Cephalalgia. 2024 Nov;44(11):3331024241299453. doi: 10.1177/03331024241299453.

ABSTRACT

BACKGROUND: Migraine with aura (MwA) is a debilitating disorder characterized by paroxysmal attacks of pain preceded or accompanied by reversible neurological symptoms. While the pathophysiology remains unclear, trigeminovascular system activation and cortical spreading depression have been implicated. This study aims to comprehensively investigate and characterize the diverse clinical features and manifestations of aura, as well as the types of acute medications self-administered for aura management.

METHODS: A multicenter, cross-sectional study was conducted using data from the Italian Headache Registry (RICe). Aura characteristics, frequency, duration and associated migraine premonitory symptoms were collected. Acute medication use and timing (headache or aura phase) were assessed.

RESULTS: The study included 272 patients with a diagnosis of MwA. Most patients (99.3%) experienced typical aura symptoms, with visual aura (96.3%) being the most prevalent, followed by sensory (33.0%) and speech and/or language aura (25.6%). Brainstem aura (8.5%) and motor aura (1.8%) were less common. Notably, 13.0% of patients reported aura relapses within 24 hours. Triptans (39.7%), non-steroidal anti-inflammatory drugs (47.8%) and nutraceuticals (59.9%) were commonly used for acute aura management.

CONCLUSIONS: This study reports several different aura manifestations, highlighting atypical features, aura relapse rates and treatment approaches for aura. These findings could contribute to a deeper understanding of aura and its management in clinical settings.

PMID:39587967 | DOI:10.1177/03331024241299453

Pharmacotherapy. 2024 Nov 26. doi: 10.1002/phar.4631. Online ahead of print.

ABSTRACT

INTRODUCTION: Thiopurine drugs are metabolized by thiopurine methyltransferase (TPMT) and low TPMT activity can result in severe adverse drug reactions. Therefore, TPMT testing is recommended for individuals receiving thiopurines to reduce the risk of toxicity.

OBJECTIVES: The objectives of this study were to assess the rate of TPMT testing among individuals receiving thiopurines and explore factors associated with undergoing TPMT testing in Australia.

METHODS: This retrospective cohort study utilized administrative data from the Pharmaceutical Benefits Scheme (PBS), Medicare Benefits Schedule (MBS), and the 2021 Census, accessed via the Person Level Integrated Data Asset (PLIDA) at the Australian Bureau of Statistics (ABS) DataLab. Individuals receiving thiopurines aged 18 years or above were identified using PBS data and exposure to TPMT testing was determined using MBS data. Multivariate logistic regression was performed to identify factors associated with TPMT testing.

RESULTS: A total of 62,574 prevalent thiopurine users were identified between 2020 and 2022. Of these, 20,327 (32.5%) underwent TPMT testing (2011-2022). The most significant factor associated with TPMT testing was having at least one thiopurine medication prescribed by a medical specialist (adjusted odds ratio [aOR] 2.12, 95% confidence interval [CI] 2.02-2.22), compared to having medication solely prescribed by primary care physicians (PCPs). Other significant factors associated with TPMT testing included speaking a non-English language at home (aOR 1.29, 95% CI 1.22-1.36), having no chronic health conditions (aOR 1.18, 95% CI 1.13-1.24), not requiring assistance with core activities (aOR 1.16, 95% CI 1.08-1.23), and having a higher educational attainment (aOR 1.11, 95% CI 1.06-1.11). Compared to living in major cities, individuals living in remote areas were significantly less likely to undergo testing (aOR 0.49, 95% CI 0.39-0.60).

CONCLUSION: Our study highlights the low utilization of TPMT testing in Australia and suggests the need for targeted interventions to address disparities and improve TPMT testing.

PMID:39587965 | DOI:10.1002/phar.4631

Clin Pharmacol Ther. 2024 Nov 25. doi: 10.1002/cpt.3502. Online ahead of print.

ABSTRACT

Mavacamten, the first drug in the class of β-cardiac myosin modulator, is used for the treatment of patients with hypertrophic cardiomyopathy. This orally administered drug demonstrates wide interpatient variability in pharmacokinetics parameters, due in part to variant CYP2C19 alleles. Individuals who are CYP2C19 poor metabolizers have increased exposure and are at increased risk of reduced cardiac hypercontractility. To ensure the safety of all patients, European Medicines Agency recommends CYP2C19 preemptive genotyping, and consecutively, to adapt maintenance and initial mavacamten doses, and to manage drug-drug interactions, according to CYP2C19 phenotype. In this article, we summarize evidence from the literature supporting the association between CYP2C19 phenotype and pharmacological features of mavacamten and provide, beyond biologic guidelines, therapeutic recommendations for the use of mavacamten based on CYP2C19 and CYP3A4/CYP3A5 genotype.

PMID:39584620 | DOI:10.1002/cpt.3502

Front Endocrinol (Lausanne). 2024 Nov 8;15:1445712. doi: 10.3389/fendo.2024.1445712. eCollection 2024.

ABSTRACT

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is one of the world's major public health problems. It is characterized by a major inflammatory response, where vitamin D, due to its role in regulating the immune system, and genetic variants involved in its metabolism may play an essential role. The aim of this study is to evaluate the association between 13 polymorphisms related to vitamin D metabolism and the COPD risk.

MATERIAL AND METHODS: A retrospective longitudinal study was designed in which 152 cases of COPD diagnosed at the University Hospital Virgen de las Nieves and 456 controls without the pathology, matched by age and sex, were included. The determination of the 13 polymorphisms was carried out using TaqMan™ probes.

RESULTS: Statistical analysis showed that the AA genotype and the A allele of the CYP27B1 rs4646536 polymorphism may be associated with an increased risk of developing COPD according to genotypic models (OR = 2. 6; 95% CI = 1.38-5.22; p = 0.004), dominant (OR = 1.69; 95% CI = 1.15-2.5; p = 0.008), recessive (OR = 2.24; 95% CI = 1.22-4.41; p = 0.013) and additive (OR = 1.56; 95% CI = 1.18-2.08; p = 0.020) models. Likewise, the AA genotype and the A allele of the CYP2R1 rs10741657 polymorphism were also associated with the risk of developing COPD according to the genotypic (OR = 1.9; 95% CI = 1.06-3.36; p = 0.028) and additive (OR = 1.37; 95% CI = 1.04-1.81; p = 0.027) models. Likewise, an association was found between GATG (p = 0.002; OR = 2.05; 95%CI = 1.32-3.20) and AGGT (p < 0.0001; OR = 2.1e46; 95%CI = 2.1e46-2.1e46) haplotypes and an increased risk of COPD.

CONCLUSIONS: We can therefore conclude that those variants could be used in the early detection of the disease in the future.

PMID:39583968 | PMC:PMC11581940 | DOI:10.3389/fendo.2024.1445712

Cureus. 2024 Oct 25;16(10):e72348. doi: 10.7759/cureus.72348. eCollection 2024 Oct.

ABSTRACT

Background Madhumega Chooranam (MMC), a traditional Siddha polyherbal formulation, is used for diabetes management. Understanding its pharmacokinetics is crucial for evaluating its efficacy and safety in clinical practice. This study aimed to assess the pharmacokinetics of gallic acid, a key component of MMC. Methodology Ten healthy volunteers were selected based on their willingness to participate and the absence of significant clinical conditions, including liver, kidney, heart, peripheral nerve disorders, or allergies. During the screening phase, participants with abnormal laboratory results in blood chemistry, hematology, or urine analysis were excluded. All participants provided written informed consent before the initiation of the study. Participants were administered a single oral dose of 6 g of MMC. Blood samples were collected at predetermined intervals over 24 hours to estimate gallic acid content used as a pharmacokinetic marker. Results Gallic acid concentration peaked in some participants' plasma samples at varying intervals post-administration, indicating individual differences in absorption and metabolism. In contrast, no gallic acid peaks were detected in the plasma samples of three participants, suggesting potential variability in metabolic response or rapid clearance. Conclusions The study's findings underscore the complexity of MMC's pharmacokinetics, influenced by individual metabolic and genetic factors. Additionally, this research highlights the need for an interdisciplinary approach, integrating traditional medicine with modern pharmacogenomics and gut microbiota studies, to fully understand Siddha formulations' pharmacokinetics and therapeutic potential. Future studies should focus on larger sample sizes and consider genetic and dietary factors to enhance the understanding of MMC's efficacy and safety in diverse populations.

PMID:39583368 | PMC:PMC11585863 | DOI:10.7759/cureus.72348

IDCases. 2024 Oct 31;38:e02105. doi: 10.1016/j.idcr.2024.e02105. eCollection 2024.

ABSTRACT

Oritavancin is a novel long-acting lipoglycopeptide with in vitro activity against methicillin-resistant (MR) Gram-positive pathogens and a good bactericidal activity even in presence of biofilm forming bacteria. It has been approved for acute bacterial skin and skin structure infections (ABSSSI), but recent reports have demonstrated possible off-label uses, as for prosthetic joint infections (PJI), which, in more than half of cases, are caused by MR Gram positive organisms. We reported a case of a man in his eighties with a late shoulder PJI caused by methicillin resistant Staphyloccus epidermidis (MRSE) with contraindications for surgical replacement and few oral therapeutic options for a long term suppressive antibiotic therapy. The prosthesis was retained, and the patient received ten outpatient sequential doses of 1200 mg of oritavancin for 28 weeks, based on therapeutic drug monitoring (TDM) as a guide for correct timing of administration of each dose. During oritavancin administration, the patient achieved clinical cure, with disappearance of the pain and regaining pre-infection joint mobility, with no side effects reported and no further surgery or hospitalization needed. The treatment is ongoing as a long-lasting suppressive antimicrobial therapy. Oritavancin could represent an excellent solution for treating PJI caused by MR organism, especially in patients who need a long-term suppressive therapy.

PMID:39582750 | PMC:PMC11584596 | DOI:10.1016/j.idcr.2024.e02105

J Am Coll Clin Pharm. 2024 Jun;7(6):581-588. doi: 10.1002/jac5.1958. Epub 2024 May 8.

ABSTRACT

Pharmacogenomics is a growing area of medicine, and pharmacists across clinical practice settings have the opportunity to individualize medication selection and dosing using genetic data. However, many practicing pharmacists may feel ill-equipped to interpret pharmacogenomic test results because of insufficient education and training. Evidence-based, updated, and freely available resources such as the Clinical Pharmacogenetics Implementation Consortium guidelines can help pharmacists interpret and apply pharmacogenomic test results to patient care. Although gaps for the application of pharmacogenomic information exist, this commentary aims to demystify the interpretation of pharmacogenomic test results and empower pharmacists to apply genetic data alongside other clinical variables to optimize medication-related outcomes for their patients. An "ABCD" framework is proposed to guide pharmacists through the steps: (1) Actionability - Are the gene(s) clinically relevant for the patient? (2) Be Mindful of Limitations - What are the caveats with pharmacogenomic test results and reports? (3) Clinical Practice Guidelines - How do you use pharmacogenomic test results to guide clinical decision-making? and (4) Document and Discuss - How do you educate the patient about their pharmacogenomic test results and document the results for future use? Key concepts are illustrated using a psychiatric patient case example.

PMID:39582510 | PMC:PMC11583779 | DOI:10.1002/jac5.1958

Psychol Med. 2024 Nov 25:1. doi: 10.1017/S0033291724002095. Online ahead of print.

NO ABSTRACT

PMID:39582390 | DOI:10.1017/S0033291724002095

Crit Rev Oncol Hematol. 2024 Nov 22:104574. doi: 10.1016/j.critrevonc.2024.104574. Online ahead of print.

ABSTRACT

BRAF p.V600E exon 15 hotspot mutation can identify a molecular subgroup of metastatic colorectal cancer (mCRC) patients exhibiting poor prognosis under the conventional chemotherapy regimen. Recently, the chemotherapy-free combination of encorafenib and cetuximab has been approved as the standard of care for previously treated BRAF p.V600E mCRC patients, and genomic testing for BRAF mutations at the time of mCRC diagnosis is currently recommended. In clinical practice, BRAF mutation testing strategies are dramatically impacted by a lack of harmonization and standardization, both in the pre-analytical and analytical phases, which can result in BRAF-mutated patients not receiving the most appropriate therapy at recurrence. This paper proposes nine statements providing practical and concise advice on BRAF mutation testing in CRC, derived from collegial discussion and analysis of a multidisciplinary team of experts, including referral Italian oncologists and pathologists. The statements overview pivotal aspects implied in the detection, treatment and management of BRAF-mutated patients and have been drafted to represent a valuable tool for healthcare professionals committed to mCRC patient management. In addition, they represent a platform for implementing diagnostic-therapeutic workflows that can adapt to the variability of local resources while respecting the high-quality standards required by modern precision oncology.

PMID:39581242 | DOI:10.1016/j.critrevonc.2024.104574

Pharmacogenomics J. 2024 Nov 23;24(6):39. doi: 10.1038/s41397-024-00358-7.

ABSTRACT

Thiopurine drugs are cornerstone treatment for patients with inflammatory bowel disease (IBD). The most common adverse drug reaction is thiopurine-induced myelosuppression (TIM), that may partly be explained by the genetic polymorphism NUDT15*3. The aim of this retrospective study was to determine the NUDT15*3 polymorphism frequency and its association with TIM in an IBD patient population in the Netherlands. DNA from patients previously genotyped for TPMT was genotyped for NUDT15*3. In IBD patients treated with thiopurines association tests with TIM were conducted. Out of 988 included patients, 13 (1.3%) were heterozygous for NUDT15*3. Of all patients, 606 had IBD and received thiopurine treatment. In these patients, 8/606 (1.3%) were heterozygous polymorphic for NUDT15*3 of which 50.0% developed TIM compared to 2.3% in the wild type patients (p < 0.001). The study results show a clinically relevant prevalence of NUDT15*3 in the Dutch patient population. Its strong association with TIM suggests pre-therapeutic genotyping potentially clinically utile.

PMID:39580429 | DOI:10.1038/s41397-024-00358-7

Semin Arthritis Rheum. 2024 Nov 7:152579. doi: 10.1016/j.semarthrit.2024.152579. Online ahead of print.

NO ABSTRACT

PMID:39580340 | DOI:10.1016/j.semarthrit.2024.152579

Pharmacogenomics J. 2024 Nov 22;24(6):38. doi: 10.1038/s41397-024-00351-0.

ABSTRACT

Late-life depression (LLD) is often accompanied by medical comorbidities such as psychiatric disorders and cardiovascular diseases, posing challenges to antidepressant treatment. Recent studies highlighted significant associations between treatment-resistant depression (TRD) and polygenic risk score (PRS) for attention deficit hyperactivity disorder (ADHD) in adults as well as a negative association between antidepressant symptom improvement with both schizophrenia and bipolar. Here, we sought to validate these findings with symptom remission in LLD. We analyzed the Incomplete Response in Late Life Depression: Getting to Remission (IRL-GRey) sample consisting of adults aged 60+ with major depression (N = 342) treated with venlafaxine for 12 weeks. We constructed PRSs for ADHD, depression, schizophrenia, bipolar disorder, neuroticism, general intelligence, antidepressant symptom remission and antidepressant percentage symptom improvement using summary statistics from the Psychiatric Genomics Consortium and the GWAS Catalog. Logistic regression was used to test the association of PRSs with venlafaxine symptom remission and percentage symptom improvement, co-varying for the genomic principal components, age, sex and depressive symptoms severity at baseline. We found a nominal (i.e., p value ≤ 0.05) association between symptom remission and both PRS for ADHD and (OR = 1.36 [1.07, 1.73], p = 0.011) and PRS for bipolar disorder (OR = 0.75 [0.58, 0.97], p = 0.031), as well as between percentage symptom improvement and PRS for general intelligence (beta = 6.81 (SE = 3.122), p = 0.03). However, the ADHD association was in the opposite direction as expected, and both associations did not survive multiple testing corrections. Altogether, these findings suggest that previous findings regarding ADHD PRS and antidepressant response (measured with various outcomes) do not replicate in older adults.

PMID:39578436 | DOI:10.1038/s41397-024-00351-0

Pharmacogenomics J. 2024 Nov 22;24(6):37. doi: 10.1038/s41397-024-00359-6.

ABSTRACT

Venetoclax (VEN) was the only Bcl-2 inhibitor approved yet and showed large differences in clinical efficacy. The aim of the study was to explore the relationships between the plasma concentration and efficacy of VEN, and identify potential influencing factors. A retrospective cohort study was conducted and a total of 76 trough (C0h) and 91 6 h post-dose plasma concentration (C6h) blood concentrations of VEN were collected in 54 patients. C6h/D concentration of VEN was found to be significantly correlated with treatment efficacy (p = 0.006) in leukemia patients with good or intermediate prognosis stratification. A ROC curve was then established and the cut-off value was calculated as 0.2868 μg/ml (AUC = 0.7097, p = 0.1081). Besides, patients co-administered with triazoles or carrying CYP3A5 rs776746 AA/AG genotypes were prone to induce higher VEN plasma concentration regardless of whether VEN dosage was reduced or not. Through LASSO-logistic regression and nomogram analysis, chemotherapy regimens and neutrophil percentages were identified as the critical elements that may predict drug response. Above all, in addition to identify prognostic stratification, AML patients taken with VEN were suggested to test plasma concentration routinely so as to achieve desired efficacy, especially when co-administered with triazoles or carried with CYP3A5 rs776746 AA/AG.

PMID:39578425 | DOI:10.1038/s41397-024-00359-6

Arch Pathol Lab Med. 2024 Nov 22. doi: 10.5858/arpa.2024-0207-CP. Online ahead of print.

ABSTRACT

CONTEXT.—: Genomic reports are primarily organized in a narrative and unstructured format with variations in content and format. Regulatory requirements and professional guidelines for genetic test reporting exist but provide little guidance for effective communication of information.

OBJECTIVE.—: To assess clinical genomic reporting practices across 5 disciplines within molecular diagnostics, including germline, somatic solid tumors, somatic hematologic malignancies, pharmacogenomics, and prenatal cell-free DNA screening.

DESIGN.—: Reporting practices were assessed by using a structured review of clinical genomic reports from multiple laboratories in 5 molecular disciplines spanning different practice settings. Report content was reviewed by the presence/absence of from 27 to 44 elements, including 23 elements required by the College of American Pathologists and/or the Clinical Laboratory Improvement Amendments of 1988 (CLIA). If present, the element's location on the report was recorded.

RESULTS.—: A total of 69 genomics reports from 31 laboratories were reviewed. Overall, the reports were compliant with regulatory requirements but showed variability in both format and content. Six of 7 required reporting elements (per CLIA, 42 CFR [Code of Federal Regulations] 493.1291) were included in 90% of the reports. However, these elements were often located in different report sections. Only patient demographics were always found in a specific report section (header).

CONCLUSIONS.—: These results show that reports are overall compliant with regulatory requirements, despite some reporting elements being less consistently reported. The lack of consistent presentation of the data elements presents an opportunity to improve the communication of molecular testing results to clinicians and patients.

PMID:39576195 | DOI:10.5858/arpa.2024-0207-CP

Future Sci OA. 2024 Dec;10(1):2428077. doi: 10.1080/20565623.2024.2428077. Epub 2024 Nov 22.

ABSTRACT

BACKGROUND: Single-nucleotide polymorphisms (SNPs) in enzyme-coding genes play a role in susceptibility to anti-cancer therapy.

MATERIALS & METHODS: A prospective study was performed of the relationship between enzyme activity and treatment response, drug toxicity and hypersensitivity reactions in 51 patients with colorectal cancer treated with fluoropyrimidine-based chemotherapy. SNP analysis was performed in 22 enzyme-coding genes with a previously described role in treatment efficacy.

RESULTS: SLC6 and MTHR enzyme activity was related with rates of progressive disease, GSTP1 activity with anti-EGFR antibodies-related skin toxicity, CYP3A5 and MTHR with chemotherapy dose reduction, CYP2B6, IL10, MTHR and TYMS activity with the risk of drug hypersensitivity reactions.

CONCLUSION: Pharmacogenetics is a valuable predictive marker in oncology, related to chemotherapy treatment response, toxicity and hypersensitivity.

PMID:39576003 | DOI:10.1080/20565623.2024.2428077

Stud Health Technol Inform. 2024 Nov 22;321:240-244. doi: 10.3233/SHTI241100.

ABSTRACT

Pharmacogenetics (PGx) explores the influence of genetic variability on drug efficacy and tolerability. Synthetic Data Generation (SDG) has emerged as a promising alternative to the labor-intensive process of collecting real-world PGx data, which is required for high-qualitative prediction models. This study investigates the performance of two Generative Adversarial Network (GAN) models, CTGAN and CTAB-GAN+, in generating synthetic PGx data. The benchmarking is based on utility metrics (Hellinger distance and Random Forest accuracy) and ϵ-identifiability. Results demonstrate that synthetic data generated by CTAB-GAN+ can surpass the original dataset in terms of utility. For instance, CTAB-GAN+ achieves higher Random Forest accuracy compared to the original data, indicating better predictive performance. These improvements suggest that synthetic data not only capture the essential patterns of the original data but also enhance model generalization and prediction capabilities, providing a more robust training ground for machine learning models. Consequently, SDG offers a promising solution to address data scarcity and imbalance in pharmacogenetic research.

PMID:39575816 | DOI:10.3233/SHTI241100

BMC Cancer. 2024 Nov 21;24(1):1435. doi: 10.1186/s12885-024-13173-x.

ABSTRACT

BACKGROUND: Exosome small RNAs are believed to be involved in the pathogenesis of cancer, but their role in breast cancer is still unclear. This study utilized machine learning models to screen for key exosome small RNAs and analyzed and validated them.

METHOD: Peripheral blood samples from breast cancer screening positive and negative people were used for small RNA sequencing of plasma exosomes. The differences in the expression of small RNAs between the two groups were compared. We used machine learning algorithms to analyze small RNAs with significant differences between the two groups, fit the model through training sets, and optimize the model through testing sets. We recruited new research subjects as validation samples and used PCR-based quantitative detection to validate the key small RNAs screened by the machine learning model. Finally, target gene prediction and functional enrichment analysis were performed on these key RNAs.

RESULTS: The machine learning model incorporates six small RNAs: piR-36,340, piR-33,161, miR-484, miR-548ah-5p, miR-4282, and miR-6853-3p. The area under the ROC curve (AUC) of the machine learning model in the training set was 0.985 (95% CI = 0.948-1), while the AUC in the test set was 0.972 (95% CI = 0.882-0.995). RT-qPCR was used to detect the expression levels of these key small RNAs in the validation samples, and the results revealed that their expression levels were significantly different between the two groups (P < 0.05). Through target gene prediction and functional enrichment analysis, it was found that the functions of the target genes were enriched mainly in the chemokine signaling pathway.

CONCLUSION: The combination of six plasma exosome small RNAs has good prognostic value for women with positive breast cancer by imaging screening. The chemokine signaling pathway may be involved in the early stage of breast cancer. It is worth further exploring whether small RNAs mediate chemokine signaling pathways in the pathogenesis of breast cancer through the delivery of exosomes.

PMID:39574053 | DOI:10.1186/s12885-024-13173-x

Med Mycol. 2024 Nov 20:myae113. doi: 10.1093/mmy/myae113. Online ahead of print.

ABSTRACT

Coccidioidomycosis can cause severe meningitis requiring lifelong treatment. In this study, we sought to better understand the potential effect of pharmacogenomic testing on treatment outcomes of patients with coccidioidal meningitis. Of 13 patients with coccidioidal meningitis who underwent pharmacogenomic testing, 11 had genetic variants of CYP2C19 and CYP3A5 that affect antifungal efficacy. These results led to real-time treatment changes and future antifungal planning. Routine pharmacogenomic testing helps to avoid antifungal treatments that are futile or lead to adverse effects.

PMID:39567855 | DOI:10.1093/mmy/myae113

Nat Rev Genet. 2024 Nov 20. doi: 10.1038/s41576-024-00794-y. Online ahead of print.

ABSTRACT

Precision medicine provides patients with access to personally tailored treatments based on individual-level data. However, developing personalized therapies requires analyses with substantial statistical power to map genetic and epidemiologic associations that ultimately create models informing clinical decisions. As one solution, biobanks have emerged as large-scale, longitudinal cohort studies with long-term storage of biological specimens and health information, including electronic health records and participant survey responses. By providing access to individual-level data for genotype-phenotype mapping efforts, pharmacogenomic studies, polygenic risk score assessments and rare variant analyses, biobanks support ongoing and future precision medicine research. Notably, due in part to the geographical enrichment of biobanks in Western Europe and North America, European ancestries have become disproportionately over-represented in precision medicine research. Herein, we provide a genetics-focused review of biobanks from around the world that are in pursuit of supporting precision medicine. We discuss the limitations of their designs, ongoing efforts to diversify genomics research and strategies to maximize the benefits of research leveraging biobanks for all.

PMID:39567741 | DOI:10.1038/s41576-024-00794-y

Comput Biol Med. 2024 Nov 19;184:109415. doi: 10.1016/j.compbiomed.2024.109415. Online ahead of print.

ABSTRACT

Gastric cancer (GC) is a common cancer worldwide. Therefore, searching for effective treatments is essential, and drug repositioning can be a promising strategy to find new potential drugs for GC therapy. For the first time, we sought to identify molecular alterations and validate new mechanisms related to Mebendazole (MBZ) treatment in GC cells through transcriptome analysis using microarray technology. Data revealed 1066 differentially expressed genes (DEGs), of which 345 (2.41 %) genes were upregulated, 721 (5.04 %) genes were downregulated, and 13,231 (92.54 %) genes remained unaltered after MBZ exposure. The overexpressed genes identified were CCL2, IL1A, and CDKN1A. In contrast, the H3C7, H3C11, and H1-5 were the top 3 underexpressed genes. Gene set enrichment analysis (GSEA) identified 8 pathways significantly overexpressed in the treated group (p < 0.05 and FDR<0.25). The validation of the expression of top desregulated genes by RT-qPCR confirmed the transcriptome results, where MBZ increased the CCL2, IL1A, and CDKN1A and reduced the H3C7, H3C11, and H1-5 transcript levels. Expression analysis in samples from TCGA databases correlated that the lower ILI1A and higher H3C11 and H1-5 gene expression are associated with decreased overall survival rates in patients with GC, indicating that MBZ treatment can improve the prognosis of patients. Thus, the data demonstrated that the drug MBZ alters the transcriptome of the AGP-01 lineage, mainly modulating the expression of histone proteins and inflammatory cytokines, indicating a possible epigenetic and immunological effect on tumor cells, these findings highlight new mechanisms of action related to MBZ treatment. Additional studies are still needed to better clarify the epigenetic and immune mechanism of MBZ in the therapy of GC.

PMID:39566281 | DOI:10.1016/j.compbiomed.2024.109415