Pharmacogenomics

The Status Quo of Pharmacogenomics of Tyrosine Kinase Inhibitors in Precision Oncology: A Bibliometric Analysis of the Literature

Sat, 2024-02-24 06:00

Pharmaceutics. 2024 Jan 25;16(2):167. doi: 10.3390/pharmaceutics16020167.

ABSTRACT

Precision oncology and pharmacogenomics (PGx) intersect in their overarching goal to institute the right treatment for the right patient. However, the translation of these innovations into clinical practice is still lagging behind. Therefore, this study aimed to analyze the current state of research and to predict the future directions of applied PGx in the field of precision oncology as represented by the targeted therapy class of tyrosine kinase inhibitors (TKIs). Advanced bibliometric and scientometric analyses of the literature were performed. The Scopus database was used for the search, and articles published between 2001 and 2023 were extracted. Information about productivity, citations, cluster analysis, keyword co-occurrence, trend topics, and thematic evolution were generated. A total of 448 research articles were included in this analysis. A burst of scholarly activity in the field was noted by the year 2005, peaking in 2017, followed by a remarkable decline to date. Research in the field was hallmarked by consistent and impactful international collaboration, with the US leading in terms of most prolific country, institutions, and total link strength. Thematic evolution in the field points in the direction of more specialized studies on applied pharmacokinetics of available and novel TKIs, particularly for the treatment of lung and breast cancers. Our results delineate a significant advancement in the field of PGx in precision oncology. Notwithstanding the practical challenges to these applications at the point of care, further research, standardization, infrastructure development, and informed policymaking are urgently needed to ensure widespread adoption of PGx.

PMID:38399228 | DOI:10.3390/pharmaceutics16020167

Categories: Literature Watch

Epigallocatechin Gallate for the Treatment of Benign and Malignant Gynecological Diseases-Focus on Epigenetic Mechanisms

Sat, 2024-02-24 06:00

Nutrients. 2024 Feb 17;16(4):559. doi: 10.3390/nu16040559.

ABSTRACT

The most common malignant gynecologic diseases are cervical, uterine, ovarian, vaginal, and vulvar cancer. Among them, ovarian cancer causes more deaths than any other cancer of the female reproductive system. A great number of women suffer from endometriosis, uterine fibroids (UFs), adenomyosis, dysmenorrhea, and polycystic ovary syndrome (PCOS), which are widespread benign health problems causing troublesome and painful symptoms and significantly impairing the quality of life of affected women, and they are some of the main causes of infertility. In addition to the available surgical and pharmacological options, the effects of supporting standard treatment with naturally occurring compounds, mainly polyphenols, are being studied. Catechins are responsible for the majority of potential health benefits attributed to green tea consumption. Epigallocatechin gallate (EGCG) is considered a non-toxic, natural compound with potential anticancer properties. Antioxidant action is its most common function, but attention is also drawn to its participation in cell division inhibition, apoptosis stimulation and epigenetic regulation. In this narrative review, we describe the role of EGCG consumption in preventing the development of benign reproductive disorders such as UF, endometriosis, and PCOS, as well as malignant gynecologic conditions. We discuss possible epigenetic mechanisms that may be related to the action of EGCG.

PMID:38398883 | DOI:10.3390/nu16040559

Categories: Literature Watch

Validation of Endogenous Control Genes by Real-Time Quantitative Reverse Transcriptase Polymerase Chain Reaction for Acute Leukemia Gene Expression Studies

Sat, 2024-02-24 06:00

Genes (Basel). 2024 Jan 24;15(2):151. doi: 10.3390/genes15020151.

ABSTRACT

Reference genes are used as internal reaction controls for gene expression analysis, and for this reason, they are considered reliable and must meet several important criteria. In view of the absence of studies regarding the best reference gene for the analysis of acute leukemia patients, a panel of genes commonly used as endogenous controls was selected from the literature for stability analysis: Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), Abelson murine leukemia viral oncogene human homolog 1 (ABL), Hypoxanthine phosphoribosyl-transferase 1 (HPRT1), Ribosomal protein lateral stalk subunit P0 (RPLP0), β-actin (ACTB) and TATA box binding protein (TBP). The stability of candidate reference genes was analyzed according to three statistical methods of assessment, namely, NormFinder, GeNorm and R software (version 4.0.3). From this study's analysis, it was possible to identify that the endogenous set composed of ACTB, ABL, TBP and RPLP0 demonstrated good performances and stable expressions between the analyzed groups. In addition to that, the GAPDH and HPRT genes could not be classified as good reference genes, considering that they presented a high standard deviation and great variability between groups, indicating low stability. Given these findings, this study suggests the main endogenous gene set for use as a control/reference for the gene expression in peripheral blood and bone marrow samples from patients with acute leukemias is composed of the ACTB, ABL, TBP and RPLP0 genes. Researchers may choose two to three of these housekeeping genes to perform data normalization.

PMID:38397141 | DOI:10.3390/genes15020151

Categories: Literature Watch

Genetic Biomarkers of Sorafenib Response in Patients with Hepatocellular Carcinoma

Sat, 2024-02-24 06:00

Int J Mol Sci. 2024 Feb 12;25(4):2197. doi: 10.3390/ijms25042197.

ABSTRACT

The identification of biomarkers for predicting inter-individual sorafenib response variability could allow hepatocellular carcinoma (HCC) patient stratification. SNPs in angiogenesis- and drug absorption, distribution, metabolism, and excretion (ADME)-related genes were evaluated to identify new potential predictive biomarkers of sorafenib response in HCC patients. Five known SNPs in angiogenesis-related genes, including VEGF-A, VEGF-C, HIF-1a, ANGPT2, and NOS3, were investigated in 34 HCC patients (9 sorafenib responders and 25 non-responders). A subgroup of 23 patients was genotyped for SNPs in ADME genes. A machine learning classifier method was used to discover classification rules for our dataset. We found that only the VEGF-A (rs2010963) C allele and CC genotype were significantly associated with sorafenib response. ADME-related gene analysis identified 10 polymorphic variants in ADH1A (rs6811453), ADH6 (rs10008281), SULT1A2/CCDC101 (rs11401), CYP26A1 (rs7905939), DPYD (rs2297595 and rs1801265), FMO2 (rs2020863), and SLC22A14 (rs149738, rs171248, and rs183574) significantly associated with sorafenib response. We have identified a genetic signature of predictive response that could permit non-responder/responder patient stratification. Angiogenesis- and ADME-related genes correlation was confirmed by cumulative genetic risk score and network and pathway enrichment analysis. Our findings provide a proof of concept that needs further validation in follow-up studies for HCC patient stratification for sorafenib prescription.

PMID:38396873 | DOI:10.3390/ijms25042197

Categories: Literature Watch

MicroRNAs: The Missing Link between Hypertension and Periodontitis?

Sat, 2024-02-24 06:00

Int J Mol Sci. 2024 Feb 6;25(4):1992. doi: 10.3390/ijms25041992.

ABSTRACT

Cardiovascular diseases are the leading cause of death worldwide, and arterial hypertension is a recognized cardiovascular risk factor that is responsible for high morbidity and mortality. Arterial hypertension is the result of an inflammatory process that results in the remodeling and thickening of the vascular walls, which is associated with an immunological response. Previous studies have attempted to demonstrate the relationship between oral disease, inflammation, and the development of systemic diseases. Currently, the existence of an association between periodontitis and hypertension is a controversial issue because the underlying pathophysiological processes and inflammatory mechanisms common to both diseases are unknown. This is due to the fact that periodontitis is a chronic inflammatory disease that affects the interface of teeth and surrounding tissues. However, the most likely explanation for understanding this association is related to low-grade chronic inflammation. An initial path in the study of the relationship between the mentioned pathologies is the possibility of an epigenetic influence, mediated by noncoding RNAs as microRNAs. Thus, in the present review we describe the role of microRNAs related to arterial hypertension and/or periodontitis. In addition, we identified 13 common microRNAs between periodontitis and hypertension. According to the predictions of the DIANA-mirPath program, they can regulate genes involved in 52 signaling pathways.

PMID:38396672 | DOI:10.3390/ijms25041992

Categories: Literature Watch

Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study

Fri, 2024-02-23 06:00

Transl Psychiatry. 2024 Feb 23;14(1):109. doi: 10.1038/s41398-024-02811-4.

ABSTRACT

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

PMID:38395906 | DOI:10.1038/s41398-024-02811-4

Categories: Literature Watch

Evidence for sex differences in the impact of cytochrome P450 genotypes on early subjective effects of cannabis

Fri, 2024-02-23 06:00

Addict Behav. 2024 Feb 21;153:107996. doi: 10.1016/j.addbeh.2024.107996. Online ahead of print.

ABSTRACT

Early positive subjective effects of cannabis predict the development of cannabis use disorder (CUD). Genetic factors, such as the presence of cytochrome P450 genetic variants that are associated with reduced Δ9-tetrahydrocannabinol (THC) metabolism, may contribute to individual differences in subjective effects of cannabis. Young adults (N = 54) with CUD or a non-CUD substance use disorder (control) provided a blood sample for DNA analysis and self-reported their early (i.e., effects upon initial uses) and past-year positive and negative subjective cannabis effects. Participants were classified as slow metabolizers if they had at least one CYP2C9 or CYP3A4 allele associated with reduced activity. Though the CUD group and control group did not differ in terms of metabolizer status, slow metabolizer status was more prevalent among females in the CUD group than females in the control group. Slow metabolizers reported greater past year negative THC effects compared to normal metabolizers; however, slow metabolizer status did not predict early subjective cannabis effects (positive or negative) or past year positive effects. Post-hoc analyses suggested males who were slow metabolizers reported more negative early subjective effects of cannabis than female slow metabolizers. Other sex-by-genotype interactions were not significant. These initial findings suggest that genetic variation in CYP2C9 and CYP3A4 may have sex-specific associations with cannabis-related outcomes. Slow metabolizer genes may serve as a risk factor for CUD for females independent of subjective effects. Male slow metabolizers may instead be particularly susceptible to the negative subjective effects of cannabis.

PMID:38394959 | DOI:10.1016/j.addbeh.2024.107996

Categories: Literature Watch

A Narrative Review of Preclinical In Vitro Studies Investigating microRNAs in Myocarditis

Fri, 2024-02-23 06:00

Curr Issues Mol Biol. 2024 Feb 6;46(2):1413-1423. doi: 10.3390/cimb46020091.

ABSTRACT

According to the World Health Organization's statement, myocarditis is an inflammatory myocardium disease. Although an endometrial biopsy remains the diagnostic gold standard, it is an invasive procedure, and thus, cardiac magnetic resonance imaging has become more widely used and is called a non-invasive diagnostic gold standard. Myocarditis treatment is challenging, with primarily symptomatic therapies. An increasing number of studies are searching for novel diagnostic biomarkers and potential therapeutic targets. Microribonucleic acids (miRNAs) are small, non-coding RNA molecules that decrease gene expression by inhibiting the translation or promoting the degradation of complementary mRNAs. Their role in different fields of medicine has been recently extensively studied. This review discusses all relevant preclinical in vitro studies regarding microRNAs in myocarditis. We searched the PubMed database, and after excluding unsuitable studies and clinical and preclinical in vivo trials, we included and discussed 22 preclinical in vitro studies in this narrative review. Several microRNAs presented altered levels in myocarditis patients in comparison to healthy controls. Moreover, microRNAs influenced inflammation, cell apoptosis, and viral replication. Finally, microRNAs were also found to determine the level of myocardial damage. Further studies may show the vital role of microRNAs as novel therapeutic agents or diagnostic/prognostic biomarkers in myocarditis management.

PMID:38392209 | DOI:10.3390/cimb46020091

Categories: Literature Watch

Long-Term Effects of a Stepwise, Multimodal, Non-Restrictive Antimicrobial Stewardship Programme for Reducing Broad-Spectrum Antibiotic Use in the ICU

Fri, 2024-02-23 06:00

Antibiotics (Basel). 2024 Jan 29;13(2):132. doi: 10.3390/antibiotics13020132.

ABSTRACT

Information on the long-term effects of non-restrictive antimicrobial stewardship (AMS) strategies is scarce. We assessed the effect of a stepwise, multimodal, non-restrictive AMS programme on broad-spectrum antibiotic use in the intensive care unit (ICU) over an 8-year period. Components of the AMS were progressively implemented. Appropriateness of antibiotic prescribing was also assessed by monthly point-prevalence surveys from 2013 onwards. A Poisson regression model was fitted to evaluate trends in the reduction of antibiotic use and in the appropriateness of their prescription. From 2011 to 2019, a total of 12,466 patients were admitted to the ICU. Antibiotic use fell from 185.4 to 141.9 DDD per 100 PD [absolute difference, -43.5 (23%), 95% CI -100.73 to 13.73; p = 0.13] and broad-spectrum antibiotic fell from 41.2 to 36.5 [absolute difference, -4.7 (11%), 95% CI -19.58 to 10.18; p = 0.5]. Appropriateness of antibiotic prescribing rose by 11% per year [IRR: 0.89, 95% CI 0.80 to 1.00; p = 0.048], while broad-spectrum antibiotic use showed a dual trend, rising by 22% until 2015 and then falling by 10% per year since 2016 [IRR: 0.90, 95% CI 0.81 to 0.99; p = 0.03]. This stepwise, multimodal, non-restrictive AMS achieved a sustained reduction in broad-spectrum antibiotic use in the ICU and significantly improved appropriateness of antibiotic prescribing.

PMID:38391518 | DOI:10.3390/antibiotics13020132

Categories: Literature Watch

Failure of second challenge with Mogamulizumab in CCR4-positive cutaneous T-cell lymphoma

Fri, 2024-02-23 06:00

Br J Dermatol. 2024 Feb 23:ljae085. doi: 10.1093/bjd/ljae085. Online ahead of print.

NO ABSTRACT

PMID:38390970 | DOI:10.1093/bjd/ljae085

Categories: Literature Watch

Genetic-Guided Pharmacotherapy for Coronary Artery Disease: A Systematic and Critical Review of Economic Evaluations

Fri, 2024-02-23 06:00

J Am Heart Assoc. 2024 Feb 23:e030058. doi: 10.1161/JAHA.123.030058. Online ahead of print.

ABSTRACT

BACKGROUND: Genetic-guided pharmacotherapy (PGx) is not recommended in clinical guidelines for coronary artery disease (CAD). We aimed to examine the extent and quality of evidence from economic evaluations of PGx in CAD and to identify variables influential in changing conclusions on cost-effectiveness.

METHODS AND RESULTS: From systematic searches across 6 databases, 2 independent reviewers screened, included, and rated the methodological quality of economic evaluations of PGx testing to guide pharmacotherapy for patients with CAD. Of 35 economic evaluations included, most were model-based cost-utility analyses alone, or alongside cost-effectiveness analyses of PGx testing to stratify patients into antiplatelets (25/35), statins (2/35), pain killers (1/35), or angiotensin-converting enzyme inhibitors (1/35) to predict CAD risk (8/35) or to determine the coumadin doses (1/35). To stratify patients into antiplatelets (96/151 comparisons with complete findings of PGx versus non-PGx), PGx was more effective and more costly than non-PGx clopidogrel (28/43) but less costly than non-PGx prasugrel (10/15) and less costly and less effective than non-PGx ticagrelor (22/25). To predict CAD risk (51/151 comparisons), PGx using genetic risk scores was more effective and less costly than clinical risk score (13/17) but more costly than no risk score (16/19) or no treatment (9/9). The remaining comparisons were too few to observe any trend. Mortality risk was the most common variable (47/294) changing conclusions.

CONCLUSIONS: Economic evaluations to date found PGx to stratify patients with CAD into antiplatelets or to predict CAD risk to be cost-effective, but findings varied based on the non-PGx comparators, underscoring the importance of considering local practice in deciding whether to adopt PGx.

PMID:38390792 | DOI:10.1161/JAHA.123.030058

Categories: Literature Watch

No link between type I interferon autoantibody positivity and adverse reactions to COVID-19 vaccines

Thu, 2024-02-22 06:00

NPJ Vaccines. 2024 Feb 22;9(1):42. doi: 10.1038/s41541-024-00829-9.

ABSTRACT

Type I interferons act as gatekeepers against viral infection, and autoantibodies that neutralize these signaling molecules have been associated with COVID-19 severity and adverse reactions to the live-attenuated yellow fever vaccine. On this background, we sought to examine whether autoantibodies against type I interferons were associated with adverse events following COVID-19 vaccination. Our nationwide analysis suggests that type I interferon autoantibodies were not associated with adverse events after mRNA or viral-vector COVID-19 vaccines.

PMID:38388530 | DOI:10.1038/s41541-024-00829-9

Categories: Literature Watch

PillHarmonics: An Orchestrated Pharmacogenetics Medication Clinical Decision Support Service

Thu, 2024-02-22 06:00

Appl Clin Inform. 2024 Feb 22. doi: 10.1055/a-2274-6763. Online ahead of print.

ABSTRACT

OBJECTIVES: Pharmacogenetics (PGx) is increasingly important in individualizing therapeutic management plans, but is often implemented apart from other types of medication clinical decision support (CDS). The lack of integration of pharmacogenetics into existing CDS may result in incomplete interaction information, which may pose patient safety concerns. We sought to develop a cloud-based orchestrated medication CDS service that integrates PGx with a broad set of drug screening alerts and evaluate it through a clinician utility study.

METHODS: We developed the PillHarmonicsTM service for implementation per the CDS Hooks protocol, algorithmically integrating a wide range of drug interaction knowledge using cloud-based screening services from First Databank (drug-drug/allergy/condition), PharmGKB (drug-gene), and locally curated content (drug-renal/hepatic/race). We performed a user study, presenting 13 clinicians and pharmacists with a prototype of the system's usage in synthetic patient scenarios. We collected feedback via a standard questionnaire and structured interview.

RESULTS: Clinician assessment of PillHarmonics via the Technology Acceptance Model questionnaire shows significant evidence of perceived utility. Thematic analysis of structured interviews revealed that aggregated knowledge, concise actionable summaries, and information accessibility were highly valued, and that clinicians would use the service in their practice.

CONCLUSIONS: Medication safety and optimizing efficacy of therapy regimens remain significant issues. A comprehensive medication CDS system that leverages patient clinical and genomic data to perform a wide range of interaction checking and present a concise and holistic view of medication knowledge back to the clinician, is feasible and perceived as highly valuable for more informed decision-making. Such a system can potentially address many of the challenges identified with current medication related CDS.

PMID:38388174 | DOI:10.1055/a-2274-6763

Categories: Literature Watch

Overcoming Barriers to Discovery and Implementation of Equitable Pharmacogenomic Testing in Oncology

Thu, 2024-02-22 06:00

J Clin Oncol. 2024 Feb 22:JCO2301748. doi: 10.1200/JCO.23.01748. Online ahead of print.

ABSTRACT

Pharmacogenomics (PGx), the study of inherited genomic variation and drug response or safety, is a vital tool in precision medicine. In oncology, testing to identify PGx variants offers patients the opportunity for customized treatments that can minimize adverse effects and maximize the therapeutic benefits of drugs used for cancer treatment and supportive care. Because individuals of shared ancestry share specific genetic variants, PGx factors may contribute to outcome disparities across racial and ethnic categories when genetic ancestry is not taken into account or mischaracterized in PGx research, discovery, and application. Here, we examine how the current scientific understanding of the role of PGx in differential oncology safety and outcomes may be biased toward a greater understanding and more complete clinical implementation of PGx for individuals of European descent compared with other genetic ancestry groups. We discuss the implications of this bias for PGx discovery, access to care, drug labeling, and patient and provider understanding and use of PGx approaches. Testing for somatic genetic variants is now the standard of care in treatment of many solid tumors, but the integration of PGx into oncology care is still lacking despite demonstrated actionable findings from PGx testing, reduction in avoidable toxicity and death, and return on investment from testing. As the field of oncology is poised to expand and integrate germline genetic variant testing, it is vital that PGx discovery and application are equitable for all populations. Recommendations are introduced to address barriers to facilitate effective and equitable PGx application in cancer care.

PMID:38386947 | DOI:10.1200/JCO.23.01748

Categories: Literature Watch

Effect of the NFIB rs28379954 T>C polymorphism on CYP2D6-catalyzed metabolism of solanidine

Thu, 2024-02-22 06:00

Clin Transl Sci. 2024 Feb;17(2):e13743. doi: 10.1111/cts.13743.

ABSTRACT

Cytochrome P450 2D6 (CYP2D6) is important for metabolism of 20%-25% of all clinically used drugs. Many known genetic variants contribute to the large interindividual variability in CYP2D6 metabolism, but much is still unexplained. We recently described that nuclear factor 1B (NFIB) regulates hepatic CYP2D6 expression with the minor allele of NFIB rs28379954 T>C significantly increasing CYP2D6-mediated risperidone metabolism. In this study, we investigated the effect of NFIB T>C on metabolism of solanidine, a dietary CYP2D6 substrate. Analyses of solanidine and metabolites (M414, M416, and M444) were performed by ultra-high performance liquid chromatography-high-resolution mass spectrometry in a cohort of 463 CYP2D6-genotyped patients of which with 58 (12.5%) carried NFIB TC (n = 56) or CC (n = 2). Increased metabolism of solanidine was found in CYP2D6 normal metabolizers (NMs; n = 258, 55.7%) carrying the NFIB C variant (n = 27, 5.8%) with 2.83- and 3.38-fold higher M416-to-solanidine (p = 0.039) and M444-to-solanidine (p = 0.046) ratios, respectively, whereas this effect was not significant among intermediate metabolizers (n = 166, 35.9%) (p ≥ 0.09). Importantly, no effect of the NFIB polymorphism on solanidine metabolism was seen in TC or CC carriers lacking CYP2D6 activity (poor metabolizers, n = 30, 6.5%, p ≥ 0.74). Furthermore, the NFIB polymorphism significantly explained variability in solanidine metabolism (M414 p = 0.013, M416 p = 0.020, and M416 and M444 p = 0.009) in multiple linear regression models for each metabolic ratio in the entire population, correcting for covariates (including CYP2D6 genotypes). Thus, the study confirms the effect of NFIB in regulating CYP2D6 activity, suggesting an about 200% increase in CYP2D6-mediated clearance in NMs being NFIB CT or CC carriers, comprising around 6% of Europeans.

PMID:38385986 | DOI:10.1111/cts.13743

Categories: Literature Watch

Use of Genomics to Develop Novel Therapeutics and Personalize Hypertension Therapy

Thu, 2024-02-22 06:00

Arterioscler Thromb Vasc Biol. 2024 Feb 22. doi: 10.1161/ATVBAHA.123.319220. Online ahead of print.

ABSTRACT

Hypertension is a prevalent public health problem, contributing to >10 million deaths annually. Though multiple therapeutics exist, many patients suffer from treatment-resistant hypertension or try several medications before achieving blood pressure control. Genomic advances offer mechanistic understanding of blood pressure variability, therapeutic targets, therapeutic response, and promise a stratified approach to treatment of primary hypertension. Cyclic guanosine monophosphate augmentation, aldosterone synthase inhibitors, and angiotensinogen blockade with silencing RNA and antisense therapies are among the promising novel approaches. Pharmacogenomic studies have also been done to explore the genetic bases underpinning interindividual variability in response to existing therapeutics. A polygenic approach using risk scores is likely to be the next frontier in stratifying responses to existing therapeutics.

PMID:38385287 | DOI:10.1161/ATVBAHA.123.319220

Categories: Literature Watch

Identification of hub genes significantly linked to temporal lobe epilepsy and apoptosis <em>via</em> bioinformatics analysis

Thu, 2024-02-22 06:00

Front Mol Neurosci. 2024 Feb 7;17:1300348. doi: 10.3389/fnmol.2024.1300348. eCollection 2024.

ABSTRACT

BACKGROUND: Epilepsy stands as an intricate disorder of the central nervous system, subject to the influence of diverse risk factors and a significant genetic predisposition. Within the pathogenesis of temporal lobe epilepsy (TLE), the apoptosis of neurons and glial cells in the brain assumes pivotal importance. The identification of differentially expressed apoptosis-related genes (DEARGs) emerges as a critical imperative, providing essential guidance for informed treatment decisions.

METHODS: We obtained datasets related to epilepsy, specifically GSE168375 and GSE186334. Utilizing differential expression analysis, we identified a set of 249 genes exhibiting significant variations. Subsequently, through an intersection with apoptosis-related genes, we pinpointed 16 genes designated as differentially expressed apoptosis-related genes (DEARGs). These DEARGs underwent a comprehensive array of analyses, including enrichment analyses, biomarker selection, disease classification modeling, immune infiltration analysis, prediction of miRNA and transcription factors, and molecular docking analysis.

RESULTS: In the epilepsy datasets examined, we successfully identified 16 differentially expressed apoptosis-related genes (DEARGs). Subsequent validation in the external dataset GSE140393 revealed the diagnostic potential of five biomarkers (CD38, FAIM2, IL1B, PAWR, S100A8) with remarkable accuracy, exhibiting an impressive area under curve (AUC) (The overall AUC of the model constructed by the five key genes was 0.916, and the validation set was 0.722). Furthermore, a statistically significant variance (p < 0.05) was observed in T cell CD4 naive and eosinophil cells across different diagnostic groups. Exploring interaction networks uncovered intricate connections, including gene-miRNA interactions (164 interactions involving 148 miRNAs), gene-transcription factor (TF) interactions (22 interactions with 20 TFs), and gene-drug small molecule interactions (15 interactions involving 15 drugs). Notably, IL1B and S100A8 demonstrated interactions with specific drugs.

CONCLUSION: In the realm of TLE, we have successfully pinpointed noteworthy differentially expressed apoptosis-related genes (DEARGs), including CD38, FAIM2, IL1B, PAWR, and S100A8. A comprehensive understanding of the implications associated with these identified genes not only opens avenues for advancing our comprehension of the underlying pathophysiology but also bears considerable potential in guiding the development of innovative diagnostic methodologies and therapeutic interventions for the effective management of epilepsy in the future.

PMID:38384278 | PMC:PMC10879302 | DOI:10.3389/fnmol.2024.1300348

Categories: Literature Watch

Curcumin mediated dendritic cell maturation by modulating cancer associated fibroblasts-derived exosomal miRNA-146a

Thu, 2024-02-22 06:00

J Cancer Res Ther. 2023 Jan 1;19(Suppl 2):S649-S657. doi: 10.4103/jcrt.jcrt_1286_22. Epub 2023 Apr 28.

ABSTRACT

BACKGROUND: Though cancer associated fibroblasts (CAFs), being a main component of tumor microenvironment (TME), are known to modulate immune response through secretion of various growth hormones, exosomes carrying miRNAs and cytokines; their effect on dendritic cells (DCs) are yet to be elucidated. Thus, aim of this study was to assess the effect of miRNAs and cytokines released by lung-CAFs and to evaluate immunomodulatory potential of curcumin on DC maturation through modulating their TME.

MATERIAL AND METHODS: To check the effect of CAFs derived exosomes on DC maturation, we cultured imDCs in the presence of CAFs derived conditioned media (CAFs-CM) and characterized by the presence of maturation markers CD80, CD83, CD86 and CTLA4 using qRT-PCR. Additionally, expression of miR-221, miR-222, miR-155, miR-142-3p and miR-146a was assessed to evaluate the role of epigenetic regulators on DC maturation. Likewise, cytokine profiling of CAFs-CM as well as CAFs-CM treated with curcumin was also conducted using ELISA.

RESULTS: Results revealed the generation of regulatory DCs which were characterized by decreased expression of maturation markers in the presence of CAFs-CM. In addition, such DCs showed higher expression of epigenetic regulator miR-146a which was positively correlated with increased expression of anti-inflammatory cytokines like IL-6, IL-10, TGF-β and decreased expression of TNF-α (pro-inflammatory). Moreover, curcumin had the potential to convert regulatory DCs generated by CAFs into mDCs, which were characterized by high expression of co-stimulatory molecules, low expression of CTLA4, lower levels of immune suppressive cytokines production and lower levels of miR-146a.

CONCLUSION: Collectively, these findings provide insight into understanding the immunomodulatory role of curcumin in targeting CAFs and modulating TME, thus enhancing antitumor immune response in DC based therapy.

PMID:38384034 | DOI:10.4103/jcrt.jcrt_1286_22

Categories: Literature Watch

The dopamine 3 receptor as a candidate biomarker and therapeutic for opioid use disorder

Wed, 2024-02-21 06:00

Addict Biol. 2024 Feb;29(2):e13369. doi: 10.1111/adb.13369.

ABSTRACT

Here, we present recent studies suggesting that specific DRD3 single nucleotide polymorphisms (SNPs, e.g. rs324029 and rs2654754) might serve as prognostic biomarkers for opioid use disorder (OUD). Additionally, preclinical studies with novel dopamine 3 receptor (D3R) partial agonists and antagonists have been evaluated as candidate OUD therapeutics and have shown a reduced risk of cardiovascular toxicity compared with the original D3R antagonist. From these findings, we argue that DRD3 SNPs could serve as a diagnostic tool for assessing OUD risk and that more research is warranted examining the D3R as a safe and effective therapeutic target for treating OUD.

PMID:38380709 | DOI:10.1111/adb.13369

Categories: Literature Watch

<em>NUDT15</em> and <em>TPMT</em> polymorphisms in three distinct native populations of the Brazilian Amazon

Wed, 2024-02-21 06:00

Front Pharmacol. 2024 Feb 6;15:1359570. doi: 10.3389/fphar.2024.1359570. eCollection 2024.

ABSTRACT

This is the first report of the distribution of TPMT and NUDT15 single nucleotide polymorphisms and metabolic phenotypes associated with cytotoxicity of thiopurine drugs, in indigenous groups of Brazilian Amazon: Munduruku, Paiter-Suruí and Yanomami. The minor allele frequency (MAF) of NUDT15 rs116855232 did not differ significantly across the groups; TPMT rs1800462 was absent, while rs1800460 and rs1142345 were in strong linkage disequilibrium, and 10- and 30-fold more common in Paiter-Suruí. Indeed, the MAFs in Paiter-Surui (0.193 and 0.188) are the largest report globally. The distribution of combined NUDT15/TPMT metabolic phenotypes differed significantly (p < 0.0001) and largely (Cramér´s V = 0.37) across cohorts. This has important pharmacogenetic implications: the Clinical Pharmacogenetics Implementation Consortium recommendations to reduce or consider reduction of thiopurine dose applies to 4.4% Yanomami, 5.6% Munduruku, versus 41% Paiter-Suruí. The proportion of Paiter-Suruí at risk of thiopurine intolerance is 3- to 4-fold higher than any other population worldwide.

PMID:38379902 | PMC:PMC10876798 | DOI:10.3389/fphar.2024.1359570

Categories: Literature Watch

Pages