bioRxiv [Preprint]. 2024 Mar 25:2024.03.25.585959. doi: 10.1101/2024.03.25.585959.

ABSTRACT

Neurofibromatosis Type 1 (NF1) is a common cancer predisposition syndrome, caused by heterozygous loss of function mutations in the tumor suppressor gene NF1 . Individuals with NF1 develop benign tumors of the peripheral nervous system (neurofibromas), originating from the Schwann cell linage after somatic loss of the wild type NF1 allele, some of which progress further to malignant peripheral nerve sheath tumors (MPNST). There is only one FDA approved targeted therapy for symptomatic plexiform neurofibromas and none approved for MPNST. The genetic basis of NF1 syndrome makes associated tumors ideal for using synthetic drug sensitivity approaches to uncover therapeutic vulnerabilities. We developed a drug discovery pipeline to identify therapeutics for NF1-related tumors using isogeneic pairs of NF1- proficient and deficient immortalized human Schwann cells. We utilized these in a large-scale high throughput screen (HTS) for drugs that preferentially kill NF1 -deficient cells, through which we identified 23 compounds capable of killing NF1- deficient Schwann cells with selectivity. Multiple hits from this screen clustered into classes defined by method of action. Four clinically interesting drugs from these classes were tested in vivo using both a genetically engineered mouse model of high-grade peripheral nerve sheath tumors and human MPNST xenografts. All drugs tested showed single agent efficacy in these models as well as significant synergy when used in combination with the MEK inhibitor selumetinib. This HTS platform yielded novel therapeutically relevant compounds for the treatment of NF1-associated tumors and can serve as a tool to rapidly evaluate new compounds and combinations in the future.

PMID:38585724 | PMC:PMC10996510 | DOI:10.1101/2024.03.25.585959

Front Pharmacol. 2024 Mar 22;15:1332752. doi: 10.3389/fphar.2024.1332752. eCollection 2024.

ABSTRACT

Objectives: Isoniazid is a key drug in the chemotherapy of tuberculosis (TB), however, interindividual variability in pharmacokinetic parameters and drug plasma levels may affect drug responses including drug induced hepatotoxicity. The current study investigated the relationships between isoniazid exposure and isoniazid metabolism-related genetic factors in the context of occurrence of drug induced hepatotoxicity and TB treatment outcomes. Methods: Demographic characteristics and clinical information were collected in a prospective TB cohort study in Latvia (N = 34). Time to sputum culture conversion (tSCC) was used as a treatment response marker. Blood plasma concentrations of isoniazid (INH) and its metabolites acetylisoniazid (AcINH) and isonicotinic acid (INA) were determined at three time points (pre-dose (0 h), 2 h and 6 h after drug intake) using liquid chromatography-tandem mass spectrometry. Genetic variations of three key INH-metabolizing enzymes (NAT2, CYP2E1, and GSTM1) were investigated by application PCR- and Next-generation sequencing-based methods. Depending on variables, group comparisons were performed by Student's t-test, one-way ANOVA, Mann-Whitney-Wilcoxon, and Kruskal-Wallis tests. Pearson correlation coefficient was calculated for the pairs of normally distributed variables; model with rank transformations were used for non-normally distributed variables. Time-to-event analysis was performed to analyze the tSCC data. The cumulative probability of tSCC was obtained using Kaplan-Meier estimators. Cox proportional hazards models were fitted to estimate hazard rate ratios of successful tSCC. Results: High TB treatment success rate (94.1%) was achieved despite the variability in INH exposure. Clinical and demographic factors were not associated with either tSCC, hepatotoxicity, or INH pharmacokinetics parameters. Correlations between plasma concentrations of INH and its metabolites were NAT2 phenotype-dependent, while GSTM1 genetic variants did not showed any effects. CYP2E1*6 (T > A) allelic variant was associated with INH pharmacokinetic parameters. Decreased level of AcINH was associated with hepatotoxicity, while decreased values of INA/INH and AcINH/INH were associated with month two sputum culture positivity. Conclusion: Our findings suggest that CYP2E1, but not GSTM1, significantly affects the INH pharmacokinetics along with NAT2. AcINH plasma level could serve as a biomarker for INH-related hepatotoxicity, and the inclusion of INH metabolite screening in TB therapeutic drug monitoring could be beneficial in clinical studies for determination of optimal dosing strategies.

PMID:38584604 | PMC:PMC10995391 | DOI:10.3389/fphar.2024.1332752

Front Pharmacol. 2024 Mar 22;15:1347882. doi: 10.3389/fphar.2024.1347882. eCollection 2024.

ABSTRACT

Objective: Our study provides an innovative approach to exploring herbal formulas that contribute to the promotion of sustainability and biodiversity conservation. We employ data mining, integrating keyword extraction, association rules, and LSTM-based generative models to analyze classical Traditional Chinese Medicine (TCM) texts. We systematically decode classical Chinese medical literature, conduct statistical analyses, and link these historical texts with modern pharmacogenomic references to explore potential alternatives. Methods: We present a novel iterative keyword extraction approach for discerning diverse herbs in historical TCM texts from the Pu-Ji Fang copies. Utilizing association rules, we uncover previously unexplored herb pairs. To bridge classical TCM herbal pairs with modern genetic relationships, we conduct gene-herb searches in PubMed and statistically validate this genetic literature as supporting evidence. We have expanded on the present work by developing a generative language model for suggesting innovative TCM formulations based on textual herb combinations. Results: We collected associations with 7,664 PubMed cross-search entries for gene-herb and 934 for Shenqifuzheng Injection as a positive control. We analyzed 16,384 keyword combinations from Pu-Ji Fang's 426 volumes, employing statistical methods to probe gene-herb associations, focusing on examining differences among the target genes and Pu-Ji Fang herbs. Conclusion: Analyzing Pu-Ji Fang reveals a historical focus on flavor over medicinal aspects in TCM. We extend our work on developing a generative model from classical textual keywords to rapidly produces novel herbal compositions or TCM formulations. This integrated approach enhances our comprehension of TCM by merging ancient text analysis, modern genetic research, and generative modeling.

PMID:38584602 | PMC:PMC10995307 | DOI:10.3389/fphar.2024.1347882

J Pharm Biomed Anal. 2024 Apr 1;244:116126. doi: 10.1016/j.jpba.2024.116126. Online ahead of print.

ABSTRACT

Polydopamine (PDA) is an insoluble biopolymer with a dark brown-black color that forms through the autoxidation of dopamine. Because of its outstanding biocompatibility and durability, PDA holds enormous promise for various applications, both in the biomedical and non-medical domains. To ensure human safety, protect health, and minimize environmental impacts, the assessment of PDA toxicity is important. In this study, metabolomics and lipidomics assessed the impact of acute PDA exposure on Caenorhabditis elegans (C. elegans). The findings revealed a pronounced perturbation in the metabolome and lipidome of C. elegans at the L4 stage following 24 hours of exposure to 100 µg/mL PDA. The changes in lipid composition varied based on lipid classes. Increased lipid classes included lysophosphatidylethanolamine, triacylglycerides, and fatty acids, while decreased species involved in several sub-classes of glycerophospholipids and sphingolipids. Besides, we detected 37 significantly affected metabolites in the positive and 8 in the negative ion modes due to exposure to PDA in C. elegans. The metabolites most impacted by PDA exposure were associated with purine metabolism, biosynthesis of valine, leucine, and isoleucine; aminoacyl-tRNA biosynthesis; and cysteine and methionine metabolism, along with pantothenate and CoA biosynthesis; the citrate cycle (TCA cycle); and beta-alanine metabolism. In conclusion, PDA exposure may intricately influence the metabolome and lipidome of C. elegans. The combined application of metabolomics and lipidomics offers additional insights into the metabolic perturbations involved in PDA-induced biological effects and presents potential biomarkers for the assessment of PDA safety.

PMID:38581931 | DOI:10.1016/j.jpba.2024.116126

Clin Transl Sci. 2024 Apr;17(4):e13792. doi: 10.1111/cts.13792.

ABSTRACT

The aggregated risk of recurrent stroke in stroke/transient ischemic attack (TIA) patients carrying CYP2C19 LoF alleles who take clopidogrel has not been investigated recently, and the available research is limited. This study aimed to perform an updated meta-analysis to assess the association between CYP2C19 LoF alleles and the risk of recurrent stroke in patients taking clopidogrel. Databases were searched for the literature on eligible studies. The end points were recurrent stroke, composite vascular events, and bleeding events. Odds ratios (ORs) were calculated using RevMan software, where p < 0.05 was considered statistically significant. Patients carrying CYP2C19 LoF alleles who were treated with clopidogrel had a significantly increased risk of recurrent ischemic stroke compared with non-carriers (OR 2.18, 96% CI 1.80-2.63; p < 0.00001). The risk of recurrent stroke was only significantly different in Asian patients (OR 2.29, 96% CI 1.88-2.80; p < 0.00001) but not in patients of other ethnicities; however, there were a limited number of studies in other ethnic groups. Both observational studies (OR 2.83, 96% CI 2.20-3.65; p < 0.00001) and RCTs (OR 1.48, 96% CI 1.10-1.98; p = 0.009) found associations with a significantly increased risk of recurrent ischemic stroke. Asian stroke patients or TIA patients carrying CYP2C19 LoF alleles and taking clopidogrel were at a significantly higher risk of recurrent ischemic stroke than non-carriers. Significantly increased risk of recurrent ischemic stroke was found in both observational studies and RCTs.

PMID:38581109 | DOI:10.1111/cts.13792

BMC Microbiol. 2024 Apr 5;24(1):119. doi: 10.1186/s12866-024-03278-5.

ABSTRACT

Obesity is a metabolic disorder closely associated with profound alterations in gut microbial composition. However, the dynamics of species composition and functional changes in the gut microbiome in obesity remain to be comprehensively investigated. In this study, we conducted a meta-analysis of metagenomic sequencing data from both obese and non-obese individuals across multiple cohorts, totaling 1351 fecal metagenomes. Our results demonstrate a significant decrease in both the richness and diversity of the gut bacteriome and virome in obese patients. We identified 38 bacterial species including Eubacterium sp. CAG:274, Ruminococcus gnavus, Eubacterium eligens and Akkermansia muciniphila, and 1 archaeal species, Methanobrevibacter smithii, that were significantly altered in obesity. Additionally, we observed altered abundance of five viral families: Mesyanzhinovviridae, Chaseviridae, Salasmaviridae, Drexlerviridae, and Casjensviridae. Functional analysis of the gut microbiome indicated distinct signatures associated to obesity and identified Ruminococcus gnavus as the primary driver for function enrichment in obesity, and Methanobrevibacter smithii, Akkermansia muciniphila, Ruminococcus bicirculans, and Eubacterium siraeum as functional drivers in the healthy control group. Additionally, our results suggest that antibiotic resistance genes and bacterial virulence factors may influence the development of obesity. Finally, we demonstrated that gut vOTUs achieved a diagnostic accuracy with an optimal area under the curve of 0.766 for distinguishing obesity from healthy controls. Our findings offer comprehensive and generalizable insights into the gut bacteriome and virome features associated with obesity, with the potential to guide the development of microbiome-based diagnostics.

PMID:38580930 | DOI:10.1186/s12866-024-03278-5

OMICS. 2024 Apr 5. doi: 10.1089/omi.2024.0049. Online ahead of print.

NO ABSTRACT

PMID:38579137 | DOI:10.1089/omi.2024.0049

World J Hepatol. 2024 Mar 27;16(3):366-378. doi: 10.4254/wjh.v16.i3.366.

ABSTRACT

BACKGROUND: The prevalence of metabolic-associated fatty liver disease (MAFLD) is a growing public health issue in people living with human immunodeficiency virus (PLWH). However, the pathophysiology of MAFLD is still unknown, and the role of genetic variables is only now becoming evident.

AIM: To evaluate the associations of gene-polymorphism-related MAFLD in PLWH.

METHODS: The study employed transient elastography with a controlled attenuation parameter ≥ 248 dB/m to identify MAFLD in patients from a Super Tertiary Hospital in central Thailand. Candidate single-nucleotide polymorphisms (SNPs) were genotyped using TaqMan® MGB probe 5' nuclease assays for seven MAFLD-related genes. Statistical analyses included SNP frequency analysis, Fisher's Exact and Chi-square tests, odds ratio calculations, and multivariable logistic regression.

RESULTS: The G-allele carriers of PNPLA3 (rs738409) exhibited a two-fold rise in MAFLD, increasing by 2.5 times in MAFLD with human immunodeficiency virus infection. The clinical features and genetic patterns imply that LEP rs7799039 A-allele carriers had a nine times (P = 0.001) more significant chance of developing aberrant triglyceride among PLWH.

CONCLUSION: The current study shows an association between PNPLA3 rs738409 and LEP rs7799039 with MAFLD in PLWH.

PMID:38577531 | PMC:PMC10989307 | DOI:10.4254/wjh.v16.i3.366

J Coll Physicians Surg Pak. 2024 Apr;34(4):383-389. doi: 10.29271/jcpsp.2024.04.383.

ABSTRACT

OBJECTIVE: To evaluate the efficacy and safety of pharmacogenomics (PGx)-guided treatment in individuals with resistant hypertension (RH).

STUDY DESIGN: Randomised controlled open-label study. Place and Duration of the Study: Department of Cardiology, The First Hospital of China Medical University, Shenyang, Liaoning Province, China, from June 2019 to November 2021.

METHODOLOGY: The study assigned RH patients to two groups. The intervention group (IG) received 12 weeks of PGx-guided treatment, while the control group (CG) followed a consensus-based approach. Examining 10 genes and their alleles with 31 antihypertensive drugs in the IG, the study provided specific medication advice. The primary outcome measured the difference in office systolic blood pressure (SBP) change from baseline at 12 weeks. Secondary outcomes included changes in diastolic blood pressure (DBP), hepatic and renal function, and major adverse cardiovascular events.

RESULTS: Fifty-nine patients from the First Hospital of China Medical University participated, with 29 in the IG and 30 in the CG. Significant differences were noted in SBP reduction (IG: 31.26 ± 18.64 mmHg; CG: 14.61 ± 17.74 mmHg; p=0.001) and DBP reduction (IG: 19.61 ± 17.32 mmHg; CG: 7.81 ± 11.23 mmHg; p = 0.003) after 12 weeks. One IG patient had a heart attack, and one CG subject developed heart failure. At week 12, hepatic insufficiency was observed in one IG patient and six CG patients, while renal insufficiency occurred in five patients of both groups.

CONCLUSION: Treatment guided by PGx demonstrated significant reductions in both SBP and DBP compared to consensus-based treatment.

KEY WORDS: Resistant hypertension, Treatment, Pharmacogenomics, Clinical study.

PMID:38576277 | DOI:10.29271/jcpsp.2024.04.383

Drug Metab Dispos. 2024 Apr 4:DMD-MR-2023-001302. doi: 10.1124/dmd.123.001302. Online ahead of print.

ABSTRACT

In the area of drug development and clinical pharmacotherapy, a profound understanding of the pharmacokinetics and potential adverse reactions associated with the drug under investigation is paramount. Essential to this endeavour is a comprehensive understanding about interindividual variations in ADME genetics and the predictive capabilities of in vitro systems, shedding light on metabolite formation and the risk of adverse drug reactions (ADRs). Both the domains of pharmacogenomics and the advancement of in vitro systems are experiencing rapid expansion. Here we present an update on these burgeoning fields, providing an overview of their current status and illuminating potential future directions. Significance Statement There is a very rapid development in the area of pharmacogenomics and in vitro systems for predicting drug pharmacokinetics and risk for adverse drug reactions. We provide an update of the current status of pharmacogenomics and developed in vitro systems on these aspects aimed to achieve a better personalized pharmacotherapy.

PMID:38575185 | DOI:10.1124/dmd.123.001302

Sci Rep. 2024 Apr 4;14(1):7967. doi: 10.1038/s41598-024-58254-w.

ABSTRACT

Behçet's disease (BD) manifests as an autoimmune disorder featuring recurrent ulcers and multi-organ involvement, influenced by genetic factors associated with both HLA and non-HLA genes, including TNF-α and ERAP1. The study investigated the susceptible alleles of both Class I and II molecules of the HLA gene in 56 Thai BD patients and 192 healthy controls through next-generation sequencing using a PacBio kit. The study assessed 56 BD patients, primarily females (58.9%), revealing diverse manifestations including ocular (41.1%), vascular (35.7%), skin (55.4%), CNS (5.4%), and GI system (10.7%) involvement. This study found associations between BD and HLA-A*26:01:01 (OR 3.285, 95% CI 1.135-9.504, P-value 0.028), HLA-B*39:01:01 (OR 6.176, 95% CI 1.428-26.712, P-value 0.015), HLA-B*51:01:01 (OR 3.033, 95% CI 1.135-8.103, P-value 0.027), HLA-B*51:01:02 (OR 6.176, 95% CI 1.428-26.712, P-value 0.015), HLA-C*14:02:01 (OR 3.485, 95% CI 1.339-9.065, P-value 0.01), HLA-DRB1*14:54:01 (OR 1.924, 95% CI 1.051-3.522, P-value 0.034), and HLA-DQB1*05:03:01 (OR 3.00, 95% CI 1.323-6.798, P-value 0.008). However, after Bonferroni correction none of these alleles were found to be associated with BD. In haplotype analysis, we found a strong linkage disequilibrium in HLA-B*51:01:01, HLA-C*14:02:01 (P-value 0.0, Pc-value 0.02). Regarding the phenotype, a significant association was found between HLA-DRB1*14:54:01 (OR 11.67, 95% CI 2.86-47.57, P-value 0.001) and BD with ocular involvement, apart from this, no distinct phenotype-HLA association was documented. In summary, our study identifies specific HLA associations in BD. Although limited by a small sample size, we acknowledge the need for further investigation into HLA relationships with CNS, GI, and neurological phenotypes in the Thai population.

PMID:38575661 | DOI:10.1038/s41598-024-58254-w

Acta Pharm Sin B. 2024 Apr;14(4):1711-1725. doi: 10.1016/j.apsb.2024.01.001. Epub 2024 Jan 4.

ABSTRACT

Drug repurposing offers an efficient approach to therapeutic development. In this study, our bioinformatic analysis first predicted an association between obesity and lansoprazole (LPZ), a commonly prescribed drug for gastrointestinal ulcers. We went on to show that LPZ treatment increased energy expenditure and alleviated the high-fat diet-induced obesity, insulin resistance, and hepatic steatosis in mice. Treatment with LPZ elicited thermogenic gene expression and mitochondrial respiration in primary adipocytes, and induced cold tolerance in cold-exposed mice, suggesting the activity of LPZ in promoting adipose thermogenesis and energy metabolism. Mechanistically, LPZ is an efficient inhibitor of adipose phosphocholine phosphatase 1 (PHOSPHO1) and produces metabolic benefits in a PHOSPHO1-dependent manner. Our results suggested that LPZ may stimulate adipose thermogenesis by inhibiting the conversion of 2-arachidonoylglycerol-lysophosphatidic acid (2-AG-LPA) to 2-arachidonoylglycerol (2-AG) and reduce the activity of the thermogenic-suppressive cannabinoid receptor signaling. In summary, we have uncovered a novel therapeutic indication and mechanism of LPZ in managing obesity and its related metabolic syndrome, and identified a potential metabolic basis by which LPZ improves energy metabolism.

PMID:38572109 | PMC:PMC10985025 | DOI:10.1016/j.apsb.2024.01.001

Eur J Hum Genet. 2024 Apr 3. doi: 10.1038/s41431-024-01572-4. Online ahead of print.

ABSTRACT

By developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy, the Dutch Pharmacogenetics Working Group (DPWG) aims to advance the implementation of pharmacogenetics (PGx). This guideline outlines the gene-drug interaction of CYP2C9 and HLA-B with phenytoin, HLA-A and HLA-B with carbamazepine and HLA-B with oxcarbazepine and lamotrigine. A systematic review was performed and pharmacotherapeutic recommendations were developed. For CYP2C9 intermediate and poor metabolisers, the DPWG recommends lowering the daily dose of phenytoin and adjust based on effect and serum concentration after 7-10 days. For HLA-B*15:02 carriers, the risk of severe cutaneous adverse events associated with phenytoin, carbamazepine, oxcarbazepine, and lamotrigine is strongly increased. For carbamazepine, this risk is also increased in HLA-B*15:11 and HLA-A*31:01 carriers. For HLA-B*15:02, HLA-B*15:11 and HLA-A*31:01 positive patients, the DPWG recommends choosing an alternative anti-epileptic drug. If not possible, it is recommended to advise the patient to report any rash while using carbamazepine, lamotrigine, oxcarbazepine or phenytoin immediately. Carbamazepine should not be used in an HLA-B*15:02 positive patient. DPWG considers CYP2C9 genotyping before the start of phenytoin "essential" for toxicity prevention. For patients with an ancestry in which the abovementioned HLA-alleles are prevalent, the DPWG considers HLA-B*15:02 genotyping before the start of carbamazepine, phenytoin, oxcarbazepine, and lamotrigine "beneficial", as well as genotyping for HLA-B*15:11 and HLA-A*31:01 before initiating carbamazepine.

PMID:38570725 | DOI:10.1038/s41431-024-01572-4

PLoS One. 2024 Apr 3;19(4):e0299993. doi: 10.1371/journal.pone.0299993. eCollection 2024.

ABSTRACT

The selection of proper reference genes is critical for accurate gene expression analysis in all fields of biological and medical research, mainly because there are many distinctions between different tissues and specimens. Given this variability, even in known classic reference genes, demands of a comprehensive analysis platform is needed to identify the most suitable genes for each study. For this purpose, we present an analysis tool for assisting in decision-making in the analysis of reverse transcription-quantitative polymerase chain reaction (RT-qPCR) data. EndoGeneAnalyzer, an open-source web tool for reference gene analysis in RT-qPCR studies, was used to compare the groups/conditions under investigation. This interactive application offers an easy-to-use interface that allows efficient exploration of datasets. Through statistical and stability analyses, EndoGeneAnalyzer assists in the select of the most appropriate reference gene or set of genes for each condition. It also allows researchers to identify and remove unwanted outliers. Moreover, EndoGeneAnalyzer provides a graphical interface to compare the evaluated groups, providing a visually informative differential analysis.

PMID:38568963 | DOI:10.1371/journal.pone.0299993

Front Psychiatry. 2024 Mar 19;15:1363051. doi: 10.3389/fpsyt.2024.1363051. eCollection 2024.

ABSTRACT

INTRODUCTION: The standard approach to treatment in psychiatry is known as "treatment as usual" (TAU), in which the same types of treatment are administered to a group of patients. TAU often requires numerous dose adjustments and medication changes due to ineffectiveness and/or the occurrence of adverse drug reactions (ADRs). This process is not only time-consuming but also costly. Antipsychotic medications are commonly used to treat various psychiatric disorders such as schizophrenia and mood disorders. Some of the inter-individual differences in efficacy and ADRs observed in psychopharmacotherapy can be explained by genetic variability in the pharmacokinetics and pharmacodynamics of antipsychotics. A better understanding of (in)efficacy and possible ADRs can be achieved by pharmacogenetic analysis of genes involved in the metabolism of antipsychotics. Most psychotropic drugs are metabolized by genetically variable CYP2D6, CYP1A2, CYP3A4, and CYP2C19 enzymes. To demonstrate the utility of pharmacogenetic testing for tailoring antipsychotic treatment, in this paper, we present the case of a patient in whom a pharmacogenetic approach remarkably altered an otherwise intolerant or ineffective conventional TAU with antipsychotics.

METHODS: In this case report, we present a 60-year-old patient with psychotic symptoms who suffered from severe extrapyramidal symptoms and a malignant neuroleptic syndrome during treatment with risperidone, fluphenazine, aripiprazole, brexpiprazole, and olanzapine. Therefore, we performed a pharmacogenetic analysis by genotyping common functional variants in genes involved in the pharmacokinetic pathways of prescribed antipsychotics, namely, CYP2D6, CYP3A4, CYP3A5, CYP1A2, ABCB1, and ABCG2. Treatment recommendations for drug-gene pairs were made according to available evidence-based pharmacogenetic recommendations from the Dutch Pharmacogenetics Working Group (DPWG) or Clinical Pharmacogenetics Implementation Consortium (CPIC).

RESULTS: Pharmacogenetic testing revealed a specific metabolic profile and pharmacokinetic phenotype of the patient, which in retrospect provided possible explanations for the observed ADRs. Based on the pharmacogenetic results, the choice of an effective and safe medication proved to be much easier. The psychotic symptoms disappeared after treatment, while the negative symptoms persisted to a lesser extent.

CONCLUSION: With the case presented, we have shown that taking into account the pharmacogenetic characteristics of the patient can explain the response to antipsychotic treatment and associated side effects. In addition, pharmacogenetic testing enabled an informed choice of the most appropriate drug and optimal dose adjustment. This approach makes it possible to avoid or minimize potentially serious dose-related ADRs and treatment ineffectiveness. However, due to the complexity of psychopathology and the polypharmacy used in this field, it is of great importance to conduct further pharmacokinetic and pharmacogenetic studies to better assess gene-drug and gene-gene-drug interactions.

PMID:38566958 | PMC:PMC10985247 | DOI:10.3389/fpsyt.2024.1363051

Curr Rheumatol Rev. 2024 Apr 2. doi: 10.2174/0115733971285147240327051637. Online ahead of print.

ABSTRACT

Rheumatoid arthritis is a crippling autoimmune disease affecting more than 18 million people worldwide and thus becoming one of the important contributors to the global health burden. The majority of the affected are females, especially those above the age of 50, but males and younger adults are equally vulnerable. It is a constellation of genetic and environmental factors that interplay to manifest the joint deformities and disabilities that are the hallmarks of this disease. Painkillers are used alongside disease-modifying anti-rheumatic drugs to minimize the patient's agony and also to halt the progression of the disease. Worldwide, methotrexate is recommended as the first-line drug, but unexpected resistance is encountered in a significant number of patients. This review summarizes the pathophysiology, clinical findings, and therapeutic strategies for rheumatoid with a focus on research studies performed to establish a genetic basis for response fluctuations of methotrexate across different population groups.

PMID:38566379 | DOI:10.2174/0115733971285147240327051637

bioRxiv [Preprint]. 2024 Mar 19:2024.03.18.585604. doi: 10.1101/2024.03.18.585604.

ABSTRACT

Progression through the G1 phase of the cell cycle is the most highly regulated step in cellular division. We employed a chemogenomics approach to discover novel cellular networks that regulate cell cycle progression. This approach uncovered functional clusters of genes that altered sensitivity of cells to inhibitors of the G1/S transition. Mutation of components of the Polycomb Repressor Complex 2 rescued growth inhibition caused by the CDK4/6 inhibitor palbociclib, but not to inhibitors of S phase or mitosis. In addition to its core catalytic subunits, mutation of the PRC2.1 accessory protein MTF2, but not the PRC2.2 protein JARID2, rendered cells resistant to palbociclib treatment. We found that PRC2.1 (MTF2), but not PRC2.2 (JARID2), was critical for promoting H3K27me3 deposition at CpG islands genome-wide and in promoters. This included the CpG islands in the promoter of the CDK4/6 cyclins CCND1 and CCND2, and loss of MTF2 lead to upregulation of both CCND1 and CCND2. Our results demonstrate a role for PRC2.1, but not PRC2.2, in promoting G1 progression.

PMID:38562687 | PMC:PMC10983909 | DOI:10.1101/2024.03.18.585604

Biosens Bioelectron. 2024 Mar 28;255:116255. doi: 10.1016/j.bios.2024.116255. Online ahead of print.

ABSTRACT

Single nucleotide polymorphisms (SNPs) are closely associated with many biological processes, including genetic disease, tumorigenesis, and drug metabolism. Accurate and efficient SNP determination has been proved pivotal in pharmacogenomics and diagnostics. Herein, a universal and high-fidelity genotyping platform is established based on the dual toeholds regulated Cas12a sensing methodology. Different from the conventional single stranded or double stranded activation mode, the dual toeholds regulated mode overcomes protospacer adjacent motif (PAM) limitation via cascade toehold mediated strand displacement reaction, which is highly universal and ultra-specific. To enhance the sensitivity for biological samples analysis, a modified isothermal recombinant polymerase amplification (RPA) strategy is developed via utilizing deoxythymidine substituted primer and uracil-DNA glycosylase (UDG) treatment, designated as RPA-UDG. The dsDNA products containing single stranded toehold domain generated in the RPA-UDG allow further incorporation with dual toeholds regulated Cas12a platform for high-fidelity human sample genotyping. We discriminate all the single-nucleotide polymorphisms of ApoE gene at rs429358 and rs7412 loci with human buccal swab samples with 100% accuracy. Furthermore, we engineer visual readout of genotyping results by exploiting commercial lateral flow strips, which opens new possibilities for field deployable implementation.

PMID:38565025 | DOI:10.1016/j.bios.2024.116255

BMC Cancer. 2024 Apr 2;24(1):410. doi: 10.1186/s12885-024-12143-7.

ABSTRACT

BACKGROUND: High expression of the glycosyltransferase UGT2B17 represents an independent adverse prognostic marker in chronic lymphocytic leukemia (CLL). It also constitutes a predictive marker for therapeutic response and a drug resistance mechanism. The key determinants driving expression of the UGT2B17 gene in normal and leukemic B-cells remain undefined. The UGT2B17 transcriptome is complex and is comprised of at least 10 alternative transcripts, identified by previous RNA-sequencing of liver and intestine. We hypothesized that the transcriptional program regulating UGT2B17 in B-lymphocytes is distinct from the canonical expression previously characterized in the liver.

RESULTS: RNA-sequencing and genomics data revealed a specific genomic landscape at the UGT2B17 locus in normal and leukemic B-cells. RNA-sequencing and quantitative PCR data indicated that the UGT2B17 enzyme is solely encoded by alternative transcripts expressed in CLL patient cells and not by the canonical transcript widely expressed in the liver and intestine. Chromatin accessible regions (ATAC-Seq) in CLL cells mapped with alternative promoters and non-coding exons, which may be derived from endogenous retrotransposon elements. By luciferase reporter assays, we identified key cis-regulatory STAT3, RELA and interferon regulatory factor (IRF) binding sequences driving the expression of UGT2B17 in lymphoblastoid and leukemic B-cells. Electrophoretic mobility shift assays and pharmacological inhibition demonstrated key roles for the CLL prosurvival transcription factors STAT3 and NF-κB in the leukemic expression of UGT2B17.

CONCLUSIONS: UGT2B17 expression in B-CLL is driven by key regulators of CLL progression. Our data suggest that a NF-κB/STAT3/IRF/UGT2B17 axis may represent a novel B-cell pathway promoting disease progression and drug resistance.

PMID:38566115 | DOI:10.1186/s12885-024-12143-7

PLoS One. 2024 Apr 2;19(4):e0299081. doi: 10.1371/journal.pone.0299081. eCollection 2024.

ABSTRACT

Community engagement (CE) is praised to be a powerful vehicle in empowering communities with knowledge and skills to make informed decisions for better health care. Several CE approaches have been proposed to improve participants' and research communities' understanding of genomic research including pharmacogenomic information and results. However, there is limited literature on how these approaches can be used to communicate findings of pharmacogenomic research to communities of people living with HIV. This study explored stakeholders' perspectives on the role of community engagement in promoting understanding of pharmacogenomic research results among people living with HIV. We adopted a qualitative approach that involved 54 stakeholders between September 2021 and February 2022. We held five focus group discussions among 30 community representatives from five research institutions, 12 key informant interviews among researchers, and 12 in-depth interviews among ethics committee members. A thematic approach was used to analyze the results. Five themes merged from this data and these included (i) benefits of engaging communities prior to returning individual pharmacogenomic research results to participants. (ii) Obtaining community consensus on the kinds of pharmacogenomic results to be returned. (iii) Opinions on how pharmacogenomic research information and results should be communicated at community and individual levels. (iv) Perceived roles of community stakeholders in promoting participants' understanding and utilization of pharmacogenomic research results. (v) Perceived challenges of engaging communities when returning individual results to research participants. Stakeholders opined that CE facilitates co-learning between researchers and research communities. Researchers can adapt existing CE approaches that are culturally acceptable for meaningful engagement with minimal ethical and social risks when communicating pharmacogenomic research results. CE approaches can facilitate understanding of pharmacogenomic research and findings among research participants and communities. Therefore, if creatively adapted, existing and new CE approaches can enable researchers to communicate simple and understandable results of pharmacogenomic research.

PMID:38564575 | DOI:10.1371/journal.pone.0299081