). The GSTP1 (rs1695) wild-type showed low risk with gastrointestinal toxicity (RR, 0.69; 95% CI, 0.52-0.92; p = 0.01). Additionally, the ABCC4 (rs9561778) wild-type also showed low risk with gastrointestinal toxicity (RR, 0.50; 95% CI, 0.28-0.88; p = 0.02). Our findings confirm that the polymorphisms of CYP2C19*2, GSTT1, GSTP1 (rs1695), and ABCC4 (rs9561778) play an important role in predicting the risk of hematological, gastrointestinal, and other toxicities in patients undergoing CTX treatment.

PMID:40667789 | DOI:10.1111/cts.70301

Future Sci OA. 2025 Dec;11(1):2528490. doi: 10.1080/20565623.2025.2528490. Epub 2025 Jul 16.

ABSTRACT

Epilepsy, a prevalent neurological disorder, is characterized by recurring seizures due to atypical neural activity, impacting millions globally. Epileptic seizures are the sudden, involuntary jerking or trembling movements caused by abnormal neural activity and may lead to damage in the brain or other parts of the body. Although epilepsy is usually manageable with anti-seizure medications (ASMs), a considerable subset of patients experiences drug resistance or suboptimal treatment responses, highlighting the need for a more elaborate approach to therapy. Studies show that genetic factors significantly influence not only the susceptibility to epilepsy but also the variability in individual responses to ASMs. This signifies the importance of personalized medicine in optimizing treatment guidelines based on genetic profiles. This review examines the pharmacogenetic factors influencing the efficacy and safety of anti-ASMs in Arab populations. In populations across Saudi Arabia, Jordan, Egypt, Tunisia, and Iraq, genetic testing for variants in genes like MTHFR, MDR1, ABCB1, miR-146a, GABARG2, IL-1β, EPHX1, and CYP3A422 can predict drug resistance, and response, improve drug dosing, and minimize ADRs. Clinicians can personalize therapy by employing specific genetic markers associated with drug metabolism and efficacy, leading to better treatment outcomes and reduced risk of drug-induced complications.

PMID:40667778 | DOI:10.1080/20565623.2025.2528490

Front Pharmacol. 2025 Jul 1;16:1649258. doi: 10.3389/fphar.2025.1649258. eCollection 2025.

NO ABSTRACT

PMID:40667512 | PMC:PMC12259549 | DOI:10.3389/fphar.2025.1649258

bioRxiv [Preprint]. 2025 Jun 21:2025.06.17.660113. doi: 10.1101/2025.06.17.660113.

ABSTRACT

Here we present a new iPSC resource of apparently healthy subject biospecimens available to the research community through the National Institute of General Medical Sciences Human Genetic Cell Repository (NIGMS Repository). This resource includes five iPSCs and matched parental cell lines with accompanying publicly available, HiFi whole-genome sequencing data. Structural variant (SV) and single nucleotide variant (SNV) concordance between iPSC and parental lines was generally high; however, we found a notable reduction in concordance between the iPSC reprogrammed with retroviral reprogramming and its parental line consistent with previous work showing newer Sendai approaches to be more robust in preserving genomic integrity. This iPSC resource additionally includes pharmacogenomic and human leukocyte antigen (HLA) gene annotations as well as a set of user-friendly, web-based search tools to visualize and explore SVs and SNVs. This new resource is designed to offer a highly characterized set of in vitro models for research into cell-type specific functional characterization of genetic, genomic and pharmacogenomic variation. More generally, these renewable biospecimens and genomic data search tools are available to the scientific community to support high-quality and reproducible biomedical research.

PMID:40667225 | PMC:PMC12262493 | DOI:10.1101/2025.06.17.660113

Pharmacogenomics J. 2025 Jul 15;25(4):21. doi: 10.1038/s41397-025-00381-2.

NO ABSTRACT

PMID:40664657 | DOI:10.1038/s41397-025-00381-2

Per Med. 2025 Jul 15:1-7. doi: 10.1080/17410541.2025.2531734. Online ahead of print.

ABSTRACT

BACKGROUND: Pharmacogenomics (PGx) examines how genetic variations influence individual responses to medications, enabling more precise drug and dose selection. Drug labeling communicates PGx information to healthcare providers. However, in many countries, including Jordan, PGx integration into clinical practice remains limited.

OBJECTIVE: This study aimed to evaluate the availability of PGx labeling in medications approved by the Jordan Food and Drug Administration (JFDA). It also compared PGx labeling in Jordan with that in drug labels from the United States and Hungary.

METHODS: A manual review of drug leaflets was conducted using the JFDA online database between July and September 2024. Drugs were categorized based on the presence or absence of PGx information. Data were then compared with the U.S. FDA's PGx Biomarker Table and the Hungarian National Institute of Pharmacy's SmPCs.

RESULTS: Among 75 reviewed JFDA-approved drugs, only 15 (20%) included complete PGx information. Neurology (50%), psychiatry (26.7%), and oncology (25%) had the highest representation, while cardiology (10%) and urology (0%) were underrepresented. Compared to the USA and Hungary, PGx labeling in Jordan was markedly limited.

CONCLUSION: The findings show a significant gap in PGx labeling in Jordan, emphasizing the need for regulatory updates to support personalized medicine.

PMID:40662687 | DOI:10.1080/17410541.2025.2531734

Curr Neuropharmacol. 2025 Jul 14. doi: 10.2174/011570159X353727250314065140. Online ahead of print.

ABSTRACT

The review focuses on the ways that ontologies are revolutionising precision medicine in their effort to understand neurodegenerative illnesses. Ontologies, which are structured frameworks that outline the relationships between concepts in a certain field, offer a crucial foundation for combining different biological data. Novel insights into the construction of a precision medicine approach to treat neurodegenerative diseases (NDDs) are given by growing advancements in the area of pharmacogenomics. Affected parts of the central nervous system may develop neurological disorders, including Alzheimer's, Parkinson's, autism spectrum, and attention-deficit/hyperactivity disorder. These models allow for standard and helpful data marking, which is needed for crossdisciplinary study and teamwork. With case studies, you can see how ontologies have been used to find biomarkers, understand how sicknesses work, and make models for predicting how drugs will work and how the disease will get worse. For example, problems with data quality, meaning variety, and the need for constant changes to reflect the growing body of scientific knowledge are discussed in this review. It also looks at how semantic data can be mixed with cutting-edge computer methods such as artificial intelligence and machine learning to make brain disease diagnostic and prediction models more exact and accurate. These collaborative networks aim to identify patients at risk, identify patients in the preclinical or early stages of illness, and develop tailored preventative interventions to enhance patient quality of life and prognosis. They also seek to identify new, robust, and effective methods for these patient identification tasks. To this end, the current study has been considered to examine the essential components that may be part of precise and tailored therapy plans used for neurodegenerative illnesses.

PMID:40662545 | DOI:10.2174/011570159X353727250314065140

J Clin Invest. 2025 Jul 15;135(14):e194434. doi: 10.1172/JCI194434. eCollection 2025 Jul 15.

ABSTRACT

Purine nucleotides are critical for nucleic acid synthesis, signaling, and cellular metabolism. Thiopurines (TPs), including 6-mercaptopurine and 6-thioguanine, are cornerstone agents for the treatment of acute lymphoblastic leukemia (ALL). TP efficacy and cytotoxicity depend on the metabolism and intracellular activation of TPs, a process influenced by pharmacogenes such as thiopurine-S methyltransferase (TPMT) and NUDIX (nucleoside diphosphates linked to moiety-X) hydrolase 15 (NUDT15). In this issue of the JCI, Maillard et al. identified NUDT5 as a determinant of TP pharmacology. They demonstrated that loss of NUDT5 conferred TP resistance by impairing drug activation and DNA damage responses. Metabolomics studies by Maillard and others revealed that NUDT5 may regulate the balance between the de novo purine synthesis and salvage pathways. Clinically, NUDT5 expression variants were associated with altered TP tolerance. These findings position NUDT5 as a key modulator of nucleotide metabolism and TP efficacy, with potential implications for pharmacogenomics-guided therapy optimization in ALL.

PMID:40662363 | DOI:10.1172/JCI194434

J Clin Invest. 2025 Jul 15;135(14):e190443. doi: 10.1172/JCI190443. eCollection 2025 Jul 15.

ABSTRACT

Thiopurines are anticancer agents used for the treatment of leukemia and autoimmune diseases. These purine analogs are characterized by a narrow therapeutic index because of the risk of myelosuppression. With the discovery of NUDIX hydrolase 15 (NUDT15) as a major modulator of thiopurine metabolism and toxicity, we sought to comprehensively examine all members of the NUDIX hydrolase family for their effect on the pharmacologic effects of thiopurine. By performing a NUDIX-targeted CRISPR/Cas9 screen in leukemia cells, we identified NUDT5, whose depletion led to drastic thiopurine resistance. NUDT5 deficiency resulted in a nearly complete depletion of active metabolites of thiopurine and the loss of thioguanine incorporation into DNA. Mechanistically, NUDT5 deletion resulted in substantial alteration in purine nucleotide biosynthesis, as determined by steady-state metabolomics profiling. Stable isotope tracing demonstrated that the loss of NUDT5 was linked to a marked suppression of the purine salvage pathway but with minimal effects on purine de novo synthesis. Finally, we comprehensively identified germline genetic variants in NUDT5 associated with thiopurine-induced myelosuppression in 582 children with acute lymphoblastic leukemia. Collectively, these results pointed to NUDT5 as a key regulator of the thiopurine response primarily through its effects on purine homeostasis, highlighting its potential to inform individualized thiopurine therapy.

PMID:40662362 | DOI:10.1172/JCI190443

Genet Med. 2025 Jul 12:101529. doi: 10.1016/j.gim.2025.101529. Online ahead of print.

ABSTRACT

PURPOSE: Pharmacogenomics (PGx) is a critical component of precision healthcare that aims to improve drug efficacy and reduce adverse events. Terminologies and standards have not always aligned between PGx and broader genomic medicine communities, which is a barrier to PGx implementation. An updated assessment of community barriers, needs, and perspectives is critical to enable more standardized terminologies and interpretation frameworks.

METHODS: The Clinical Genome Resource's (ClinGen) PGx Interpretation Committee (PGxIC, formerly referred to as the PGx Working Group, PGxWG) conducted two surveys targeting the PGx and genomic medicine communities (n=508) to evaluate perspectives on PGx clinical validity and actionability frameworks, as well as other barriers to PGx implementation. Surveys were tailored toward self-reported familiarity with PGx. Data primarily consisted of free text, which was analyzed using qualitative content analysis methods.

RESULTS: Survey responses indicated conflation of terminology across disciplines including confusion around differing definitions of terms in PGx and non-PGx contexts. Data also indicated broad support for leveraging existing PGx guidelines and framework structures alongside the standardization of approaches and centralization of resources.

CONCLUSION: These novel survey results demonstrate broad consensus on the importance of integrating PGx into clinical practice, including support for development of gene-drug response clinical validity and actionability frameworks aligned with ClinGen frameworks for gene-disease relationships.

PMID:40662343 | DOI:10.1016/j.gim.2025.101529

Schizophr Bull. 2025 Jul 14:sbaf076. doi: 10.1093/schbul/sbaf076. Online ahead of print.

ABSTRACT

BACKGROUND: The antipsychotic aripiprazole is mainly metabolized by the cytochrome P450 (CYP) 2D6. The main objective of this study was to evaluate the influence of CYP2D6 phenotypes on aripiprazole plasma levels and treatment duration.

DESIGN: 466 patients treated with aripiprazole for up to 12 months and with at least one aripiprazole plasma level in steady-state condition were selected. CYP2D6 genotypes and phenoconversion to poor metabolizer status due to strong CYP2D6 inhibition were considered. Aripiprazole plasma level-to-dose ratios and treatment duration up to discontinuation, defined as switching to another psychotropic drug and/or stopping the follow-up, were analyzed using robust linear models and Cox regression, respectively. Akaike variable selection was applied.

RESULTS: CYP2D6 poor metabolizers (genetically determined n = 19 and phenoconverted, n = 52) showed higher aripiprazole concentration-to-dose (P < .001) and aripiprazole plus dehydroaripiprazole concentration-to-dose (P < .001) ratios when compared to normal metabolizers (n = 255). CYP2D6 extreme metabolizers (ie, poor and ultrarapid metabolizers) had higher risk of treatment discontinuation versus intermediate and normal metabolizers after 3, 6, and 12 months of treatment (HR: 2.08, 1.75, 1.59, respectively; P = .013, P = .019, and P = .047, respectively). For a pharmacogenetic-guided treatment, the number of patients needed to genotype to prevent 1 patient from aripiprazole discontinuation was 15.

CONCLUSION: CYP2D6 poor metabolism was associated with increased aripiprazole and aripiprazole plus dehydroaripiprazole concentrations-to-dose. CYP2D6 extreme phenotypes were associated with increased risk of treatment discontinuation over 1 year of treatment. This finding supports the applicability of pre-emptive CYP2D6 genotyping, which is expected to decrease aripiprazole adverse events and inefficacy that would probably lead to treatment discontinuation.

PMID:40662264 | DOI:10.1093/schbul/sbaf076

J Obes. 2025 Jun 30;2025:5530467. doi: 10.1155/jobe/5530467. eCollection 2025.

ABSTRACT

Calcium signaling contributes to obesity and its related disorders, such as diabetes. We herein investigated the effects of calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitors on diet-induced obesity in mice. In mice fed a high-fat diet (HFD), the administration of the CaMKII inhibitor KN-93 and the glycolipid acremomannolipin A with the suppression of CaMKII phosphorylation reduced fat mass in the whole body, epididymal and subcutaneous white adipose tissue weights, and lipid accumulation in epididymal and subcutaneous white adipose tissues, but not muscle mass or bone mineral density at the tibia. Moreover, the administration of KN-93 and acremomannolipin A improved glucose intolerance in HFD-fed mice. In an in vitro study on preadipocytic 3T3-L1 cells and mouse adipose tissue-derived stromal cells, KN-93 and acremomannolipin A suppressed adipogenic differentiation, proliferation, and lipid accumulation. In conclusion, this is the first study to demonstrate that CaMKII inhibitors mitigated the development of diet-induced obesity in mice partly through the suppression of adipogenic differentiation, cell proliferation, and lipid accumulation in adipocytes. Inhibiting CaMKII could be a potential strategy for obesity treatment.

PMID:40662171 | PMC:PMC12259312 | DOI:10.1155/jobe/5530467

Cureus. 2025 Jun 14;17(6):e85992. doi: 10.7759/cureus.85992. eCollection 2025 Jun.

ABSTRACT

As the global population ages, polypharmacy-the concurrent use of multiple medications-has become increasingly common among older adults with multiple chronic conditions. While often clinically necessary, polypharmacy is associated with significant challenges, including medication nonadherence, adverse drug events, and increased hospitalizations. This narrative review synthesizes current evidence to explore the burden of polypharmacy, identify barriers to safe medication use, and assess intervention strategies aimed at improving outcomes in older adults. Drawing from diverse sources including clinical trials, observational studies, and policy reports, this review highlights the multifaceted nature of medication management in older adults. Contributing factors to nonadherence include cognitive decline, regimen complexity, low health literacy, and fragmented care. Interventions such as pharmacist-led medication reviews, deprescribing initiatives, motivational interviewing, and digital health tools have demonstrated potential in improving adherence and therapeutic safety. Emerging approaches-including pharmacogenomic-guided prescribing and AI-driven clinical decision support-also offer promising avenues for personalized care. A comprehensive, multidisciplinary framework that incorporates patient-centered communication, integrated care models, and supportive policy infrastructure is essential for addressing the complexities of polypharmacy in older populations. Continued research and collaboration across healthcare disciplines will be critical to translating these strategies into routine practice and enhancing medication safety for this vulnerable demographic.

PMID:40662024 | PMC:PMC12257869 | DOI:10.7759/cureus.85992

Front Endocrinol (Lausanne). 2025 Jun 30;16:1536402. doi: 10.3389/fendo.2025.1536402. eCollection 2025.

ABSTRACT

PURPOSE: Metformin efficacy and tolerance vary at equivalent dose in type 2 diabetes. Inter-individual variability in the response to metformin with approximately 35% of patients failing to achieve initial glycemic control may be explained by genetic polymorphisms that affect the drug's pharmacokinetics and pharmacodynamics. Differences in the frequencies of pharmacogenomic risk alleles associated with metformin response may also account for interethnic variability in drug effects. The aim of this study was to assess the impact of M420del, R61c, and G401S polymorphisms in the SLC22A1 gene which encodes the organic cation transporter (OCT1) on metformin response and tolerance in a cohort of Tunisian patients with type 2 diabetes.

METHODS: This prospective study included 73 newly diagnosed type 2 diabetic patients. Clinical and biological assessments were conducted before and three months after initiation of metformin therapy. Patients were genotyped for the M420del, R61c, and G401S polymorphism of SLC22A1 using Polymerase Chain Reaction (PCR) followed by Restriction Fragment Length Polymorphism (RFLP) analysis. Metformin efficacy was defined as an HbA1c reduction of ≥ 1% and metformin- induced gastrointestinal adverse effects were recorded using a questionnaire.

RESULTS: Thirty-nine patients (53%) were classified as responders to metformin. The M420del, R61C and G401S variants were not significantly associated with metformin efficacy (p: 0.8, p: 0.77, and p: 0.49 respectively). Twenty-seven patients (37%) experienced gastrointestinal adverse effects following metformin initiation. The G401S polymorphism and the haplotype (NoDel) CA were significantly associated with gastrointestinal adverse effects.

CONCLUSION: In Tunisian type 2 diabetes, the M420del and R61C do not appear to be associated with metformin efficacy or the gastrointestinal intolerance. However, the G401S polymorphism may be implicated in the occurrence of metformine-induced gastrointestinal adverse effects.

PMID:40661743 | PMC:PMC12257032 | DOI:10.3389/fendo.2025.1536402

Hum Genomics. 2025 Jul 14;19(1):82. doi: 10.1186/s40246-025-00786-x.

ABSTRACT

Personalized Medicine has the potential to transform modern healthcare by tailoring medical decisions to an individual's unique genomic profile. However, its integration into routine clinical practice is hindered by limited genomics education among healthcare professionals and a general lack of public awareness. To address these challenges, we introduce the BioSTEM initiative, an innovative educational tool designed for primary, elementary, and high school students. BioSTEM combines optimized online learning modules with interactive audiovisual content, fostering direct communication between students and educators. It also integrates alternative learning strategies, such as online games and comics, to enhance engagement with topics in Biology, Molecular Biology, Genetics, and Personalized Medicine. Since 2016, BioSTEM has reached over 6,000 students across three countries through a combination of theoretical instruction and hands-on experiments using a portable molecular biology laboratory. Our results indicate that participation in BioSTEM significantly improved students' and educators' perception of their understanding of concepts in Genetics and Personalized Medicine. Participants reported a stronger grasp of genomic concepts and expressed support for incorporating BioSTEM into the standard biology curriculum. These findings suggest that BioSTEM is a promising and scalable approach to advancing biomedical education and fostering the development of genomic-literate citizens.

PMID:40660411 | DOI:10.1186/s40246-025-00786-x

Cancer Chemother Pharmacol. 2025 Jul 15;95(1):75. doi: 10.1007/s00280-025-04787-4.

ABSTRACT

PURPOSE: The impact of the unrecognized mutational dihydropyrimidine-dehydrogenase-gene-(DPYD)-status on high-grade CTC-AE-grades ≥ 3 (NCI-Common Terminology Criteria for Adverse Events, vs. 3.0) was assessed in patients with upper rectal cancer (inferior tumor margin ≥ 12 cm above the anal verge) treated with upfront surgery and 5-Fluorouracil (5-FU) based adjuvant chemotherapy (CTx).

METHODS: 75 participants of the GAST-05-phase-IIb-trial (ISRCTN35198481) were tested in this single center analysis for DPYD*2A-wildtype (WT) at staging. After surgery, 43 patients (stages II and III, according to the current 8th TNM/UICC-classification, 2017) received FOLFOX-CTx and entered follow-up (median: 101 months). According to recent recommendations of the European Medicines Agency (EMA) and national guidelines, post-hoc genotyping for DPYD*2A (c.1905 + 1G > A; IVS14 + 1G > A; rs3918290), DPYD*13 (c.1679T > G; rs55886062), polymorphism c.2846 A > T (rs67376798) and Haplotype B3 (HapB3) (c.1236G > A; c.1129-5923 C > G) was performed using cryopreserved blood samples and standardized PCR-techniques.

RESULTS: Five patients were found to have a heterozygous (het_) DPYD-HapB3-status. Across all patients, the adherence to CTx-cycles 1 to 4 was 100%, 97.7%, 95.3%, and 93.0%, respectively. Grade ≥ 3 CTC-AEs were observed in 0.9% of both het_HapB3- and WT-patients. The mean administered dose of 5-FU was 68.8% of the target in DPYD-HapB3 carriers, compared to 92.6% in 38 WT patients. Logistic regression analysis revealed that 5-FU dose reductions were significantly associated with DPYD-HapB3 carrier status (odds ratio [OR] 12.55, p = 0.044) and male sex (OR 0.23, p = 0.049). During follow-up het_HapB3-patients had a recurrence rate of 60.0%, compared to 13,6% for WT-patients. The disease-free survival (DFS) for het_HapB3-patients was significantly reduced vs. WT (p = 0.010). Multivariable analysis showed that het_HapB3-patients had an increased risk for reduced DFS (HR 3.774; p = 0.057). Interestingly, 5-FU dose reductions per se were not significantly associated with limited DFS in the total population.

CONCLUSION: DPYD genotyping revealed a het_HapB3 variant in 11.6% of DPYD*2A-WT patients treated with FOLFOX. While not linked to increased toxicity, HapB3 status was associated with reduced DFS, suggesting an impact on treatment efficacy. These results support DPYD genotyping and highlight the need for adequate 5-FU plasma level assessment followed by subtile dose escalation (therapeutic drug monitoring) to personalize 5-FU dosing more precisely, safely and most effective.

PMID:40659880 | DOI:10.1007/s00280-025-04787-4

Sci Rep. 2025 Jul 14;15(1):25367. doi: 10.1038/s41598-025-08653-4.

ABSTRACT

The process of drug discovery is intricate, and encompasses a series of detailed phases of research, development, and testing, aimed at evaluating the safety and effectiveness of prospective therapeutic agents. Artificial Intelligence has emerged as a transformative tool in this domain, adept at analysing vast datasets to uncover intricate patterns and relationships unperceivable to humans. This study introduces a bioactivity prediction application employing the Quantitative Structure-Activity Relationship model to forecast bioactivity against Angiotensin II receptor, a major drug target in hypertension management. Angiotensin II receptor modulation holds promise for treating a spectrum of diseases, including hypertension, cardiovascular ailments, and renal disorders. Through AI-driven approaches researchers in the field of drug discovery are able to effectively identify a majority of promising drug candidates, expediting the lead optimization process while reducing costs. This paradigm shift not only accelerates therapeutic development but also minimizes the need for exhaustive in vitro or in vivo testing, thus enhancing the efficiency of drug discovery endeavours.

PMID:40659675 | DOI:10.1038/s41598-025-08653-4

Transl Clin Pharmacol. 2025 Jun;33(2):51-65. doi: 10.12793/tcp.2025.33.e9. Epub 2025 Jun 27.

ABSTRACT

Tuberculosis (TB) remains one of the leading causes of infectious disease-related deaths worldwide. Model-informed precision dosing-based therapeutic drug monitoring (TDM) is a promising strategy to optimize anti-TB drugs doses based on pharmacokinetic (PK) profiles of patients. However, this approach requires significant time and trained personnel to interpret the results. To address this limitation, we developed and utilized an automated, web-based TDM platform that simplifies implementation and enhances accessibility, ultimately aiming to improve treatment outcomes. The system incorporates population PK models for both first- and second-line anti-TB drugs, integrating clinical data including demographics, NAT2 genotype and drug concentrations from limited sampling strategies. Bayesian forecasting is used to estimate individual PK parameters and simulate optimized dosing regimens. Clinicians can use the platform to automatically generate the individual concentration-time curve plot that compares a patient's exposure with population level references, along with a table displaying the estimated individual PK parameters. If the dose adjustment is needed, users may input alternative regimens and run the simulation to predict the corresponding PK metrics. These features enable users to visualize predicted outcomes, compare exposures against therapeutic targets, and support optimal dose selection. The system produces downloadable reports containing patient specific data, PK parameter values, graphical PK profiles, and pharmacogenomic interpretations with minimal user input. This automated web-based platform enhances the time-efficiency and accessibility of TDM, making it a practical tool for personalized TB therapy. It is especially valuable in resource-limited settings where expert support is limited, by supporting clinical decision making and improving patient outcomes.

PMID:40657439 | PMC:PMC12242390 | DOI:10.12793/tcp.2025.33.e9

J Cancer. 2025 Jun 23;16(9):2903-2916. doi: 10.7150/jca.114801. eCollection 2025.

ABSTRACT

Different subtypes of breast cancer pose great challenges for precision therapy, especially triple-negative breast cancer (TNBC), because it lacks effective therapeutic targets and is highly resistant to chemotherapy. In this study, the transmembrane protein ITM2A was systematically identified as a novel prognostic biomarker and potential therapeutic target for TNBC. ITM2A was found to be significantly under expressed in TNBC tissues, as revealed by differential expression profiling. Furthermore, patients exhibiting low ITM2A expression demonstrated worse overall survival (OS), recurrence-free survival (RFS), and distant metastasis-free survival (DMFS). A combined multi-omics analysis revealed a significant association between low ITM2A expression and immunosuppressive microenvironmental features. It is noteworthy that the ITM2A high-expression group exhibited substantial clinical benefits in anti-PD-L1 treatment (AUC=0.982) and CAR-T treatment (AUC=0.827). Gene Ontology functional annotation and KEGG pathway enrichment analysis indicated that ITM2A may coordinate anti-tumor immune responses by regulating copper ion metabolic reprogramming and immune checkpoint networks. Pharmacogenomic analysis further confirmed that the expression level of ITM2A was negatively correlated with the sensitivity of etoposide. By establishing the 'immunometabolism-therapeutic response' regulatory axis of ITM2A, this study hopes to provide an innovative theoretical basis for the targeted treatment of TNBC and the precise stratification of immunotherapy.

PMID:40657365 | PMC:PMC12244017 | DOI:10.7150/jca.114801