Adv Clin Exp Med. 2022 Nov 18. doi: 10.17219/acem/155373. Online ahead of print.

ABSTRACT

BACKGROUND: Chronic graft-versus-host disease (cGvHD) is a complex disorder that typically manifests after allogeneic hematopoietic stem cell transplantation (HSCT). It is a major cause of non-relapse mortality, which makes finding biomarkers associated with its occurrence a priority. Recent studies increasingly indicate that microRNAs (miRNAs, short regulatory RNA molecules) can be used as biomarkers of various disorders. They can circulate in patients' bodies encapsulated within extracellular vesicles (EVs).

OBJECTIVES: To identify miRNAs associated with the occurrence of cGvHD in EVs isolated from the plasma of patients after allogeneic HSCT.

MATERIAL AND METHODS: We performed global miRNA expression profiling in a pilot cohort of 3 cGvHD cases and 4 non-cGvHD patients without disease symptoms 90 days after the transplantation (control group).

RESULTS: The 2 groups were naturally clustered according to their miRNA profiles using unsupervised hierarchical clustering analysis. We identified 3 miRNAs that were differentially expressed in the cGvHD patients compared to the non-cGvHD patients. The levels of hsa-miR-630 and hsa-miR-374b-5p were lower in the cGvHD patients: 4.1-fold (p = 0.002) and 2.7-fold (p = 0.044), respectively. In contrast, the levels of hsa-miR-29c-3p were 5.8-fold higher (p = 0.004).

CONCLUSIONS: Our results suggest that miRNA profiles from plasma EVs may act as markers of cGvHD onset.

PMID:36398373 | DOI:10.17219/acem/155373

Evid Based Complement Alternat Med. 2022 Nov 8;2022:3336516. doi: 10.1155/2022/3336516. eCollection 2022.

ABSTRACT

Cannabigerol (CBG) is a cannabinoid from the plant Cannabis sativa that lacks psychotomimetic effects. Its precursor is the acidic form, cannabigerolic acid (CBGA), which is, in turn, a biosynthetic precursor of the compounds cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC). CBGA decarboxylation leads to the formation of neutral cannabinoid CBG, through a chemical reaction catalyzed by heat. On the basis of the growing interest in CBG and with the aim of highlighting scientific information on this phytocannabinoid, we focused the content of this article on its pharmacokinetic and pharmacodynamic characteristics and on its principal pharmacological effects. CBG is metabolized in the liver by the enzyme CYP2J2 to produce hydroxyl and di-oxygenated products. CBG is considered a partial agonist at the CB1 receptor (R) and CB2R, as well as a regulator of endocannabinoid signaling. Potential pharmacological targets for CBG include transient receptor potential (TRP) channels, cyclooxygenase (COX-1 and COX-2) enzymes, cannabinoid, 5-HT1A, and alpha-2 receptors. Pre-clinical findings show that CBG reduces intraocular pressure, possesses antioxidant, anti-inflammatory, and anti-tumoral activities, and has anti-anxiety, neuroprotective, dermatological, and appetite-stimulating effects. Several findings suggest that research on CBG deserves to be deepened, as it could be used, alone or in association, for novel therapeutic approaches for several disorders.

PMID:36397993 | PMC:PMC9666035 | DOI:10.1155/2022/3336516

Pharmgenomics Pers Med. 2022 Nov 8;15:959-965. doi: 10.2147/PGPM.S371709. eCollection 2022.

ABSTRACT

INTRODUCTION: Pharmacogenetics studies provide clinically relevant information on the identified associations between genetic variants and individual variability in drug response, which, in turn, offers great promise for guiding personalized drug therapy and clinical trial design. However, there is a lack of information concerning the evidence-based clinical annotations of specific CYP2E1 genetic variants.

AIM: To design and evaluate the next-generation sequencing-based method for full-length CYP2E1 gene polymorphism analysis.

MATERIALS AND METHODS: Seven gene-specific oligonucleotide primer pairs targeting overlapping CYP2E1 gene fragments spanning all nine gene exons with interleaving introns, untranslated (UTR) and intergenic regions were designed. Human DNA samples (n = 3) were used as a training set to check the primer performance and to optimize the PCR conditions. The effectiveness of the developed target amplification and sequencing protocol was evaluated using the test set comprising human DNA samples (n = 3) obtained from tuberculosis patients. Sequencing data analysis was performed on the Galaxy online-based platform.

RESULTS: The sequencing data quality was sufficient for the detection of genetic variants dispersed throughout the CYP2E1 gene with a high degree of confidence in fully covered regions achieving optimal reading depth of the targeted fragment with high base call accuracy.

CONCLUSION: Developed protocol can be applied in subpopulation-level association studies to determine whether single nucleotide variants (SNVs) or variant combinations from multiple regions of the CYP2E1 gene are of clinical significance.

PMID:36393979 | PMC:PMC9653044 | DOI:10.2147/PGPM.S371709

Pharmgenomics Pers Med. 2022 Nov 7;15:943-950. doi: 10.2147/PGPM.S385272. eCollection 2022.

ABSTRACT

The opioid epidemic in the United States has exposed the need for providers to limit opioid dispensing and identify at-risk patients prior to prescribing opioids. With pharmacogenomic testing, clinicians can analyze hundreds of medications-including commonly prescribed opioids-against genetic results to understand and predict risk and response. Moreover, knowledge of genotypic variants and altered function can help decrease trial and error prescribing, identify patients at-risk for adverse drug events, and improve pain control. This patient case demonstrates how pharmacogenomic test results identified drug-gene interactions and provided insight about a patient's inadequate opioid therapy response. With pharmacogenomic information, the patient's healthcare team discontinued opioid therapy and selected a more appropriate regimen for osteoarthritis (ie, celecoxib), resulting in improved pain control and quality of life.

PMID:36393978 | PMC:PMC9651068 | DOI:10.2147/PGPM.S385272

Pharmgenomics Pers Med. 2022 Nov 8;15:951-957. doi: 10.2147/PGPM.S377210. eCollection 2022.

ABSTRACT

PURPOSE: Autistic spectrum disorders (ASD) children and adolescents usually present comorbidities, with 40-70% of them affected by attention deficit hyperactivity disorders (ADHD). The first option of pharmacological treatment for these patients is methylphenidate (MPH). ASD children present more side effects and poorer responses to MPH than ADHD children. The objective of our study is to identify genetic biomarkers of response to MPH in ASD children and adolescents to improve its efficacy and safety.

PATIENTS AND METHODS: A retrospective study with a total of 140 ASD children and adolescents on MPH treatment was included. Fifteen polymorphisms within genes coding for the MPH target NET1 (SLC6A2) and for its primary metabolic pathway (CES1) were genotyped. Multivariate analyses including response phenotypes (efficacy, side-effects, presence of somnolence, irritability, mood alterations, aggressivity, shutdown, other side-effects) were performed for every polymorphism and haplotype.

RESULTS: Single marker analyses considering gender, age, and dose as covariates showed association between CES1 variants and MPH-induced side effects (rs2244613-G (p=0.04), rs2302722-C (p=0.02), rs2307235-A (p=0.03), and rs8192950-T alleles (p=0.03)), and marginal association between the CES1 rs2302722-C allele and presence of somnolence (p=0.05) and the SLC6A2 rs36029-G allele and shutdown (p=0.05). A CES1 haplotype combination was associated with efficacy and side effects (p=0.02 and 0.03 respectively). SLC6A2 haplotype combination was associated with somnolence (p=0.05).

CONCLUSION: CES1 genetic variants may influence the clinical outcome of MPH treatment in ASD comorbid with ADHD children and adolescents.

PMID:36393977 | PMC:PMC9653043 | DOI:10.2147/PGPM.S377210

Front Cell Dev Biol. 2022 Oct 28;10:1044672. doi: 10.3389/fcell.2022.1044672. eCollection 2022.

ABSTRACT

Mitochondrial dysfunction is strongly implicated in neurodegenerative diseases including age-related macular degeneration (AMD), which causes irreversible blindness in over 50 million older adults worldwide. A key site of insult in AMD is the retinal pigment epithelium (RPE), a monolayer of postmitotic polarized cells that performs essential functions for photoreceptor health and vision. Recent studies from our group and others have identified several features of mitochondrial dysfunction in AMD including mitochondrial fragmentation and bioenergetic defects. While these studies provide valuable insight at fixed points in time, high-resolution, high-speed live imaging is essential for following mitochondrial injury in real time and identifying disease mechanisms. Here, we demonstrate the advantages of live imaging to investigate RPE mitochondrial dynamics in cell-based and mouse models. We show that mitochondria in the RPE form extensive networks that are destroyed by fixation and discuss important live imaging considerations that can interfere with accurate evaluation of mitochondrial integrity such as RPE differentiation status and acquisition parameters. Our data demonstrate that RPE mitochondria show localized heterogeneities in membrane potential and ATP production that could reflect focal changes in metabolism and oxidative stress. Contacts between the mitochondria and organelles such as the ER and lysosomes mediate calcium flux and mitochondrial fission. Live imaging of mouse RPE flatmounts revealed a striking loss of mitochondrial integrity in albino mouse RPE compared to pigmented mice that could have significant functional consequences for cellular metabolism. Our studies lay a framework to guide experimental design and selection of model systems for evaluating mitochondrial health and function in the RPE.

PMID:36393836 | PMC:PMC9651161 | DOI:10.3389/fcell.2022.1044672

Front Med (Lausanne). 2022 Oct 25;9:1001876. doi: 10.3389/fmed.2022.1001876. eCollection 2022.

ABSTRACT

BACKGROUND: Different levels of evidence related to the variable responses of individuals to drug treatment have been reported in various pharmacogenomic (PGx) databases. Identification of gene-drug pairs with strong association evidence can be helpful in prioritizing the implementation of PGx guidelines and focusing on a gene panel. This study aimed to determine the pharmacogenes with the highest evidence-based association and to indicate their involvement in drug-gene interactions.

METHODOLOGY: The publicly available datasets CPIC, DPWG, and PharmGKB were selected to determine the pharmacogenes with the highest drug outcome associations. The upper two levels of evidence rated by the three scoring methods were specified (levels A-B in CPIC, 3-4 in DPWG, or 1-2 levels in PharmGKB). The identified pharmacogenes were further ranked in this study based on the number of medications they interacted with.

RESULTS: Fifty pharmacogenes, with high to moderately high evidence of associations with drug response alterations, with potential influence on the therapeutic and/or toxicity outcomes of 152 drugs were identified. CYP2D6, CYP2C9, CYP2C19, G6PD, HLA-B, SLCO1B1, CACNA1S, RYR1, MT-RNR1, and IFNL4 are the top 10 pharmacogenes, where each is predicted to impact patients' responses to ≥5 drugs.

CONCLUSION: This study identified the most important pharmacogenes based on the highest-ranked association evidence and their frequency of involvement in affecting multiple drugs. The obtained data is useful for customizing a gene panel for PGx testing. Identifying the strength of scientific evidence supporting drug-gene interactions aids drug prescribers in making the best clinical decision.

PMID:36388934 | PMC:PMC9640910 | DOI:10.3389/fmed.2022.1001876

Front Pharmacol. 2022 Oct 26;13:974570. doi: 10.3389/fphar.2022.974570. eCollection 2022.

ABSTRACT

Introduction: β-arrestin 1, a protein encoded by ARRB1 involved in receptor signaling, is a potential biomarker for the response to antidepressant drug (ATD) treatment in depression. We examined ARRB1 genetic variants for their association with response following ATD treatment in METADAP, a cohort of 6-month ATD-treated depressed patients. Methods: Patients (n = 388) were assessed at baseline (M0) and after 1 (M1), 3 (M3), and 6 months (M6) of treatment for Hamilton Depression Rating Scale (HDRS) changes, response, and remission. Whole-gene ARRB1 variants identified from high-throughput sequencing were separated by a minor allele frequency (MAF)≥5%. Frequent variants (i.e., MAF≥5%) annotated by RegulomeDB as likely affecting transcription factor binding were analyzed using mixed-effects models. Rare variants (i.e., MAF<5%) were analyzed using a variant set analysis. Results: The variant set analysis of rare variants was significant in explaining HDRS score changes (T = 878.9; p = 0.0033) and remission (T = -1974.1; p = 0.034). Rare variant counts were significant in explaining response (p = 0.016), remission (p = 0.022), and HDRS scores at M1 (p = 0.0021) and M3 (p=<0.001). rs553664 and rs536852 were significantly associated with the HDRS score (rs553664: p = 0.0055 | rs536852: p = 0.046) and remission (rs553664: p = 0.026 | rs536852: p = 0.012) through their interactions with time. At M6, significantly higher HDRS scores were observed in rs553664 AA homozygotes (13.98 ± 1.06) compared to AG heterozygotes (10.59 ± 0.86; p = 0.014) and in rs536852 GG homozygotes (14.88 ± 1.10) compared to AG heterozygotes (11.26 ± 0.95; p = 0.0061). Significantly lower remitter rates were observed in rs536852 GG homozygotes (8%, n = 56) compared to AG heterozygotes (42%, n = 105) at M6 (p = 0.0018). Conclusion: Our results suggest ARRB1 variants may influence the response to ATD treatment in depressed patients. Further analysis of functional ARRB1 variants and rare variant burden in other populations would help corroborate our exploratory analysis. β-arrestin 1 and genetic variants of ARRB1 may be useful clinical biomarkers for clinical improvement following ATD treatment in depressed individuals. Clinical Trial Registration: clinicaltrials.gov; identifier NCT00526383.

PMID:36386175 | PMC:PMC9644891 | DOI:10.3389/fphar.2022.974570

JAMA Netw Open. 2022 Nov 1;5(11):e2242370. doi: 10.1001/jamanetworkopen.2022.42370.

ABSTRACT

IMPORTANCE: The recent successes of poly-ADP ribose polymerase (PARP) inhibitors and belzutifan support germline genetic data as an exciting, accessible source for biomarkers in cancer treatment. This study hypothesizes, however, that most oncology clinical trials using germline data largely prioritize BRCA1/2 as biomarkers and PARP inhibitors as therapy.

OBJECTIVE: To characterize past and ongoing oncology trials that use germline data.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cross-sectional study of oncology trials used the Informa Trialtrove database to evaluate trial attributes. Trials using germline information (including the terms germline, hereditary, or inherited in the title, treatment plan, interventions, end points, objectives, results, or notes) and conducted globally between December 1, 1990, and April 4, 2022 (data freeze date), were included.

MAIN OUTCOMES AND MEASURES: Trials by cancer type, phase, participants, sponsor type, end points, outcomes, and locations were described. Associated biomarkers and mechanisms of action for studied therapeutic interventions were counted. How germline data in trial inclusion and exclusion criteria are associated with end points, outcomes, and enrollment were also examined.

RESULTS: A total of 887 of 84 297 (1.1%) oncology clinical trials in the Trialtrove database that use germline data were identified. Most trials were conducted in cancer types where PARP inhibitors are already approved. A total of 74.8% (672) of trials were performed in the phase 2 setting or above. Trials were primarily sponsored by industry (523 trials [59.0%]), academia (382 trials [43.1%]), and the government (274 trials [30.9%]), where trials may have multiple sponsor types. Among 343 trials using germline data with outcomes in Trialtrove, 180 (52.5%) reported meeting primary end points. Although BRCA1/2 are the most frequent biomarkers seen (BRCA1, 224 trials [25.3%]; BRCA2, 228 trials [25.7%]), trials also examine pharmacogenomic variants and germline mediators of somatic biomarkers. PARP inhibitors or immunotherapy were tested in 69.9% of trials; PARP inhibition was the most frequently studied mechanism (367 trials [41.4%]). An overwhelming number of trials using germline data were conducted in the US, Canada, and Europe vs other countries, mirroring disparities in cancer genetics data. Germline data in inclusion and exclusion criteria are associated with altered end point, outcomes, and enrollment compared with oncology trials with no germline data use. Examples of inclusion and exclusion criteria regarding germline data that may unintentionally exclude patients were identified.

CONCLUSIONS AND RELEVANCE: These findings suggest that for germline biomarkers to gain clinical relevance, trials must expand biomarkers, therapies, and populations under study.

PMID:36383380 | DOI:10.1001/jamanetworkopen.2022.42370

Bioinformatics. 2022 Nov 16:btac728. doi: 10.1093/bioinformatics/btac728. Online ahead of print.

ABSTRACT

MOTIVATION: Association testing on genome-wide association studies (GWAS) data is commonly performed under a single (mostly additive) genetic model framework. However, the underlying true genetic mechanisms are often unknown in practice for most complex traits. When the employed inheritance model deviates from the underlying model, statistical power may be reduced. To overcome this challenge, an integrative association test that directly infers the underlying genetic model from GWAS data has previously been proposed for single-SNP analysis.

RESULTS: In this article, we propose a Cauchy combination Genetic Model-based association test (CauchyGM) under a generalized linear model framework for SNP-set level analysis. CauchyGM does not require prior knowledge on the underlying inheritance patterns of each SNP. It performs a score test which first estimates an individual p-value of each SNP in a SNP-set with both minor allele frequency (MAF) > 1% and three genotypes and further aggregates the rest SNPs using SKAT. CauchyGM then combines the correlated p-values across multiple SNPs and different genetic models within the set using Cauchy Combination Test. To further accommodate both sparse and dense signal patterns, we also propose an omnibus association test (CauchyGM-O) by combining CauchyGM with SKAT and burden test. Our extensive simulations show that both CauchyGM and CauchyGM-O maintain type I error well at the genome-wide significance level and provide substantial power improvement compared to existing methods. We apply our methods to a pharmacogenomic GWAS data from a large cardiovascular randomized clinical trial. Both CauchyGM and CauchyGM-O identify several novel genome-wide significant genes.

AVAILABILITY AND IMPLEMENTATION: The R package CauchyGM is publicly available on github: https://github.com/ykim03517/CauchyGM.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:36383169 | DOI:10.1093/bioinformatics/btac728

Ann Hum Biol. 2022 Nov 16:1-31. doi: 10.1080/03014460.2022.2140826. Online ahead of print.

ABSTRACT

BACKGROUND: Organic anion transporting polypeptide 1B1 (OATP1B1) and the ATP-binding cassette subfamily G member 2, ABCG2, are important transporters involved in the transport of endogenous substrates and xenobiotics, including drugs. Genetic polymorphisms of these transporters have effect on transporter activity. There is significant interethnic variability in the frequency of allele variants.

AIM: To determined allele and genotype frequencies of ABCG2 and SLCO1B1 genes in Croatian populations of European descent.

SUBJECTS AND METHODS: A total of 905 subjects (482 women) were included. Genotyping for ABCG2 c.421C > A (rs2231142) and for SLCO1B1 c.521T > C (rs4149056), was performed by real-time polymerase chain reaction (PCR) using TaqMan® DME Genotyping Assays.

RESULTS: For ABCG2 c.421C > A, the frequency of CC, CA and AA genotypes was 81.4%, 17.8% and 0.8% respectively. The frequency of variant ABCG2 421A allele was 9.7%. For SLCO1B1 c.521T > C, the frequency of TT, TC and CC genotypes was 61.7%, 34.8% and 3.5% respectively. The frequency of variant SLCO1B1 521C allele was 20.9%.

CONCLUSION: The frequency of the ABCG2 and SLCO1B1 allelic variants and genotypes in the Croatian population is in accordance with other European populations. Pharmacogenetic analysis can serve to individualise drug therapy and minimise the risk of developing adverse drug reactions.

PMID:36382878 | DOI:10.1080/03014460.2022.2140826

Pharmacogenomics. 2022 Nov 16. doi: 10.2217/pgs-2022-0124. Online ahead of print.

ABSTRACT

Capecitabine is a widely-used antineoplastic drug, a prodrug to 5-fluorouracil which commonly induces gastrointestinal toxicity. Enterocolitis, as a rarely recognized gastrointestinal adverse effect (AE) of capecitabine, is potentially severe and usually results in antitumor treatment withdrawal. For the better management of severe AEs, pharmacogenetics is one promising field. Herein, we describe a case of capecitabine-induced enterocolitis presenting with severe diarrhea in order to improve recognition by clinicians. Moreover, we conduct a pharmacogenetic profile of the patient and review the current studies of gene polymorphisms of 5-fluorouracil-related diarrhea, hoping to offer a reference for further clinical pharmacogenetic practice in predicting capecitabine AEs showing diarrhea as the main symptom.

PMID:36382550 | DOI:10.2217/pgs-2022-0124

J Clin Pharm Ther. 2022 Nov 15. doi: 10.1111/jcpt.13804. Online ahead of print.

ABSTRACT

BACKGROUND: Tacrolimus is a widely prescribed immunosuppressant agent for kidney transplantation. However, optimal dosing is challenging due to its narrow therapeutic index, potentially serious adverse effects, and wide inter-individual variability in pharmacokinetics. Cytochrome P450 3A (CPY3A) enzymes metabolize tacrolimus, so allelic variants such as CYP3A4*22 and CYP3A5*3 may contribute to individual differences in pharmacokinetics and therapeutic efficacy of tacrolimus. This study assessed the frequency and influences of CYP3A4*22 and CYP3A5*3 genotypes, alone and combined, on tacrolimus pharmacokinetics and dose requirements in Egyptian kidney transplant patients.

METHODS: This is a prospective multicenter observational cohort study. Patients were genotyped for the CYP3A4*22 (rs35599367), and CYP3A5*3 (rs776746). Tacrolimus dose (mg), through blood level (ng/ml), and dose-adjusted trough concentration (C0/D) (ng/ml per mg/kg) were recorded during the first and third months post-transplantation and compared among genotype groups.

RESULTS: The CYP3A4*22 allele was rare (3.2% of subjects) while the CYP3A5*3 allele was widespread (90.38%) in this cohort. At the third month post-transplantation, median C0/D was significantly higher among CYP3A4*22 carriers than CYP3A4*1/*1 (146.25 [100-380] versus 85.57 [27-370] ng/ml per mg/kg, p = 0.028). Patients harbouring the one copy of the CYP3A4*22 allele and the CYP3A5*3/*3 genotype (n = 5) were classified as poor tacrolimus metabolizers, the CYP3A5*3/*3 plus CYP3A4*1/*1 genotype as intermediate metabolizers (n = 60), and the CYP3A4*1/*1 plus CYP3A5*1/*1 genotype as normal metabolizers (n = 13). During the first month post-transplantation, C0/D was significantly greater in poor metabolizers (113.07 ng/ml per mg/kg) than intermediate and normal metabolizers (90.380 and 49.09 ng/ml per mg/kg) (p < 0.0005). This rank order was also observed during the third month. Acute rejection rate and renal function at discharge did not differ among genotypes.

CONCLUSION: Pharmacogenetics testing for CYP3A4*22 and CYP3A5*3 before renal transplantation may help in the adjustment of tacrolimus starting dose and identify patients at risk of tacrolimus overexposure or underexposure.

PMID:36379901 | DOI:10.1111/jcpt.13804

Drug Metab Dispos. 2022 Nov 15:DMD-AR-2022-001048. doi: 10.1124/dmd.122.001048. Online ahead of print.

ABSTRACT

Warfarin, a commonly prescribed oral anticoagulant medication, is highly effective in treating deep vein thrombosis and pulmonary embolism. However, the clinical dosing of warfarin is complicated by high inter-individual variability in drug exposure and response and its narrow therapeutic index. CYP2C9 genetic polymorphism and drug-drug interactions (DDIs) are substantial contributors to this high variability of warfarin pharmacokinetics (PK), among numerous factors. Building a physiological-based pharmacokinetic (PBPK) model for warfarin is not only critical for a mechanistic characterization of warfarin PK, but also useful for investigating the complicated dose-exposure relationship of warfarin. Thus, the objective of this study was to develop a PBPK model for warfarin which integrates information regarding CYP2C9 genetic polymorphisms and their impact on DDIs. Generic PBPK models for both S- and R-warfarin, the two enantiomers of warfarin, were constructed in R with the mrgsolve package. As expected, a generic PBPK model structure did not adequately characterize the warfarin PK profile collected up to 15 days following the administration of single oral dose of warfarin, especially for S-warfarin. However, following the integration of an empirical target-mediated drug disposition (TMDD) component, the PBPK-TMDD model well characterized the PK profiles collected for both S- and R-warfarin in subjects with different CYP2C9 genotypes. Following the integration of enzyme inhibition and induction effects, the PBPK-TMDD model also characterized the PK profiles of both S- and R-warfarin in various DDI settings. The developed mathematic framework may be useful in building algorithms to better inform the clinical dosing of warfarin. Significance Statement The present study found a traditional physiology-based pharmacokinetic (PBPK) model cannot sufficiently characterize the pharmacokinetic profiles of warfarin enantiomers when warfarin is administered as a single dose, but a PBPK model with a target-mediated drug disposition mechanism can. After incorporating CYP2C9 genotypes and drug-drug interaction information, the developed model is anticipated to facilitate the understanding of warfarin disposition in subjects with different CYP2C9 genotypes in the absence and presence of both cytochrome P450 inhibitors and cytochrome P450 inducers.

PMID:36379708 | DOI:10.1124/dmd.122.001048

Drug Metab Pharmacokinet. 2022 Oct 18;47:100480. doi: 10.1016/j.dmpk.2022.100480. Online ahead of print.

ABSTRACT

Co-trimoxazole is mainly used as a first-line drug for treatment and prophylaxis against Pneumocystis jiroveci pneumonia. This drug, however, has been reported as the most common causative drug for severe cutaneous adverse reactions (SCARs). This study aimed to extensively elucidate the associations between genetic polymorphisms of HLA class I and genes involved in bioactivation and detoxification of co-trimoxazole on co-trimoxazole-induced SCARS in a large sample size and well-defined Thai SCARs patients. A total of 67 patients with co-trimoxazole-induced SCARs, consisting of 51 SJS/TEN patients and 16 DRESS patients, and 91 co-trimoxazole tolerant controls were enrolled in the study. The results clearly demonstrated that the HLA-B∗13:01 allele was significantly associated with co-trimoxazole-induced SCARs, especially with DRESS (OR = 8.44, 95% CI = 2.66-26.77, P = 2.94 × 10-4, Pc = 0.0126). Moreover, the HLA-C∗08:01 allele was significantly associated with co-trimoxazole-induced SJS/TEN in the HIV/AIDS patients with an OR of 8.51 (95% CI = 2.18-33.14, P = 8.60 × 10-4, Pc = 0.0241). None of the genes involved in the bioactivation and detoxification of co-trimoxazole investigated in this study play any major role in the development of all phenotypes of SCARs.

PMID:36379177 | DOI:10.1016/j.dmpk.2022.100480

Eur Heart J. 2022 Nov 15:ehac644. doi: 10.1093/eurheartj/ehac644. Online ahead of print.

NO ABSTRACT

PMID:36378517 | DOI:10.1093/eurheartj/ehac644

Cancer Cell Int. 2022 Nov 15;22(1):354. doi: 10.1186/s12935-022-02777-7.

ABSTRACT

Recent technological advances in nanoscience and material designing have led to the development of point-of-care devices for biomolecule sensing and cancer diagnosis. In situ and portable sensing devices for bedside, diagnosis can effectively improve the patient's clinical outcomes and reduce the mortality rate. Detection of exosomal RNAs by immuno-biochip with increased sensitivity and specificity to diagnose cancer has raised the understanding of the tumor microenvironment and many other technology-based biosensing devices hold great promise for clinical innovations to conquer the unbeatable fort of cancer metastasis. Electrochemical biosensors are the most sensitive category of biomolecule detection sensors with significantly low concentrations down to the atomic level. In this sense, this review addresses the recent advances in cancer detection and diagnosis by developing significant biological sensing devices that are believed to have better sensing potential than existing facilities.

PMID:36376956 | DOI:10.1186/s12935-022-02777-7

Tuberculosis (Edinb). 2022 Dec;137:102271. doi: 10.1016/j.tube.2022.102271. Epub 2022 Oct 20.

ABSTRACT

OBJECTIVE AND METHODS: Our objective was to investigate the role of patient pharmacogenetic variability in determining site of action target attainment during tuberculous meningitis (TBM) treatment. Rifampin and isoniazid PBPK model that included SLCO1B1 and NAT2 effects on exposures respectively were obtained from literature, modified, and validated using available cerebrospinal-fluid (CSF) concentrations. Population simulations of isoniazid and rifampin concentrations in brain interstitial fluid and probability of target attainment according to genotypes and M. tuberculosis MIC levels, under standard and intensified dosing, were conducted.

RESULTS: The rifampin and isoniazid model predicted steady-state drug concentration within brain interstitial fluid matched with the observed CSF concentrations. At MIC level of 0.25 mg/L, 57% and 23% of the patients with wild type and heterozygous SLCO1B1 genotype respectively attained the target in CNS with rifampin standard dosing, improving to 98% and 91% respectively with 35 mg/kg dosing. At MIC level of 0.25 mg/L, 33% of fast acetylators attained the target in CNS with isoniazid standard dosing, improving to 90% with 7.5 mg/kg dosing.

CONCLUSION: In this study, the combined effects of pharmacogenetic and M. tuberculosis MIC variability were potent determinants of target attainment in CNS. The potential for genotype-guided dosing during TBM treatment should be further explored in prospective clinical studies.

PMID:36375279 | DOI:10.1016/j.tube.2022.102271

Nature. 2022 Nov 14. doi: 10.1038/s41586-022-05492-5. Online ahead of print.

NO ABSTRACT

PMID:36376532 | DOI:10.1038/s41586-022-05492-5

Metabolism. 2022 Nov 11:155344. doi: 10.1016/j.metabol.2022.155344. Online ahead of print.

ABSTRACT

Arrhythmogenic cardiomyopathy (ACM) is characterized by life-threatening ventricular arrhythmias and sudden cardiac death and affects hundreds of thousands of patients worldwide. The deletion of Arginine 14 (p.R14del) in the phospholamban (PLN) gene has been implicated in the pathogenesis of ACM. PLN is a key regulator of sarcoplasmic reticulum (SR) Ca2+ cycling and cardiac contractility. Despite global gene and protein expression studies, the molecular mechanisms of PLN-R14del ACM pathogenesis remain unclear. Using a humanized PLN-R14del mouse model and human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs), we investigated the transcriptome-wide mRNA splicing changes associated with the R14del mutation. We identified >200 significant alternative splicing (AS) events and distinct AS profiles were observed in the right (RV) and left (LV) ventricles in PLN-R14del compared to WT mouse hearts. Enrichment analysis of the AS events showed that the most affected biological process was associated with "cardiac cell action potential", specifically in the RV. We found that splicing of 2 key genes, Trpm4 and Camk2d, which encode proteins regulating calcium homeostasis in the heart, were altered in PLN-R14del mouse hearts and human iPSC-CMs. Bioinformatical analysis pointed to the tissue-specific splicing factors Srrm4 and Nova1 as likely upstream regulators of the observed splicing changes in the PLN-R14del cardiomyocytes. Our findings suggest that aberrant splicing may affect Ca2+-homeostasis in the heart, contributing to the increased risk of arrythmogenesis in PLN-R14del ACM.

PMID:36375644 | DOI:10.1016/j.metabol.2022.155344