Heliyon. 2023 Apr 14;9(4):e15423. doi: 10.1016/j.heliyon.2023.e15423. eCollection 2023 Apr.

ABSTRACT

The sodium channel Nav1.9 is expressed in the sensory neurons of small diameter dorsal root ganglia that transmit pain signals, and gain-of-function Nav1.9 mutations have been associated with both painful and painless disorders. We initially determined that some Nav1.9 mutations are responsible for familial episodic pain syndrome observed in the Japanese population. We therefore generated model mice harboring one of the more painful Japanese mutations, R222S, and determined that dorsal root ganglia hyperexcitability was the cause of the associated pain. ANP-230 is a novel non-opioid drug with strong inhibitory effects on Nav1.7, 1.8 and 1.9, and is currently under clinical trials for patients suffering from familial episodic pain syndrome. However, little is known about its mechanism of action and effects on pain sensitivity. In this study, we therefore investigated the inhibitory effects of ANP-230 on the hypersensitivity of Nav1.9 p.R222S mutant model mouse to pain. In behavioral tests, ANP-230 reduced the pain response of the mice, particularly to heat or mechanical stimuli, in a concentration- and time-dependent manner. Furthermore, ANP-230 suppressed the repetitive firing of dorsal root ganglion neurons of these mutant mice. Our results clearly demonstrate that ANP-230 is an effective analgesic for familial episodic pain syndrome resulting from DRG neuron hyperexcitability, and that such analgesic effects are likely to be of clinical significance.

PMID:37151704 | PMC:PMC10161610 | DOI:10.1016/j.heliyon.2023.e15423

Cancer Rep (Hoboken). 2023 May 7:e1830. doi: 10.1002/cnr2.1830. Online ahead of print.

ABSTRACT

BACKGROUND: Choosing the most effective chemotherapeutic agent with safest side effect profile is a common challenge in cancer treatment. Although there are standardized chemotherapy protocols in place, protocol changes made after extensive clinical trials demonstrate significant improvement in the efficacy and tolerability of certain drugs. The pharmacokinetics, pharmacodynamics, and tolerance of anti-cancer medications are all highly individualized. A driving force behind these differences lies within a person's genetic makeup.

RECENT FINDINGS: Pharmacogenomics, the study of how an individual's genes impact the processing and action of a drug, can optimize drug responsiveness and reduce toxicities by creating a customized medication regimen. However, these differences are rarely considered in the initial determination of standardized chemotherapeutic protocols and treatment algorithms. Because pharmacoethnicity is influenced by both genetic and nongenetic variables, clinical data highlighting disparities in the frequency of polymorphisms between different ethnicities is steadily growing. Recent data suggests that ethnic variations in the expression of allelic variants may result in different pharmacokinetic properties of the anti-cancer medication. In this article, the clinical outcomes of various chemotherapy classes in patients of different ethnicities were reviewed.

CONCLUSION: Genetic and nongenetic variables contribute to the interindividual variability in response to chemotherapeutic drugs. Considering pharmacoethnicity in the initial determination of standard chemotherapeutic protocols and treatment algorithms can lead to better clinical outcomes of patients of different ethnicities.

PMID:37150853 | DOI:10.1002/cnr2.1830

Mol Genet Genomics. 2023 May 7. doi: 10.1007/s00438-023-02011-7. Online ahead of print.

ABSTRACT

Diabetes is known to increase susceptibility to hypertension due to increase in inflammation, oxidative stress, and endothelial dysfunction, leading to vascular stiffness. The polytherapy might lead to several drug-drug interactions (DDIs), which cause certain life-threatening complications such as diabetic nephropathy and hypoglycaemia. So, in this review we focused on drug-drug interactions and impact of genetic factors on drug responses for better disease management. Drug-drug interactions (DDIs) may act either synergistically or antagonistically. For instance, a combination of metformin with angiotensin II receptor antagonist or angiotensin-converting enzyme inhibitors (ACEIs) synergistically improves glucose absorption, whereas the same hypertensive drug combination with sulphonylurea might cause severe hypoglycaemia sometimes. Thiazolidinediones (TDZs) can cause fluid retention and heart failure when taken alone, but a combination of angiotensin II receptor antagonist with TZDs prevents these side effects. Interindividual genetic variation affects the DDI response. We found two prominent genes, GLUT4 and PPAR-γ, which are common targets for most of the drug. So, all of these findings established a connection between drug-drug interaction and genetics, which might be used for effective disease management.

PMID:37149837 | DOI:10.1007/s00438-023-02011-7

Pharmacogenomics J. 2023 May 6. doi: 10.1038/s41397-023-00308-9. Online ahead of print.

ABSTRACT

OBJECTIVES: To investigate the association between the functional Fc gamma receptor 3 A (FCGR3A) V158F and FCGR2A R131H polymorphisms and rituximab therapy in patients with autoimmune diseases.

METHODS: We searched the Medline, Embase, and Cochrane databases for relevant articles. We conducted a meta-analysis of the association between FCGR3A V158F and FCGR2A R131H polymorphisms and responsiveness to rituximab in patients with autoimmune diseases.

RESULTS: Eleven studies, consisting of 661 responders and 267 non-responders for FCGR3A V158F polymorphism and 156 responders and 89 non-responders for FCGR2A R131H polymorphism, were included. The meta-analysis revealed a significant association between the FCGR3A V allele and responsiveness to rituximab (odds ratio [OR] = 1.600, 95% confidence interval [CI] = 1.268-2.018, P < 0.001). Furthermore, associations were found using the dominant and homozygous contrast models. Subgroup analysis showed an association between the FCGR3A V allele and responsiveness to rituximab in European, RA, ITP, small (<50) and large (≥50) groups, and short- (≤6 months) and long-term follow-up periods (≥6 months). These associations were also found in recessive, dominant or homozygous contrast models. Meta-analysis revealed no association between the FCGR2A R allele and responsiveness to rituximab (OR = 1.243, 95% CI = 0.825-1.873, P = 0.229).

CONCLUSIONS: We demonstrated that the FCGR3A F158V polymorphism is associated with better responsiveness to rituximab therapy in patients with autoimmune diseases, indicating that individuals carrying the FCGR3A V allele will likely respond better to rituximab. However, FCGR2A R131H polymorphism was not associated with better response to rituximab.

PMID:37149714 | DOI:10.1038/s41397-023-00308-9

Arch Toxicol. 2023 May 6. doi: 10.1007/s00204-023-03498-0. Online ahead of print.

NO ABSTRACT

PMID:37148318 | DOI:10.1007/s00204-023-03498-0

Expert Opin Drug Saf. 2023 May 6. doi: 10.1080/14740338.2023.2212152. Online ahead of print.

ABSTRACT

BACKGROUND: Clopidogrel's responsiveness may be affected by the paraoxonase-1 (PON1) enzyme encoded by the Q192R PON1 genetic variant. We aimed to determine the aggregated risk of MACEs associated with carrying Q192R PON1 genetic variant in patients taking clopidogrel.

RESEARCH DESIGN AND METHODS: Different databases were searched systematically for eligible studies, and risk ratio (RR) was measured using RevMan software where P<0.05 was set statistically significant.

RESULTS: Nineteen studies were included consisting of 17,815 patients. It was found that patients carrying either homozygous or a combination of heterozygous and homozygous variants were not significantly associated with increased risk of MACEs compared to the non-carriers (QQ vs. RR: RR = 0.99, 95% CI 0.69-1.42, P=0.96; QQ+QR vs RR; RR=1.05, 95% CI 0.82-1.35, P=0.70). The risk of MACE was also not significantly different in other genetic model (QQ vs QR+RR) (RR=1.09, 95% CI 0.93-1.27, P=0.30). Further, bleeding events were not significantly different in different genetic models (QQ vs RR; RR=1.13, 95% CI 0.58-2.21, P=0.71; QQ+QR vs RR; RR=1.09, 95% CI 0.66-1.81, P=0.73; QQ vs QR+RR; RR=1.08, 95% CI 0.76-1.55, P=0.66).

CONCLUSIONS: The results suggest that the Q192R PON1 genetic polymorphism has no significant impact on the risk of MACEs or bleeding events in patients treated with clopidogrel.

PMID:37148265 | DOI:10.1080/14740338.2023.2212152

Farm Hosp. 2023 May 3:S1130-6343(23)00024-7. doi: 10.1016/j.farma.2023.03.004. Online ahead of print.

ABSTRACT

OBJECTIVE: Capecitabine, an antineoplastic drug used in the treatment of breast and colon cancer, can cause severe, even fatal toxicity in some patients. The interindividual variability of this toxicity is largely due to genetic variations in target genes and enzymes of metabolism of this drug, such as Thymidylate Synthase (TS) and Dihydropyrimidine Dehydrogenase (DPD). The enzyme Cytidine Deaminase (CDA), involved in the activation of capecitabine, also has several variants associated with an increased risk of toxicity to treatment, although its role as a biomarker is not yet clearly defined. Therefore, our main objective is to study the association between the presence of genetic variants in CDA gen, CDA enzymatic activity and the development of severe toxicity in patients treated with capecitabine whose initial dose was adjusted based on the genetic profile of the DPD gen (DPYD).

METHOD: Prospective multicenter observational cohort study, focused on the analysis of the genotype-phenotype association of the CDA enzyme. After the experimental phase, an algorithm will be developed to determine the dose adjustment needed to reduce the risk of treatment toxicity according to CDA genotype, developing a Clinical Guide for capecitabine dosing according to genetic variants in DPYD and CDA. Based on this guide, a Bioinformatics Tool will be created to generate the pharmacotherapeutic report automatically, facilitating the implementation of pharmacogenetic advice in clinical practice. This tool will be a great support in making pharmacotherapeutic decisions based on the patient's genetic profile, incorporating precision medicine into clinical routine. Once the usefulness of this tool has been validated, it will be offered free of charge to facilitate the implementation of pharmacogenetics in hospital centers and equitably benefit all patients on capecitabine treatment.

PMID:37147242 | DOI:10.1016/j.farma.2023.03.004

Cancer Lett. 2023 May 3:216219. doi: 10.1016/j.canlet.2023.216219. Online ahead of print.

ABSTRACT

Tumor immunotherapy is a new therapeutic approach that has been evolving in the last decade and has dramatically changed the treatment options for cancer. Circular RNAs (circRNAs) are non-coding RNAs (ncRNAs) with high stability, tissue-specific and cell-specific expression. There is growing evidence that circRNAs are involved in the regulation of both adaptive and innate immunity. They play important roles in tumor immunotherapy by affecting macrophage, NK and T cell function. The high stability and tissue specificity make them ideal candidate biomarkers for therapeutic effects. CircRNAs also represent one of promising targets or adjuvant for immunotherapy. Investigations in this field progress rapidly and provide essential support for the diagnosis, prognosis and treatment guidance of cancers in the future. In this review, we summarize the role of circRNAs on tumor immunity from the viewpoint of innate and adaptive immunity, and explore the role of circRNAs in tumor immunotherapy.

PMID:37146937 | DOI:10.1016/j.canlet.2023.216219

Front Cardiovasc Med. 2023 Apr 18;10:1162205. doi: 10.3389/fcvm.2023.1162205. eCollection 2023.

ABSTRACT

Arrhythmogenic cardiomyopathy affects significant number of patients worldwide and is characterized by life-threatening ventricular arrhythmias and sudden cardiac death. Mutations in multiple genes with diverse functions have been reported to date including phospholamban (PLN), a key regulator of sarcoplasmic reticulum (SR) Ca2+ homeostasis and cardiac contractility. The PLN-R14del variant in specific is recognized as the cause in an increasing number of patients worldwide, and extensive investigations have enabled rapid advances towards the delineation of PLN-R14del disease pathogenesis and discovery of an effective treatment. We provide a critical overview of current knowledge on PLN-R14del disease pathophysiology, including clinical, animal model, cellular and biochemical studies, as well as diverse therapeutic approaches that are being pursued. The milestones achieved in <20 years, since the discovery of the PLN R14del mutation (2006), serve as a paradigm of international scientific collaboration and patient involvement towards finding a cure.

PMID:37144056 | PMC:PMC10151546 | DOI:10.3389/fcvm.2023.1162205

Front Microbiol. 2023 Apr 18;14:1126808. doi: 10.3389/fmicb.2023.1126808. eCollection 2023.

ABSTRACT

Many lines of evidence demonstrate the associations of colorectal cancer (CRC) with intestinal microbial dysbiosis. Recent reports have suggested that maintaining the homeostasis of microbiota and host might be beneficial to CRC patients, but the underlying mechanisms remain unclear. In this study, we established a CRC mouse model of microbial dysbiosis and evaluated the effects of fecal microbiota transplantation (FMT) on CRC progression. Azomethane and dextran sodium sulfate were used to induce CRC and microbial dysbiosis in mice. Intestinal microbes from healthy mice were transferred to CRC mice by enema. The vastly disordered gut microbiota of CRC mice was largely reversed by FMT. Intestinal microbiota from normal mice effectively suppressed cancer progression as assessed by measuring the diameter and number of cancerous foci and significantly prolonged survival of the CRC mice. In the intestine of mice that had received FMT, there were massive infiltration of immune cells, including CD8+ T and CD49b+ NK, which is able to directly kill cancer cells. Moreover, the accumulation of immunosuppressive cells, Foxp3+ Treg cells, seen in the CRC mice was much reduced after FMT. Additionally, FMT regulated the expressions of inflammatory cytokines in CRC mice, including down-regulation of IL1a, IL6, IL12a, IL12b, IL17a, and elevation of IL10. These cytokines were positively correlated with Azospirillum_sp._47_25, Clostridium_sensu_stricto_1, the E. coli complex, Akkermansia, Turicibacter, and negatively correlated with Muribaculum, Anaeroplasma, Candidatus_Arthromitus, and Candidatus Saccharimonas. Furthermore, the repressed expressions of TGFb, STAT3 and elevated expressions of TNFa, IFNg, CXCR4 together promoted the anti-cancer efficacy. Their expressions were positively correlated with Odoribacter, Lachnospiraceae-UCG-006, Desulfovibrio, and negatively correlated with Alloprevotella, Ruminococcaceae UCG-014, Ruminiclostridium, Prevotellaceae UCG-001 and Oscillibacter. Our studies indicate that FMT inhibits the development of CRC by reversing gut microbial disorder, ameliorating excessive intestinal inflammation and cooperating with anti-cancer immune responses.

PMID:37143538 | PMC:PMC10151806 | DOI:10.3389/fmicb.2023.1126808

Br J Clin Pharmacol. 2023 May 4. doi: 10.1111/bcp.15762. Online ahead of print.

ABSTRACT

BACKGROUND: CYP2C19 is a hepatic enzyme involved in the metabolism of antidepressants associated with increased gastrointestinal bleed (GIB) risk. The aim of our study is to explore a possible association between loss of function CYP2C19 genotypes and GIB in South-Asian ancestry participants prescribed antidepressants.

METHODS: Genes & Health participants with a record in Barts Health NHS Trust (N 22,753) were studied using a cross-sectional approach. CYP2C19 diplotypes were assessed and metabolizer type inferred from consortia guidance. Fisher's exact test was used to compare prevalence of GIB in different metabolizer categories. Multivariable regression was used to test for association between antidepressant prescriptions and GIB and between CYP2C19 metabolizer state and GIB in the sub cohort prescribed antidepressants.

RESULTS: Antidepressants were frequently prescribed (47%, N= 10,612). 864 participants (4%) had a GIB; 534 (62%) had been prescribed a CYP2C19 metabolized antidepressant. There was an independent association between antidepressant prescriptions and GIB events (OR 1.8, CI 1.5-2.0, p <0.0001). There was no relationship between CYP2C19 inferred poor (p 0.56) or intermediate (p 0.53) metabolizer status and GIB in those prescribed an antidepressant in unadjusted analysis. A multivariable logistic regression model did not show an independent association between poor (p 0.54) or intermediate (p 0.62) CYP2C19 metabolizers and GIB in the sub cohort prescribed antidepressants.

CONCLUSIONS: CYP2C19 dependent antidepressants are associated with increased GIB prevalence. GIB appeared independent from CYP2C19 metabolizer genotype in individuals who had been prescribed antidepressants. Precision dosing based on CYP2C19 genetic information alone is unlikely to reduce GIB prevalence.

PMID:37143396 | DOI:10.1111/bcp.15762

Curr Comput Aided Drug Des. 2023 May 4. doi: 10.2174/1573409919666230504111802. Online ahead of print.

ABSTRACT

INTRODUCTION: To investigate the mechanism of Danggui Liuhuang Tang (DGLHT) in the treatment of hyperthyroidism (HT), we explored the multi-component, multi-target, and multi-pathway mechanism based on the network pharmacology method of traditional Chinese medicine.

METHOD: To take DGLHT into the blood components as the research object, we used GeneCards, Drungbank, Therapeutic Target Database (TTD), Online Mendelian Inheritance in Man (OMIM), Pharmacogenetics and Pharmacogenomics Knowledge Base (PharmGKB), and other databases to predict the potential target of the components. Then, it was integrated with the predicted targets of HT disease to obtain the potential targets of DGLHT in the treatment of HT. We used String database and Cytoscape software for protein-protein interaction network (PPI) construction, and DAVID platform for Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation, the Cytoscape software was used to construct a "component-target-pathway" network; the AutoDock Vina platform was used to conduct molecular docking between the blood entry components and key targets.

RESULT: According to the analysis, a total of 93 active ingredients, 348 disease-related targets, and 36 potential targets were screened out. Among them, key targets such as MAPK1, CCND1, AKT1, and TNF exert curative effects, and the main pathways are the HIF-1 signaling pathway, FoxO signaling pathway, Chemokine signaling pathway, TNF signaling pathway, Toll-like receptor signaling pathway, T cell receptor signaling pathway, Jak-STAT signaling pathway, and other pathways. Molecular docking results verified the interaction between active ingredients and key targets, among which rustication and quercetin had high docking affinity with key target proteins MAPK1 and CCND1.

CONCLUSION: This study preliminary revealed that DGLHT has the characteristics of multi-component, multi-target, and multi-pathway in the treatment of HT, and it established a scientific foundation for a more detailed investigation of DGLHT's molecular mechanism in the treatment of HT.

PMID:37143282 | DOI:10.2174/1573409919666230504111802

Placenta. 2023 Apr 26;137:88-95. doi: 10.1016/j.placenta.2023.04.019. Online ahead of print.

ABSTRACT

INTRODUCTION: The aim of this study was to investigate the effects of cytochrome P450 (CYP) 2J2, CYP2C9, CYP2C19 and CYP4F2, CYP4F3 and CYP4A11 genetic polymorphisms in preeclampsia and gestational hypertension (GHT) patients in a sample of Turkish population.

MATERIALS-METHODS: Patients (n = 168; 110 GHT and 58 preeclampsia) and healthy pregnant women (n = 155, controls) participated in the study. For genotyping, polymerase chain reaction (PCR) and restriction analysis (RFLP) were used. Substance levels were measured using LC-MS.

RESULTS: Plasma DHET levels in GHT and preeclampsia patients were significantly lower than those in the control group (62.7%, 66.3% vs.100.0%, respectively, p < 0.0001). An increase in CYP2J2*7 allele frequency was observed in the preeclampsia group, as compared to GHT group (12.1% vs. 4.5%; odds ratio, O.R. = 2.88, p < 0.01). The frequencies of CYP2C19*2 and*17 alleles were higher in GHT group as compared to the control group (17.7% vs. 11.6%, O.R. = 1.99, p < 0.01; and 28.6% vs.18.4%, O.R. = 2.03, p < 0.01, respectively). An increased frequency of CYP4F3 rs3794987 G allele was found in GHT group as compared to the control group (48.0% vs. 38.0%; O.R. = 1.53, p < 0.01).

DISCUSSION: DHET plasma levels were significantly reduced in hypertensive pregnant groups as compared to the control group. The allele frequency distributions for CYP2J2*7, CYP2C19 *2, *17 and CYP4F3 rs3794987 were significantly different in hypertensive pregnant patients as compared to the healthy control subjects. Our results may suggest that investigated genetic polymorphisms may be useful in diagnosis and clinical management of GHT and preeclampsia patients.

PMID:37141740 | DOI:10.1016/j.placenta.2023.04.019

Pharmacogenomics J. 2023 May 4. doi: 10.1038/s41397-023-00306-x. Online ahead of print.

ABSTRACT

Pharmacogenomics (PGx) is rapidly growing branch of molecular genetics with high potentials to influence therapeutics. This review evaluates knowledge and attitudes of medical and pharmacy students about PGx. A literature search was conducted in electronic databases and studies were selected by following precise eligibility criteria. After quality assessment, studies were reviewed systematically, and meta-analyses of proportions were performed to estimate response rates of students. Fifteen studies (5509 students; 69% [95% confidence interval (CI): 60%, 77%] females) were included. Among students, 28% [95%CI: 12, 46] had adequate PGx knowledge; 65% [95%CI: 55, 75] were willing to have PGx test for their own risk assessment; 78% [95%CI: 71, 84] had intention to incorporate PGx in future practice; and 32% [95%CI: 21, 43] were satisfied with current PGx component of curriculum. Age, advanced year of educational program, and more time spent in PGx education were positively associated with PGx knowledge and positive attitudes.

PMID:37142641 | DOI:10.1038/s41397-023-00306-x

JCO Precis Oncol. 2023 May;7:e2200557. doi: 10.1200/PO.22.00557.

ABSTRACT

PURPOSE: Analysis of somatic variant profiles in retrospectively collected pairs of primary tumors and synchronous liver metastases from surgically treated patients with colorectal carcinomas. Mutational profiles were compared between groups of patients stratified by response to chemotherapy and survival.

PATIENTS AND METHODS: The study used whole-exome sequencing of tumor sample pairs from 20 patients diagnosed and treated at a single center. The Cancer Genome Atlas COAD-READ data set (n = 380) was used for validation in silico, where possible.

RESULTS: The most frequently altered oncodrivers were APC (55% in primaries and 60% in metastases), TP53 (50/45), TRIP11 (30/5), FAT4 (20/25), and KRAS (15/25). Harboring variants with a high or moderate predicted functional effect in KRAS in primary tumors was significantly associated with poor relapse-free survival in both our sample set and the validation data set. We found a number of additional prognostic associations, including mutational load, alterations in individual genes, oncodriver pathways, and single base substitution (SBS) signatures in primary tissues, which were not confirmed by validation. Altered ATM, DNAH11, and MUC5AC, or a higher share of SBS24 signature in metastases seemed to represent poor prognostic factors, but because of a lack of suitable validation data sets, these results must be treated with extreme caution. No gene or profile was significantly associated with response to chemotherapy.

CONCLUSION: Taken together, we report subtle differences in exome mutational profiles between paired primary tumors and synchronous liver metastases and a distinct prognostic relevance of KRAS in primary tumors. Although the general scarcity of primary tumor-synchronous metastasis sample pairs with high-quality clinical data makes robust validation difficult, this study provides potentially valuable data for utilization in precision oncology and could serve as a springboard for larger studies.

PMID:37141551 | DOI:10.1200/PO.22.00557

Cancer Res. 2023 May 4:CAN-22-2996. doi: 10.1158/0008-5472.CAN-22-2996. Online ahead of print.

ABSTRACT

Major advances have been made in the field of precision medicine for treating cancer. However, many open questions remain that need to be answered to realize the goal of matching every cancer patient to the most efficacious therapy. To facilitate these efforts, we have developed CellMinerCDB:NCATS (https://discover.nci.nih.gov/rsconnect/cellminercdb_ncats/), which makes available activity information for 2,675 drugs and compounds, including multiple non-oncology drugs and 1,866 drugs and compounds unique to the National Center for Advancing Translational Sciences (NCATS). CellMinerCDB:NCATS comprises 183 cancer cell lines with 72 unique to NCATS including some from previously understudied tissues of origin. Multiple forms of data from different institutes are integrated, including single and combination drug activity, DNA copy number, methylation and mutation, transcriptome, protein levels, histone acetylation and methylation, metabolites, CRISPR and miscellaneous signatures. Curation of cell lines and drug names enables cross-database (CDB) analyses. Comparison of the datasets is made possible by the overlap between cell lines and drugs across databases. Multiple univariate and multivariate analysis tools are built-in, including linear regression and LASSO. Examples have been presented here for the clinical topoisomerase I (TOP1) inhibitors topotecan and irinotecan/SN-38. This web-application provides both substantial new data and significant pharmacogenomic integration allowing exploration of interrelationships.

PMID:37140427 | DOI:10.1158/0008-5472.CAN-22-2996

Brief Bioinform. 2023 May 3:bbad154. doi: 10.1093/bib/bbad154. Online ahead of print.

ABSTRACT

Circular RNAs (circRNAs) are single-stranded and covalently closed non-coding RNA molecules originated from RNA splicing. Their functions include regulatory potential over other RNA species, such as microRNAs, messenger RNAs and RNA binding proteins. For circRNA identification, several algorithms are available and can be classified in two major types: pseudo-reference-based and split-alignment-based approaches. In general, the data generated from circRNA transcriptome initiatives is deposited on public specific databases, which provide a large amount of information on different species and functional annotations. In this review, we describe the main computational resources for the identification and characterization of circRNAs, covering the algorithms and predictive tools to evaluate its potential role in a particular transcriptomics project, including the public repositories containing relevant data and information for circRNAs, recapitulating their characteristics, reliability and amount of data reported.

PMID:37139555 | DOI:10.1093/bib/bbad154

Rev Med Suisse. 2023 Apr 19;19(823):783. doi: 10.53738/REVMED.2023.19.823.783.

NO ABSTRACT

PMID:37133963 | DOI:10.53738/REVMED.2023.19.823.783

Pharmacogenomics J. 2023 May 3. doi: 10.1038/s41397-023-00303-0. Online ahead of print.

ABSTRACT

Hepatotoxicity is a frequent complication during maintenance therapy of acute lymphoblastic leukemia (ALL) with 6-mercaptopurine and methotrexate. Elevated levels of methylated 6-mercaptopurine metabolites (MeMP) are associated with hepatotoxicity. However, not all mechanisms are known that lead to liver failure in patients with ALL. Variants in the POLG gene, which encodes the catalytic subunit of mitochondrial DNA polymerase gamma (POLG1), have been related to drug-induced hepatotoxicity, for example, by sodium valproate. The association of common POLG variants with hepatotoxicity during maintenance therapy was studied in 34 patients with childhood ALL. Of the screened POLG variants, four different variants were detected in 12 patients. One patient developed severe hepatotoxicity without elevated MeMP levels and harbored a heterozygous POLG p.G517V variant, which was not found in the other patients.

PMID:37138020 | DOI:10.1038/s41397-023-00303-0

Drug Metab Dispos. 2023 May 3:DMD-AR-2022-000972. doi: 10.1124/dmd.122.000972. Online ahead of print.

ABSTRACT

In recent years, some endogenous substrates of organic anion transporting polypeptide 1B (OATP1B) have been identified and characterized as potential biomarkers to assess OATP1B-mediated clinical drug-drug interactions (DDIs). However, quantitative determination of their selectivity to OATP1B are still limited. In this study, we developed a relative activity factor (RAF) method to determine the relative contribution of hepatic uptake transporters OATP1B1, OATP1B3, OATP2B1, and sodium-taurocholate co-transporting polypeptide (NTCP) on hepatic uptake of several OATP1B biomarkers, including coproporphyrins I (CPI), CPIII, sulfate conjugates of bile acids: glycochenodeoxycholic acid sulfate (GCDCA-S), glycodeoxycholic acid sulfate (GDCA-S), and taurochenodeoxycholic acid sulfate (TCDCA-S). RAF values for OATP1B1, OATP1B3, OATP2B1, and NTCP were determined in cryopreserved human hepatocytes and transporter transfected cells using pitavastatin, cholecystokinin, resveratrol-3-O-β-D-glucuronide, and taurocholic acid (TCA) as reference compounds, respectively. OATP1B1-specific pitavastatin uptake in hepatocytes was measured in the absence and presence of 1 µM estropipate, while NTCP-specific TCA uptake was measured in the presence of 10 µM rifampin. Our studies suggested that CPI was a more selective biomarker for OATP1B1 than CPIII, while GCDCA-S and TCDCA-S were more selective to OATP1B3. OATP1B1 and OATP1B3 equally contributed to hepatic uptake of GDCA-S. The mechanistic static model, incorporating the fraction transported (ft) of CPI/III estimated by RAF and in vivo elimination data, predicted several perpetrator interactions with CPI/III. Overall, RAF method combined with pharmacogenomic and DDI studies is a useful tool to determine the selectivity of transporter biomarkers and facilitate the selection of appropriate biomarkers for DDI evaluation. Significance Statement We developed a new RAF method to quantitatively determine the contribution of hepatic uptake transporters OATP1B1, OATP1B3, OATP2B1, and NTCP on several OATP1B biomarkers (CPI, CPIII, GCDCA-S, GDCA-S, and TCDCA-S) and evaluated their predictivity on perpetrator-biomarker interactions. Our studies suggest that RAF method is a useful tool to determine the selectivity of transporter biomarkers. This method combined with pharmacogenomic and DDI studies will facilitate mechanistic interpretation and modeling of biomarker data and the selection of appropriate biomarkers for DDI evaluation.

PMID:37137718 | DOI:10.1124/dmd.122.000972