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

Nucleic Acids Res. 2024 Nov 20:gkae1127. doi: 10.1093/nar/gkae1127. Online ahead of print.

ABSTRACT

Pharmacogenomics, the study of how an individual's genetic makeup influences their response to medications, is a rapidly evolving field with significant implications for personalized medicine. As researchers and healthcare professionals face challenges in exploring the intricate relationships between genetic profiles and therapeutic outcomes, the demand for effective and user-friendly tools to access and analyze genetic data related to drug responses continues to grow. To address these challenges, we have developed PGxDB, an interactive, web-based platform specifically designed for comprehensive pharmacogenomics research. PGxDB enables the analysis across a wide range of genetic and drug response data types - informing cell-based validations and translational treatment strategies. We developed a pipeline that uniquely combines the relationship between medications indexed with Anatomical Therapeutic Chemical (ATC) codes with molecular target profiles with their genetic variability and predicted variant effects. This enables scientists from diverse backgrounds - including molecular scientists and clinicians - to link genetic variability to curated drug response variability and investigate indication or treatment associations in a single resource. With PGxDB, we aim to catalyze innovations in pharmacogenomics research, empower drug discovery, support clinical decision-making, and pave the way for more effective treatment regimens. PGxDB is a freely accessible database available at https://pgx-db.org/.

PMID:39565203 | DOI:10.1093/nar/gkae1127

Pharmacogenomics. 2024 Nov 20:1-12. doi: 10.1080/14622416.2024.2409061. Online ahead of print.

ABSTRACT

Aim: Valproic acid (VPA) is a classic broad-spectrum antiepileptic drug, with significant pharmacokinetic variability. Genetic polymorphisms contribute to this variability, influencing both VPA trough serum concentration (VPA concentration) and VPA-induced liver injury. Our study aims to investigate the association between polymorphisms of uridine diphosphate glucuronyl transferase (UGT) 1A6, UGT2B7 and VPA concentration and screen for potential genetic loci affecting VPA-induced liver injury.Methods: This study included epilepsy patients treated with VPA. PCR-RFLP method was used to determine the genotypes of UGT1A6 and UGT2B7. Chemiluminescent microparticle immunoassay was used to measure VPA concentration. Multiple linear regression and logistic regression were employed to analyze factors influencing VPA concentration and VPA-induced liver injury, respectively.Results: The correlation between UGT polymorphism and VPA concentration was analyzed in 133 samples. For VPA-induced liver injury, 105 patients were analyzed, with 29 in the liver injury group and 76 in the control group. Our finding showed patients with the UGT1A6-T19G variant had significantly lower VPA concentrations compared with wild-type patients and UGT1A6-T19G, A541G, A552C and UGT2B7-C802T, G211T, A268G polymorphisms showed no impact on VPA-induced liver injury.Conclusion: This study demonstrated UGT1A6-T19G polymorphisms affected the VPA concentration, providing a theoretical basis for the individualized clinical use of VPA.

PMID:39564784 | DOI:10.1080/14622416.2024.2409061

Pharmacogenomics. 2024 Nov 20:1-6. doi: 10.1080/14622416.2024.2429946. Online ahead of print.

ABSTRACT

This paper presents a methodology for automatically extracting insights from PubMed articles using a Natural Language Processing (NLP) framework. Our approach, leveraging advanced NLP techniques and Named Entity Recognition (NER), is crucial for advancing pharmacogenomics and other scientific fields that benefit from streamlined access to literature through automated services like RESTful APIs.Building a new NLP model presents several challenges. First, it is essential to have a thorough understanding of the field in order to define relevant entities. Second, the construction of a diverse and consistent set of examples is crucial. Finally, the effective utilization of pre-established models is of paramount importance, as demonstrated in this work.Our model, validated via ten-fold cross-validation, achieved over 70% recall and precision for all entities in the training set. We provide a reproducible pipeline for the scientific community and propose a structured approach for qualitative analysis and clustering of results. This methodology refines literature reviews, optimizes knowledge extraction, and supports broader application across diverse research domains. An online platform could further extend these benefits to researchers, educators, and practitioners.

PMID:39563601 | DOI:10.1080/14622416.2024.2429946

Pharmacogenomics. 2024 Nov 20:1-9. doi: 10.1080/14622416.2024.2429365. Online ahead of print.

ABSTRACT

AIM: The study aimed to examine the association of two selected candidate SNPs rs2242480 (CYP3A4) and rs1045642 (ABCB1) with metabolic ratio of plasma norfentanyl to fentanyl concentrations in patients undergoing major breast surgeries.

METHODS: The retrospective cross-sectional study was done in 257 female patients. DNA extraction, genotyping of selected SNPs, and drug levels measurement were employed.

RESULTS: A total of 257 female patients were recruited with no loss to follow up. There was no significant association between the two mentioned SNPs and the metabolic ratio (p value > 0.05). As an exploratory analysis, there was a moderately significant negative correlation between metabolic ratio and pupillary constriction to fentanyl (r = -0.27; p < 0.001). There was also a weak but significant positive correlation between metabolic ratio and time for first analgesia in the postoperative period (r = 0.17; p = 0.01).

CONCLUSION: There was no significant association with the selected candidate SNPs in CYP3A4 and ABCB1 genes and metabolic ratio of norfentanyl to fentanyl in South Indian patients undergoing major breast surgery.

PMID:39563600 | DOI:10.1080/14622416.2024.2429365

Biomark Res. 2024 Nov 19;12(1):142. doi: 10.1186/s40364-024-00687-6.

ABSTRACT

Epilepsy remains a prevalent chronic neurological disease that is featured by aberrant, recurrent and hypersynchronous discharge of neurons and poses a great challenge to healthcare systems. Although several therapeutic interventions are successfully utilized for treating epilepsy, they can merely provide symptom relief but cannot exert disease-modifying effect. Therefore, it is of urgent need to explore other potential mechanism to develop a novel approach to delay the epileptic progression. Since approximately 30 years ago, histone deacetylases (HDACs), the versatile epigenetic regulators responsible for gene transcription via binding histones or non-histone substrates, have grabbed considerable attention in drug discovery. There are also substantial evidences supporting that aberrant expressions and/activities of HDAC isoforms are reported in epilepsy and HDAC inhibitors (HDACi) have been successfully utilized for therapeutic purposes in this condition. However, the specific mechanisms underlying the role of HDACs in epileptic progression have not been fully understood. Herein, we reviewed the basic information of HDACs, summarized the recent findings associated with the roles of diverse HDAC subunits in epilepsy and discussed the potential regulatory mechanisms by which HDACs affected the development of epilepsy. Additionally, we also provided a brief discussion on the potential of HDACs as promising therapeutic targets for epilepsy treatment, serving as a valuable reference for basic study and clinical translation in epilepsy field.

PMID:39563472 | DOI:10.1186/s40364-024-00687-6

Pharmacogenomics J. 2024 Nov 19;24(6):36. doi: 10.1038/s41397-024-00356-9.

ABSTRACT

Pharmacogenetic (PGx) testing can enhance drug safety, improve efficacy, and reduce the risk of toxicity. However, the implementation of PGx testing in Canadian pediatric oncology centers has been limited. To address this gap, the aim of this study was to assess the barriers and facilitators to implementing PGx testing for three oncology drugs in eight Canadian pediatric oncology centers and identify strategies that could be used to support PGx testing implementation. We used semi-structured interviews to identify barriers and facilitators to PGx testing and identified evidence-based strategies for PGx testing implementation through a mapping process that utilized the Theoretical Domains Framework, the Consolidated Framework for Implementation Research and the Behavior Change Wheel. We identified 38 facilitators and 26 barriers to implementation of PGx testing and mapped these to 6 implementation strategies.

PMID:39562543 | DOI:10.1038/s41397-024-00356-9

Br J Clin Pharmacol. 2024 Nov 19. doi: 10.1111/bcp.16351. Online ahead of print.

NO ABSTRACT

PMID:39561385 | DOI:10.1111/bcp.16351

Cell Mol Life Sci. 2024 Nov 19;81(1):458. doi: 10.1007/s00018-024-05490-y.

ABSTRACT

Endosomal Sorting Complexes Required for Transport (ESCRTs) are crucial for delivering membrane receptors or intracellular organelles for lysosomal degradation which provides the cell with lysosome-derived nutrients. Yet, how ESCRT dysfunction affects cell metabolism remained elusive. To address this, we analyzed transcriptomes of cells lacking TSG101 or VPS28 proteins, components of ESCRT-I subcomplex. ESCRT-I deficiency reduced the expression of genes encoding enzymes involved in oxidation of fatty acids and amino acids, such as branched-chain amino acids, and increased the expression of genes encoding glycolytic enzymes. The changes in metabolic gene expression were associated with Warburg effect-like metabolic reprogramming that included intracellular accumulation of lipids, increased glucose/glutamine consumption and lactate production. Moreover, depletion of ESCRT-I components led to expansion of the ER and accumulation of small mitochondria, most of which retained proper potential and performed ATP-linked respiration. Mechanistically, the observed transcriptional reprogramming towards glycolysis in the absence of ESCRT-I occurred due to activation of the canonical NFκB and JNK signaling pathways and at least in part by perturbed lysosomal degradation. We propose that by activating the stress signaling pathways ESCRT-I deficiency leads to preferential usage of extracellular nutrients, like glucose and glutamine, for energy production instead of lysosome-derived nutrients, such as fatty acids and branched-chain amino acids.

PMID:39560723 | DOI:10.1007/s00018-024-05490-y

Psychiatr Genet. 2024 Nov 12. doi: 10.1097/YPG.0000000000000380. Online ahead of print.

ABSTRACT

The role of genetic factors in cluster headache etiology, suggested by familial and twin studies, remains ill-defined, with the exact pathophysiological mechanisms still largely elusive. This systematic review aims to synthesize current knowledge on cluster headache genetics and explore its implications for personalized treatment and prediction of treatment response. Thus, we searched PubMed, Scopus, and the Cochrane Library databases and reference lists of identified research articles, meta-analyses, and reviews to identify relevant studies up to 10 July 2024. The quality of the evidence was assessed using Newcastle-Ottawa Scale for case control studies and NIH Quality Assessment tool for Observational Cohort and Cross-Sectional Studies. The protocol of this study was registered via the Open Science Framework (https://osf.io/cd4s3). Fifty-one studies were selected for the qualitative synthesis: 34 candidate gene studies, 5 GWAS, 7 gene expression studies, 4 pharmacogenetic association studies, and 1 whole genome sequencing study. The bulk of genetic evidence in cluster headache underscores the involvement of genes associated with chronobiological regulation. The most studied gene in cluster headache is the HCRTR2, which is expressed in the hypothalamus; however, findings across studies continue to be inconclusive. Recent GWAS have uncovered novel risk loci for cluster headache, marking a significant advancement for the field. Nevertheless, there remains a need to investigate various genes involved in specific mechanisms and pathways.

PMID:39560176 | DOI:10.1097/YPG.0000000000000380

New Microbiol. 2024 Nov;47(3):295-297.

ABSTRACT

Numerous drugs are known to alter the colour of human body fluids. Although drug-induced bronchial secretions staining is normally harmless, it may frighten the patient and could lead to unnecessary clinical inquiries. Cefiderocol is often removed renally as an unmodified drug; bronchial secretion staining has not been seen at doses used in clinical practice. We report a possible first case of bronchoalveolar lavage staining occurred during Cefiderocol treatment in a critical patient.

PMID:39560044

Per Med. 2024 Nov 19:1-16. doi: 10.1080/17410541.2024.2391269. Online ahead of print.

ABSTRACT

Lung cancer has the highest mortality rate among all the highly prevalent neoplasia globally. The major concern with its frontline treatment-cisplatin, is the rapid progression of chemoresistance and multi-organ-based toxicities including hearing loss and tinnitus, nephrotoxicity, hepatotoxicity and myelosuppression including anemia and neutropenia. In this review, studies concluding the association of single nucleotide polymorphisms (SNP) in disparate genes with aforementioned toxicity points are summarized to observe the pharmacogenomic pattern. Especially, SNPs in ATP7B, ERCC-1, ERCC-2, MATE-1, OCT-2, ABCB-1, ABCC-1, ABCG-2, ABCC-2, SLC22A, ERCC-5, BRCA-1, GSTM-3, GSTM-4 and GSTM-5 genes appear to be associated with the therapeutic response and/or adverse effects of cisplatin. We recommend utilizing this information to minimize the risk of treatment failure due to chemoresistance and adverse effects on other organs.

PMID:39560009 | DOI:10.1080/17410541.2024.2391269

Clin Med Insights Oncol. 2024 Nov 17;18:11795549241298541. doi: 10.1177/11795549241298541. eCollection 2024.

ABSTRACT

The discovery of cancer-specific biomarkers has resulted in major advancements in the field of cancer diagnostics and therapeutics, therefore significantly lowering cancer-related morbidity and mortality. Cancer biomarkers can be generally classified as prognostic biomarkers that predict specific disease outcomes and predictive biomarkers that predict disease response to targeted therapeutic interventions. As research in the area of predictive biomarkers continues to grow, precision medicine becomes far more integrated in cancer treatment. This article presents a general overview on the most recent advancements in the area of cancer biomarkers, immunotherapy, artificial intelligence, and pharmacogenomics of the Middle East.

PMID:39559827 | PMC:PMC11571259 | DOI:10.1177/11795549241298541

Pharmacogenomics. 2024 Nov 18:1-4. doi: 10.1080/14622416.2024.2430167. Online ahead of print.

ABSTRACT

Acute generalized exanthematous pustulosis (AGEP) is a rare drug reaction characterized by numerous pustules on an erythematous base. In some cases, hydroxychloroquine (HCQ) can cause AGEP. There is an association between HLA genes and AGEP according to pharmacogenomic studies. In this case report, we present the case of a 36-year-old female who developed HCQ-induced AGEP with HLA-typing. According to our findings, the patient had HLA-B 58:01, HLA-C 08:01, and HLA-A 02:06. A pharmacoeconomic perspective of HLA genotyping before drug prescription is shown in this result.

PMID:39558667 | DOI:10.1080/14622416.2024.2430167

Pharmacogenomics J. 2024 Nov 18;24(6):35. doi: 10.1038/s41397-024-00354-x.

NO ABSTRACT

PMID:39557843 | DOI:10.1038/s41397-024-00354-x

Pharmacogenomics. 2024 Nov 18:1-6. doi: 10.1080/14622416.2024.2430163. Online ahead of print.

ABSTRACT

BACKGROUND: Our objective was to explore the pharmacogenetic impact of three known functional variants in drug target genes and determine whether they can explain the inter-individual variation in therapeutic response.

METHODS: In a post hoc analysis of data from randomized controlled clinical trials of chiglitazar, we genotyped 481 Chinese patients with T2DM and investigated the association of variants in PPAR genes with the therapeutic outcome separated by dose using linear regression.

RESULTS: rs1800234, a gain-of-function variant of PPARA, had a dose-dependent pharmacogenetic impact on the therapeutic response to chiglitazar. The C allele was significantly associated with reduced therapeutic response in the 48 mg group, while no significant association was observed in the 32 mg group. In addition, in patients without the C allele, patients treated with 48 mg chiglitazar had a better therapeutic response than those treated with 32 mg chiglitazar. To the contrary, in patients with the C allele, patients treated with 48 mg chiglitazar had a worse therapeutic response than those treated with 32 mg of chiglitazar.

CONCLUSION: The PPARA variant rs1800234 had a dose-dependent pharmacogenetic impact on the therapeutic response to chiglitazar. It could help explain the absence of a dose effect of chiglitazar and serve as a potential biomarker for the chosen dose of chiglitazar in the future. In addition, our study provided important reference for the design and clinical application of multi-target drugs.

PMID:39555806 | DOI:10.1080/14622416.2024.2430163

Aquac Nutr. 2024 Apr 5;2024:5566739. doi: 10.1155/2024/5566739. eCollection 2024.

ABSTRACT

Cinnamaldehyde is an ideal feed additive with good immune enhancement and anti-inflammatory regulation effects. However, the anti-inflammatory regulation mechanism in fat greenling (Hexagrammos otakii, H. otakii) remains unclear. The nine targets of cinnamaldehyde were gathered in identified by the Traditional Chinese Medicine Systems Pharmacology database and Uniprot database, and 1,320 intestinal inflammation disease (IIF)-related proteins were screened from DrugBank, Online Mendelian Inheritance in Man (OMIM), Genecards, and Pharmacogenetics and Pharmacogenomics Knowledge Base (PHARMGKB) Databases. According to the Gene Ontology enrichment results and Kyoto Encyclopedia of Genes and Genomes pathway results, cinnamaldehyde may regulated the responses to bacteria, lipopolysaccharide, an inflammatory cytokine, and external stimuli via the nuclear factor kappa-B (NFκB) signaling pathway within on inflammatory network. In addition, the protein-protein interaction analysis assisted in obtaining the closely related inflammatory regulatory proteins, including the C5a anaphylatoxin chemotactic receptor 1 (C5aR1), transcription factor p65 (RELA), prostaglandin G/H synthase 2 (PTGS2), and toll-like receptor 4 (TLR4), which were confirmed as the bottleneck nodes of the network to be more deeply verified via the molecular docking. Moreover, a cinnamaldehyde feeding model was established for evaluating the anti-inflammatory effect of cinnamaldehyde in vivo. According to the current findings implied that cinnamaldehyde may play a protective role against IIF H. otakii by reducing inflammation through the C5 complement (C5)/C5aR1/interleukin-6 (IL-6) and TLR4/NFκB/PTGS2 pathway. The study focused on investigating the action mechanism of cinnamaldehyde on IIF through combining pharmacology and experimental verification in vivo, which provided a fresh perspective on the promoting effect of cinnamaldehyde on IIF in fish.

PMID:39555553 | PMC:PMC11074912 | DOI:10.1155/2024/5566739