J Clin Med. 2025 Mar 21;14(7):2142. doi: 10.3390/jcm14072142.

ABSTRACT

Background/Objectives: Polymorbidity and polypharmacy are major challenges in geriatric care, resulting in a reduced quality of life and increased health care costs. Methods: We evaluated the proactive medication management of nursing home residents through personal visits and the use of a clinical decision support system (CDSS) with an integrated Beers Criteria list. Results: Among 56 nursing home residents, we observed a high prevalence of polypharmacy with an average of 7.9 regular and 5.1 on-demand prescriptions. Proactive medication management led to persistent medication changes in 87.5% of patients. Regular prescriptions were reduced in 21 residents and increased in 18 residents, resulting in a reduced use of cardiovascular drugs and antacids (p < 0.05), but no significant overall reduction in polypharmacy. CDSS alerts based on Beers Criteria made no clinically relevant contribution to medication reduction. Conclusions: Proactive geriatric medication management led to persistent medication changes and no reduction in overall polypharmacy but reduced the use of selected drug classes that are associated with an increased risk of adverse reactions and costs. The clinical relevance and implementability of Beers Criteria were low, revealing major limitations of algorithm-based alerts for older patients, who require additional personalized evaluations of their individual complex healthcare needs.

PMID:40217592 | DOI:10.3390/jcm14072142

Inflammopharmacology. 2025 Apr 12. doi: 10.1007/s10787-025-01725-x. Online ahead of print.

NO ABSTRACT

PMID:40216663 | DOI:10.1007/s10787-025-01725-x

OMICS. 2025 Apr 11. doi: 10.1089/omi.2024.0199. Online ahead of print.

ABSTRACT

Anophthalmia is the most severe ocular malformation inherited in an autosomal, X-linked, recessive, or dominant form. We report here the use of whole exome sequencing (WES) to help the clinical diagnosis of familial anophthalmia in Harare, Zimbabwe. A mother presented her two sons, who are half-brothers, at the Eye, Ear, Nose, and Throat Institute, Ophthalmology Unit in Harare, Zimbabwe. Upon clinical examination, half-brothers were diagnosed with clinical bilateral anophthalmia. The mother requested a genetic diagnosis for her two sons. To segregate the phenotype with genotype, whole blood was collected from two half-brothers, their mother, maternal aunt, and maternal uncle to the half-brothers, and an unrelated healthy control. Genetic characterization was done, first, through a candidate gene approach screening of putative genes SOX2, OTX2, VSX2, PAX6, and RAX. When no causative variants were identified, the next step employed WES. Variants in 80 genes associated with anophthalmia were prioritized and subjected to pathogenicity testing. One pathogenic variant, BCOR c.254C>T (rs121434618, p. Pro85Leu), segregated with the mother and her two sons. The present clinical genomics study of a family and a healthy control sample underscores WES as a valuable tool that can help clinical diagnosis of anophthalmia in the Zimbabwean clinical setting. In this article, we also offer a reasoned discussion and call from the field, to fund clinical genomics and omics research and development in planetary health, especially in the current era of uncertainties in international aid and funding of innovative technologies. The findings reported herein encourage further research on the clinical utility of WES as a diagnostic tool in Africa and around the world as well, given that the candidate gene approach might miss the important genes or variants of relevance to disease pathophysiology.

PMID:40216558 | DOI:10.1089/omi.2024.0199

BMJ Health Care Inform. 2025 Apr 10;32(1):e101163. doi: 10.1136/bmjhci-2024-101163.

ABSTRACT

STUDY OBJECTIVES: Describe the implementation of an interoperable solution to support pharmacogenomic-guided prescribing in primary care in the National Health Service, England.

METHODS: We used an iterative approach to software development going through clinical workflow mapping, architecture design and development, and pilot-testing.

RESULTS: We configured a commercial health data management platform to store pharmacogenomic results in a structured format and created a knowledge base of pharmacogenomic guidance. This solution was deployed 'as-a-service' using an open application programming interface (API) specification, allowing third parties to receive pharmacogenomic results and guidance by querying the service using a patient identifier and medicine code. This was integrated with existing clinical decision support tools and presented contextual information to prescribers within their native electronic health record (EHR).

DISCUSSION: Pharmacogenomic results and guidance will be used across care settings and have greatest utility at the point of prescribing. This requires a solution, which separates the data from the applications, allowing integration with different EHRs through APIs.

CONCLUSIONS: A vendor-agnostic standards-based solution can support the implementation of pharmacogenomic-guided prescribing across primary care.

PMID:40216452 | DOI:10.1136/bmjhci-2024-101163

Toxicol Appl Pharmacol. 2025 Apr 9:117341. doi: 10.1016/j.taap.2025.117341. Online ahead of print.

ABSTRACT

Amiodarone is an effective therapy for arrhythmias, its prolonged management may lead to significant adverse drug reactions. Amiodarone-induced hepatotoxicity is described by phospholipidosis, hepatic steatosis, cholestatic hepatitis, and cirrhosis. However, the systemic and hepatic lipidome disturbances and underlying toxicological mechanisms remain comprehensively elucidated. Untargeted lipidomics were utilized to analyze serum and liver samples from the rats orally administered a daily dose of amiodarone of either 100 or 300 mg/kg for one week. Changes in the expression of hepatic lipid-related genes were also examined utilizing transcriptomics. We found a higher magnitude of lipidome alterations in the 300 mg/kg than those in the 100 mg/kg groups. Treated animals showed elevated abundances of phosphatidylcholines, ether-linked phosphatidylcholines, sphingomyelins, and ceramides, and decreased levels of triacylglycerols, ether-linked triacylglycerols, and fatty acids. We also found 199 lipid-related differentially expressed hepatic genes between the 300 mg/kg group versus controls, implying lipid metabolism and signaling pathways disturbances. Specifically, elevation of serum phosphatidylcholines and ether-linked phosphatidylcholines, as well as hepatic bismonoacylglycerophosphates were associated with reduced expression of phospholipase genes and elevated expression of glycerophospholipid biosynthesis genes, possibly driving phospholipidosis. Perturbations of sphingolipid metabolism might also be the key events for amiodarone-induced toxicity. Alterations in gene expression levels related to lipid storage and metabolism, mitochondria functions, and energy homeostasis were also found. Collectively, our study characterized the sophisticated perturbations in the lipidome and transcriptome of amiodarone-treated rats and suggested potential mechanisms responsible for amiodarone-induced hepatotoxicity.

PMID:40216313 | DOI:10.1016/j.taap.2025.117341

Vet J. 2025 Apr 9:106347. doi: 10.1016/j.tvjl.2025.106347. Online ahead of print.

ABSTRACT

Multimodal analgesic administration is a promising strategy for mitigating side effects typically associated with analgesia; nevertheless, variation in analgesic effectiveness still poses a considerable safety concern for both horses and veterinarians. Pharmacogenomic studies have started delving into genetic influences on varying drug effectiveness and related side effects. However, current findings have narrow implications and are limited in their ability to individualize analgesic dosages in horses. Hydromorphone and detomidine were administered to a cohort of 48 horses at standardized time intervals, with dosage rates recorded. Analgesic effectiveness was scored (1-3) based on pain response to dura penetration during cerebrospinal fluid centesis. Genome-wide association (GWA) analyses identified two SNVs passing the nominal significance threshold (P<1×10-5) in association with analgesic effectiveness. One SNV identified on chromosome 27 (rs1142378599) is contained within the LOC100630731 disintegrin and metalloproteinase domain-containing protein 5 gene. The second identified SNV is an intergenic variant located on chromosome 29 (rs3430772468) These SNVs accounted for 26.11% and 31.72% of explained variation in analgesic effectiveness respectively, with all eight of the horses with the lowest analgesic effectiveness expressing the A/C genotype at rs3430772468, with six of which also expressing the C/T genotype at rs1142872965. Whilst highlighting the multifactorial nature of analgesic efficacy, this study serves as an important step in the application of genome-wide approaches to better understand genetic factors underpinning commonly observed variation in analgesic effectiveness in horses, with the goal of tailoring analgesic dosage to minimize commonly observed side effects and improve the outcomes of equine pain management.

PMID:40216012 | DOI:10.1016/j.tvjl.2025.106347

Biomed Pharmacother. 2025 Apr 10;186:118040. doi: 10.1016/j.biopha.2025.118040. Online ahead of print.

ABSTRACT

Human fibroblast-like synoviocytes (HFLS) are the predominant cellular component of the joint synovium. Their inflammation, known as synovitis, may contribute to the development of osteoarthritis (OA). HFLS secrete signaling factors that regulate joint function in response to mechanical trauma or OA progression. Among these factors, prostaglandin E2 (PGE2) is a key pro-inflammatory mediator, whereas prostamides, such as prostamide E2 (PME2), are synthesized from anandamide (AEA) by the same enzymes that produce PGE2. HFLS were isolated from both control subjects and OA patients (HFLS-OA) and stimulated with lipopolysaccharide (LPS, 10 ng/mL). Liquid chromatography-tandem mass spectrometry (LC-MS) was used to analyze PGE2 and PME2 secretion. Additionally, transcriptome and miRNA sequencing were conducted to identify changes in gene expression between HFLS and HFLS-OA cells. Five endocannabinoid-related genes were further validated by qPCR. Baseline PGE2 secretion differed between HFLS and HFLS-OA, with OA-related cells showing increased levels, while control cells primarily produced PME2. Upon pro-inflammatory stimulation, both cell types secreted PGE2. Changes in endocannabinoid levels and expression of endocannabinoid-related genes were observed in HFLS-OA following stimulation. miRNA sequencing revealed significant differences in miRNA expression between HFLS and HFLS-OA. Notably, HFLS-OA exhibited upregulation of Diacylglycerol lipase B (DAGLB) and downregulation of Fatty Acid-Binding Protein 4 and 5 (FABP4 and FABP5) gene expression compared to controls. The study suggests a reorganization of the endocannabinoid system in HFLS from OA patients, leading to altered cellular responses to pro-inflammatory stimuli. The molecular changes observed may drive or regulate the inflammatory response in OA synoviocytes, highlighting potential therapeutic targets. These findings provide insights into the potential mechanisms underlying OA pathogenesis and support the hypothesis of altered endocannabinoid system reactivity in HFLS in the context of inflammation.

PMID:40215649 | DOI:10.1016/j.biopha.2025.118040

JCO Glob Oncol. 2025 Apr;11:e2400608. doi: 10.1200/GO-24-00608. Epub 2025 Apr 11.

ABSTRACT

Latin America's cultural diversity, political instability, and socioeconomic inequality contribute to fragmented health systems, hindering high-quality care and health equity. Financial limitations in health care exacerbate these issues, affecting care quality and research capacity. In cancer research, such barriers result in inconsistent data, limiting the creation of evidence-based strategies and slowing progress in understanding disease and treatment outcomes. Collaborative academic groups have become essential in overcoming these obstacles. By promoting multidisciplinary cooperation, these groups enhance research, covering areas such as epidemiology, molecular studies, and pharmacogenomics, while also bridging gaps in health care education and infrastructure. Partnerships with various actors provide critical funding and training, supporting sustainable research infrastructure. This review underscores the role of academic collaborations in advancing cancer research and health care delivery in Latin America, fostering innovation and equity. Developing and sustaining these networks will be key to addressing ongoing public health challenges in the region.

PMID:40215435 | DOI:10.1200/GO-24-00608

PLoS One. 2025 Apr 11;20(4):e0319042. doi: 10.1371/journal.pone.0319042. eCollection 2025.

ABSTRACT

BACKGROUND AND OBJECTIVES: Pharmacogenomics (PGx) leverages genomic information to tailor drug therapies, enhancing precision medicine. Despite global advancements, its implementation in Lebanon, Qatar, and Saudi Arabia faces unique challenges in clinical integration. This study aimed to investigate PGx attitudes, knowledge implementation, associated challenges, forecast future educational needs, and compare findings across the three countries.

METHODS: This cross-sectional study utilized an anonymous, self-administered online survey distributed to healthcare professionals, academics, and clinicians in Lebanon, Qatar, and Saudi Arabia. The survey comprised 18 questions to assess participants' familiarity with PGx, current implementation practices, perceived obstacles, potential integration strategies, and future educational needs.

RESULTS: The survey yielded 337 responses from healthcare professionals across the three countries. Data revealed significant variations in PGx familiarity and educational involvement. Qatar and Saudi Arabia participants were more familiar with PGx compared to Lebanon (83%, 75%, and 67%, respectively). Participation in PGx-related talks was most prevalent in Saudi Arabia (96%), followed by Qatar (53%) and Lebanon (35%). Key challenges identified included test cost and reimbursement, insufficient physician knowledge, and lack of infrastructure. Lebanon reported the highest concern for test costs (16%), compared to the lowest in Saudi Arabia (5%). Despite these challenges, a strong consensus emerged on PGx's potential to improve patient outcomes, with over 86% of respondents in all three countries expressing this belief. Educational interest areas varied by country, with strong interest in PGx for cancer chemotherapy in Saudi Arabia and Lebanon and for diabetes mellitus in Qatar.

CONCLUSION: This study highlights the significant influence of varied educational backgrounds and infrastructural limitations on PGx implementation across Lebanon, Qatar, and Saudi Arabia. The findings emphasize the need for targeted strategies in each country to address these distinct barriers. Integrating PGx education into healthcare training programs and clinical workflows could unlock PGx's potential to optimize patient care.

PMID:40215419 | DOI:10.1371/journal.pone.0319042

Clin Transl Oncol. 2025 Apr 11. doi: 10.1007/s12094-025-03908-y. Online ahead of print.

ABSTRACT

PURPOSE: CYP2D6 is a key enzyme involved in converting tamoxifen into its active metabolites. However, polymorphisms in CYP2D6 lead to variable enzymatic capacities. We aimed to examine the impact of CYP2D6 polymorphisms on tamoxifen-derived side effects in breast cancer patients.

METHODS: Eighty-six patients with hormone receptor-positive breast cancer who received tamoxifen were classified as poor (PM), intermediate (IM), normal (NM), or ultrarapid (UM) metabolizers according to Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. All patients received 20 mg/day tamoxifen for 5 years, except PM, who were dose-escalated (20 mg/day for 4 months, 40 mg/day for 4 months, 60 mg/day for 4 months, then back to 20 mg/day). Adverse events-osteoarticular pain, hot flashes, asthenia, and uterine changes-were analyzed by Kaplan-Meier and Cox regression. A propensity score-matched (PSM) subgroup was also examined.

RESULTS: Rapid metabolizers (RM: NM + UM) consistently showed fewer uterine changes compared to slow metabolizers (SM: PM + IM) in both the entire cohort (HR 0.20, p = 0.001) and the PSM subgroup (HR 0.07, p = 0.011). Excluding PM and UM, comparison of IM vs. NM showed similar differences (complete group: HR 0.20, p = 0.002; PSM subgroup: HR 0.23, p = 0.068). Other side effects (joint pain, hot flashes, asthenia) were not significantly associated with CYP2D6 phenotype.

CONCLUSION: Uterine alterations in breast cancer patients treated with tamoxifen appear linked to decreased CYP2D6 activity, although we observed no association between CYP2D6 and other toxicities. These findings suggest closer monitoring for uterine toxicity in individuals with impaired CYP2D6 metabolism.

PMID:40214721 | DOI:10.1007/s12094-025-03908-y

Diabetes Care. 2025 Apr 11:dc250160. doi: 10.2337/dc25-0160. Online ahead of print.

ABSTRACT

OBJECTIVE: Bariatric surgery is an effective treatment option for individuals with obesity and type 2 diabetes (T2D). However, whether outcomes in subtypes of individuals at risk for T2D and/or comorbidities (Tübingen Clusters) differ, is unknown. Of these, cluster 5 (C5) and cluster 6 (C6) are high-risk clusters for developing T2D and/or comorbidities, while cluster 4 (C4) is a low-risk cluster. We investigated bariatric surgery outcomes, hypothesizing that high-risk clusters benefit most due to great potential for metabolic improvement.

RESEARCH DESIGN AND METHODS: We allocated participants without T2D but at risk for T2D, defined by elevated BMI, to the Tübingen Clusters. Participants had normal glucose regulation or prediabetes according to American Diabetes Association criteria. Two cohorts underwent bariatric surgery: a discovery (Lille, France) and a replication cohort (Rome, Italy). A control cohort (Tübingen, Germany) received behavioral modification counseling. Main outcomes included alteration of glucose regulation parameters and prediabetes remission.

RESULTS: In the discovery cohort, 15.0% of participants (n = 121) were allocated to C4, 22.3% (n = 180) to C5, and 62.4% (n = 503) to C6. Relative body weight loss was similar among all clusters; however, reduction of insulin resistance and improvement of β-cell function were strongest in C5. Prediabetes remission rate was lowest in low-risk C4 and highest in high-risk C5. Individuals from high-risk clusters changed to low-risk clusters in both bariatric surgery cohorts but not in the control cohort.

CONCLUSIONS: Participants in C5 had the highest benefit from bariatric surgery in terms of improvement in insulin resistance, β-cell function, and prediabetes remission. This novel classification might help identify individuals who will benefit specifically from bariatric surgery.

PMID:40214701 | DOI:10.2337/dc25-0160

Intern Med J. 2025 Apr 11. doi: 10.1111/imj.16576. Online ahead of print.

ABSTRACT

BACKGROUND: Implementing pharmacogenomic-guided management in cancer patients equitably and effectively in a large population presents challenges. DPYD genotyping determines clinically significant variants of patients at increased risk of developing grade3-5 fluoropyrimidine (FP) toxicity. FP chemotherapies are prescribed for ~16,000 Australians with a 10%-40% grade3-4 toxicity incidence and 1% mortality. Variant carriers can have FP dosing adjusted to improve treatment tolerance without compromising anticancer effect. This strategy has not been formally adopted within Australia, despite widespread international standardisation.

AIM: This pilot study determined genotyping turnaround-times (TAT) for 4 DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T and c.1236G>A/Haplotype B3) in Australian patients. Secondary objectives were identification of FP toxicities of DPYD variant carriers, and analysis of healthcare stakeholder perspectives, including enablers/barriers to implementation.

METHODS: Genotyping was determined by Real-Time Polymerase Chain Reaction. Qualitative data were determined through semi-structured questionnaire.

RESULTS: 104 patients recruited over 24 months had a mean TAT of 7.2 days, 5.2 business days (range 1-30). Grade3-4 toxicity occurred in 9/16 DPYD variant carriers, including 2 ICU admissions and 1 death. Themes from 30 questionnaire respondents suggest that clinical environment and resources were fundamental barriers, and motivation to improve patient care was the predominant enabler of change.

CONCLUSION: DPYD genotyping is feasible for improving precision-oncology for patients requiring FP chemotherapies. A TAT of 7 days is acceptable by both stakeholder respondents and national oncology clinician groups. This pilot study, although small, informs a large national project evaluating prospective DPYD genotyping and its impact on FP tolerability, patient safety and cost-effectiveness in Australia.

PMID:40214188 | DOI:10.1111/imj.16576

Front Psychiatry. 2025 Mar 27;16:1542000. doi: 10.3389/fpsyt.2025.1542000. eCollection 2025.

ABSTRACT

BACKGROUND: Although several guidelines provide dosing recommendations for antidepressants based on patients' genetic information, pharmacogenetic testing for antidepressant use is rarely routinely performed in Japan. To clarify the clinical impact of pharmacogenetic testing, this study estimated the potential drug-gene interactions for first-time antidepressant treatment in Japanese patients with major depressive disorder.

METHODS: This study retrospectively included Japanese patients who were registered for depressive episodes (F32, International Classification of Diseases, Tenth Revision) and initiated on antidepressants between July 2022 and March 2023. Antidepressant prescription rates were calculated using a nationwide hospital-based database (Medical Data Vision Co., Ltd). The incidence of actionable drug-gene interactions was estimated by multiplying the first-time prescription rate of each relevant antidepressant by the frequency of its corresponding actionable phenotype.

RESULTS: A total of 3,197 patients were included in the analysis. Escitalopram was the most frequently prescribed antidepressant (18.7%, n = 597), followed by mirtazapine (17.5%, n = 561), and sertraline (15.4%, n = 493). Of the patients receiving their first treatment of major depressive disorder, 56.5% (n = 1,807) were prescribed a drug with actionable pharmacogenetic implications, and 26.4% (n = 844) were estimated to have required actionable therapeutic recommendations. The highest incidence of actionable drug-gene interactions was observed in escitalopram and CYP2C19 pairs (12.4%, n = 398). For sertraline and CYP2C19 or CYP2B6 pairs, the incidence was 11.0% (n = 352). Among all antidepressants, paroxetine had the highest incidence of actionable drug-gene interactions related to CYP2D6 at 1.8% (n = 56); this interaction was rarely observed with other antidepressants (<1%).

CONCLUSIONS: We estimated that one in four Japanese patients with major depressive disorder who were prescribed first-time antidepressants had actionable drug-gene interactions. These results suggest that pre-emptive pharmacogenetic testing in the treatment of major depressive disorder could have important clinical implications.

PMID:40212835 | PMC:PMC11983551 | DOI:10.3389/fpsyt.2025.1542000

Pharmacogenomics. 2025 Apr 11:1-13. doi: 10.1080/14622416.2025.2490461. Online ahead of print.

ABSTRACT

As an emerging health technology, pharmacogenetic (PGx) testing has the capacity to improve medication therapy. However, implementation in medically underserved populations (MUPs) remains limited, which has the potential to increase healthcare disparities. While there is no single accepted definition for MUPs, demographic, socioeconomic, cultural, and geographic factors can lead to reduced access to healthcare, which contributes to disparate health outcomes in these populations. In the case of PGx testing, as MUPs have an increased risk of adverse drug events, have lower numbers of healthcare encounters, and are prescribed more medications which can be guided by PGx testing, additional benefits from PGx testing may occur in MUPs. Study of the acceptability and perceptions of PGx testing in MUPs, as reported in literature, provides support for the development of successful PGx testing implementations. Additionally, a few limited pilot PGx testing implementations in MUPs have assessed feasibility. However, further studies establishing the feasibility and effectiveness of PGx testing implementations in MUPs will enable more widespread PGx testing in those who are medically underserved. Thus, this narrative review explores the impact of medical underservice on health, PGx testing's potential impact on MUPs, and the research and early clinical implementations of PGx in MUPs.

PMID:40211878 | DOI:10.1080/14622416.2025.2490461

Pharmacogenomics. 2025 Apr 10:1-14. doi: 10.1080/14622416.2025.2490464. Online ahead of print.

ABSTRACT

Systemic lupus erythematosus (SLE) is a complex autoimmune disease requiring immunosuppressive medications to control symptoms and prevent organ damage. This review explores the influence of genetic polymorphisms on the pharmacokinetics and therapeutic responses of immunosuppressants in SLE. A total of 37 studies were reviewed, focusing on mycophenolic acid, tacrolimus, azathioprine, glucocorticoids, and cyclophosphamide. Genetic variants in UGT1A9, UGT2B7, CYP3A5, ABCB1,ABCC2 and TPMT significantly affect drug metabolism, efficacy, and toxicity. For instance, ABCB1 polymorphisms influence drug transport and bioavailability, impacting tacrolimus and glucocorticoid response, while ABCC2 variants alter MPA clearance, potentially affecting therapeutic outcomes, UGT1A9 and UGT2B7 variants influence mycophenolic acid metabolism, CYP3A5 impacts tacrolimus dosing, TPMT determines azathioprine metabolism, and CYP2C19 and CYP2B6 affect cyclophosphamide processing. These genetic differences can alter treatment effectiveness and risk of adverse effects. However, most pharmacogenetic studies focus on organ transplantation, leaving a critical gap in SLE-specific research, particularly among diverse populations. Addressing this gap is essential to optimizing personalized treatment for SLE. Integrating pharmacogenetics into clinical practice holds great potential to enhance the safety, efficacy, and outcomes of immunosuppressive therapy in SLE. This review highlights the urgent need for further studies to advance precision medicine for SLE patients.

PMID:40208755 | DOI:10.1080/14622416.2025.2490464

J Med Syst. 2025 Apr 10;49(1):47. doi: 10.1007/s10916-025-02182-3.

ABSTRACT

Drug response prediction (DRP) is a central task in the era of precision medicine. Over the past decade, the emergence of deep learning (DL) has greatly contributed to addressing DRP challenges. Notably, the prediction of DRP for cancer cell lines benefits significantly from data availability for model development. However, an effective predictive model is still challenging due to issues with data quality, high-dimensional data, and multi-omics data integration. In this study, we introduce MLG2Net, a deep-learning model inspired by graph neural networks designed to predict DRP in lung cancer cell lines based on pharmacogenomics data. Our model comprises two key components: drug SMILES described by local and global graph networks and cell line genomics are illustrated as a map. Our results show that MLG2Net outperforms three reference graph networks. MLG2Net performance reached a Pearson coefficient correlation ( C C p ) of 0.8616 and a root mean square error (RMSE) of 2.94e-6 in predicting drug responses for Lung Adenocarcinoma (LUAD) cell lines. Subsequent testing on the Lung Squamous Cell Carcinoma (LUSC) dataset reveals lower performance ( C C p : 0.7999, RMSE: 4.08e-6), attributed to the dataset's smaller size influencing model capacity. Moreover, we assessed the model's architecture by isolating its components, with results indicating that the global network is particularly effective in this task. In conclusion, MLG2Net exhibited promising applications in DRP for cancer cell lines, with potential advancements by incorporating larger datasets.

PMID:40208442 | DOI:10.1007/s10916-025-02182-3

Med J Aust. 2025 Apr 10. doi: 10.5694/mja2.52650. Online ahead of print.

ABSTRACT

Paediatric cancer is the leading cause of disease-related death in Australian children. Limited research focuses on cancer in Aboriginal and Torres Strait Islander children. Although there appears to be a lower incidence of cancer overall in Aboriginal and Torres Strait Islander children compared with non-Indigenous children, a high proportion of Aboriginal and Torres Strait Islander children are diagnosed with acute myeloid leukaemia. Five-year overall survival is lower for many cancer types in Aboriginal and Torres Strait Islander children. There is a need for Indigenous-specific research focused on molecular and genetic profiles, pharmacogenomics and survivorship, both within Australia and globally. Future research in this space should be co-designed and led by Aboriginal and Torres Strait Islander communities; alongside clinicians, researchers and services to ensure that the priorities of Aboriginal and Torres Strait Islander people are met.

PMID:40207417 | DOI:10.5694/mja2.52650

Mol Ther Oncol. 2025 Mar 8;33(2):200965. doi: 10.1016/j.omton.2025.200965. eCollection 2025 Jun 18.

ABSTRACT

Breast cancer patients with estrogen receptor-negative (ERneg) status, encompassing triple negative breast cancer (TNBC) and human epidermal growth factor receptor 2 positive breast cancer, are confronted with a heightened risk of drug resistance, often leading to early recurrence; the biomarkers and biological processes associated with recurrence is still unclear. In this study, we analyzed bulk RNA sequencing (RNA-seq) data from 285 cancer and paracancerous samples from 155 TNBC patients, along with transcriptome data from 11 independent public cohorts comprising 7,449 breast cancer patients and 26 single-cell RNA-seq datasets. Our results revealed differential enrichment of nerve-related pathways between TNBC patients with and without 10-year recurrence-free survival. We developed an early recurrence index (ERI) using a machine learning model and constructed a nomogram that accurately predicts the 10-year survival of ERneg patients (area under the curve [AUC]Training = 0.79; AUCTest = 0.796). Further analysis linked ERI to enhanced neural function and immunosuppression. Additionally, we identified EN1, the most significant ERI gene, as a potential biomarker that may regulate the tumor microenvironment and sensitize patients to immunotherapy.

PMID:40207200 | PMC:PMC11981748 | DOI:10.1016/j.omton.2025.200965

Front Pharmacol. 2025 Mar 26;16:1558897. doi: 10.3389/fphar.2025.1558897. eCollection 2025.

ABSTRACT

BACKGROUND: Despite the emergence of numerous innovative targeted therapies for the management of pediatric inflammatory bowel disease (IBD), azathioprine continues to be a pivotal first-line therapeutic agent. Nonetheless, the considerable frequency of myelosuppression associated with its use warrants careful consideration and further investigation. This study aims to investigate the application of pharmacogenomics in Chinese pediatric IBD treated with azathioprine, and to elucidate its association with the occurrence of myelosuppression.

METHODS: We conducted a retrospective analysis to determine the prevalence of pharmacogenetic abnormalities and thiopurine-induced myelosuppression in Chinese pediatric patients with IBD.

RESULTS: Among the 227 patients underwent pharmacogenetic testing, abnormal genetypes occurred in 66 patients, among which 7 patients exhibited aberrant TPMT and 59 had aberrant NUDT15. Of the 58 patients who were treated with azathioprine, 23 cases experienced myelosuppression. All three children with heterozygous mutations in NUDT15 developed leukopenia following azathioprine treatment. Among patients with normal pharmacogenetic results, 20 cases (36.4%) developed myelosuppression, while 35 cases (63.6%) did not. The dose of azathioprine was below the recommended level in guidelines. The mean dose of azathioprine (mg/kg/day) in the myelosuppression group was 1.22 ± 0.32, compared to 1.42 ± 0.42 in the non-myelosuppression group, which represented a statistically significant difference (p < 0.05). Age, gender, and the use of concomitant biologics, mesalazine, or glucocorticoids did not show significant differences between the groups (p > 0.05).

CONCLUSION: NUDT15 C415T is prevalent in China and is associated with an increased risk of azathioprine-induced myelosuppression. A reduced dose of azathioprine should be considered for Chinese pediatric patients with IBD, even in those with normal pharmacogenetic profiles.

PMID:40206080 | PMC:PMC11979209 | DOI:10.3389/fphar.2025.1558897

Front Pharmacol. 2025 Mar 26;16:1590955. doi: 10.3389/fphar.2025.1590955. eCollection 2025.

ABSTRACT

[This corrects the article DOI: 10.3389/fphar.2024.1526101.].

PMID:40206068 | PMC:PMC11979611 | DOI:10.3389/fphar.2025.1590955