Front Neurosci. 2022 Jun 16;16:892022. doi: 10.3389/fnins.2022.892022. eCollection 2022.

ABSTRACT

OBJECTIVE: To investigate the potential pathogenic mechanism of temporal lobe epilepsy with hippocampal sclerosis (TLE+HS) by analyzing the expression profiles of microRNA/ mRNA/ lncRNA/ DNA methylation in brain tissues.

METHODS: Brain tissues of six patients with TLE+HS and nine of normal temporal or parietal cortices (NTP) of patients undergoing internal decompression for traumatic brain injury (TBI) were collected. The total RNA was dephosphorylated, labeled, and hybridized to the Agilent Human miRNA Microarray, Release 19.0, 8 × 60K. The cDNA was labeled and hybridized to the Agilent LncRNA+mRNA Human Gene Expression Microarray V3.0,4 × 180K. For methylation detection, the DNA was labeled and hybridized to the Illumina 450K Infinium Methylation BeadChip. The raw data was extracted from hybridized images using Agilent Feature Extraction, and quantile normalization was performed using the Agilent GeneSpring. P-value < 0.05 and absolute fold change >2 were considered the threshold of differential expression data. Data analyses were performed using R and Bioconductor. BrainSpan database was used to screen for signatures that were not differentially expressed in normal human hippocampus and cortex (data from BrainSpan), but differentially expressed in TLE+HS' hippocampus and NTP' cortex (data from our cohort). The strategy "Guilt by association" was used to predict the prospective roles of each important hub mRNA, miRNA, or lncRNA.

RESULTS: A significantly negative correlation (r < -0.5) was found between 116 pairs of microRNA/mRNA, differentially expressed in six patients with TLE+HS and nine of NTP. We examined this regulation network's intersection with target gene prediction results and built a lncRNA-microRNA-Gene regulatory network with structural, and functional significance. Meanwhile, we found that the disorder of FGFR3, hsa-miR-486-5p, and lnc-KCNH5-1 plays a key vital role in developing TLE+HS.

PMID:35784838 | PMC:PMC9243442 | DOI:10.3389/fnins.2022.892022

Front Pharmacol. 2022 Jun 15;13:930470. doi: 10.3389/fphar.2022.930470. eCollection 2022.

ABSTRACT

Dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene, is the rate-limiting enzyme in 5-fluorouracil (5-FU) degradation. In Caucasians, four DPYD risk variants are recognized to be responsible for interindividual variations in the development of 5-FU toxicity. However, these risk variants have not been identified in Asian populations. Recently, 41 DPYD allelic variants, including 15 novel single nucleotide variants, were identified in 3,554 Japanese individuals by analyzing their whole-genome sequences; however, the effects of these variants on DPD enzymatic activity remain unknown. In the present study, an in vitro analysis was performed on 41 DPD allelic variants and three DPD risk variants to elucidate the changes in enzymatic activity. Wild-type and 44 DPD-variant proteins were heterologously expressed in 293FT cells. DPD expression levels and dimerization of DPD were determined by immunoblotting after SDS-PAGE and blue native PAGE, respectively. The enzymatic activity of DPD was evaluated by quantification of dihydro-5-FU, a metabolite of 5-FU, using high-performance liquid chromatography-tandem mass spectrometry. Moreover, we used 3D simulation modeling to analyze the effect of amino acid substitutions on the conformation of DPD. Among the 41 DPD variants, seven exhibited drastically decreased intrinsic clearance (CL int ) compared to the wild-type protein. Moreover, R353C and G926V exhibited no enzymatic activity, and the band patterns observed in the immunoblots after blue native PAGE indicated that DPD dimerization is required for its enzymatic activity. Our data suggest that these variants may contribute to the significant inter-individual variability observed in the pharmacokinetics and pharmacodynamics of 5-FU. In our study, nine DPD variants exhibited drastically decreased or no enzymatic activity due to dimerization inhibition or conformational changes in each domain. Especially, the rare DPYD variants, although at very low frequencies, may serve as important pharmacogenomic markers associated with the severe 5-FU toxicity in Japanese population.

PMID:35784703 | PMC:PMC9242541 | DOI:10.3389/fphar.2022.930470

Front Pharmacol. 2022 Jun 16;13:912618. doi: 10.3389/fphar.2022.912618. eCollection 2022.

ABSTRACT

Cytochrome P450 3A (CYP3A) subfamily enzymes are involved in the metabolism of 40% of drugs in clinical use. Twin studies have indicated that 66% of the variability in CYP3A4 activity is hereditary. Yet, the complexity of the CYP3A locus and the lack of distinct drug metabolizer phenotypes has limited the identification and clinical application of CYP3A genetic variants compared to other Cytochrome P450 enzymes. In recent years evidence has emerged indicating that a substantial part of the missing heritability is caused by low frequency genetic variation. In this review, we outline the current pharmacogenomics knowledge of CYP3A activity and discuss potential future directions to improve our genetic knowledge and ability to explain CYP3A variability.

PMID:35784699 | PMC:PMC9243486 | DOI:10.3389/fphar.2022.912618

J Am Coll Clin Pharm. 2022 Feb;5(2):239-250. doi: 10.1002/jac5.1582. Epub 2021 Dec 19.

ABSTRACT

Ineffective pain control is the most commonly cited reason for misuse of prescription opioids and is influenced by genetics. In particular, the gene encoding the CYP2D6 enzyme, which metabolizes some of the most commonly prescribed opioids (e.g., tramadol, hydrocodone) to their more potent forms, is highly polymorphic and can lead to reduced concentrations of the active metabolites and decreased opioid effectiveness. Consideration of the CYP2D6 genotype may allow for predicting opioid response and identifying patients who are likely to respond well to lower potency opioids as well as those who may derive greater pain relief from non-opioid analgesics versus certain opioids. There is emerging evidence that a CYP2D6-guided approach to pain management improves pain control and reduces opioid consumption and thus may be a promising means for combating opioid misuse. Clinical practice guidelines are available for select opioids and other analgesics to support medication and dose selection based on pharmacogenetic data. This article describes the evidence supporting genotype-guided pain management as a means of improving pain control and reducing opioid misuse and clinical recommendations for genotype-guided analgesic prescribing. In addition, a "how to" guide using patient case examples is provided to demystify the process for implementing pharmacogenetics-guided pain management in order to optimize analgesia and minimize adverse effects. Optimizing pain management through genotype-guided approaches may ultimately provide safer and more effective therapy for pain control while decreasing the risk for opioid misuse.

PMID:35784584 | PMC:PMC9248444 | DOI:10.1002/jac5.1582

Front Med (Lausanne). 2022 Jun 16;9:919708. doi: 10.3389/fmed.2022.919708. eCollection 2022.

ABSTRACT

BACKGROUND: Ivermectin which was widely considered as a potential treatment for COVID-19, showed uncertain clinical benefit in many clinical trials. Performing large-scale clinical trials to evaluate the effectiveness of this drug in the midst of the pandemic, while difficult, has been urgently needed.

METHODS: We performed two large multicenter randomized, double-blind, placebo-controlled clinical trials evaluating the effectiveness of ivermectin in treating inpatients and outpatients with COVID-19 infection. The intervention group received ivermectin, 0.4mg/kg of body weight per day for 3 days. In the control group, placebo tablets were used for 3 days.

RESULTS: Data for 609 inpatients and 549 outpatients were analyzed. In hospitalized patients, complete recovery was significantly higher in the ivermectin group (37%) compared to placebo group (28%; RR, 1.32 [95% CI, 1.04-1.66]; p-value = 0.02). On the other hand, the length of hospital stay was significantly longer in the ivermectin group with a mean of 7.98 ± 4.4 days compared to the placebo receiving group with a mean of 7.16 ± 3.2 days (RR, 0.80 [95% CI, 0.15-1.45]; p-value = 0.02). In outpatients, the mean duration of fever was significantly shorter (2.02 ± 0.11 days) in the ivermectin group versus (2.41 ± 0.13 days) placebo group with p value = 0.020. On the day seventh of treatment, fever (p-value = 0.040), cough (p-value = 0.019), and weakness (p-value = 0.002) were significantly higher in the placebo group compared to the ivermectin group. Among all outpatients, 7% in ivermectin group and 5% in placebo group needed to be hospitalized (RR, 1.36 [95% CI, 0.65-2.84]; p-value = 0.41). Also, the result of RT-PCR on day five after treatment was negative for 26% of patients in the ivermectin group versus 32% in the placebo group (RR, 0.81 [95% CI, 0.60-1.09]; p-value = 0.16).

CONCLUSION: Our data showed, ivermectin, compared with placebo, did not have a significant potential effect on clinical improvement, reduced admission in ICU, need for invasive ventilation, and death in hospitalized patients; likewise, no evidence was found to support the prescription of ivermectin on recovery, reduced hospitalization and increased negative RT-PCR assay for SARS-CoV-2 5 days after treatment in outpatients. Our findings do not support the use of ivermectin to treat mild to severe forms of COVID-19.

CLINICAL TRIAL REGISTRATION: www.irct.ir IRCT20111224008507N5 and IRCT20111224008507N4.

PMID:35783616 | PMC:PMC9244711 | DOI:10.3389/fmed.2022.919708

Asian J Pharm Sci. 2022 May;17(3):435-446. doi: 10.1016/j.ajps.2022.04.002. Epub 2022 Apr 30.

ABSTRACT

An effective vaccine against group A streptococcus (GAS) is highly desirable for definitive control of GAS infections. In the present study, two variants of amphiphilic chitosan nanoparticles-based GAS vaccines were developed. The vaccines were primarily composed of encapsulated KLH protein (a source of T helper cell epitopes) and lipidated M-protein derived B cell peptide epitope (lipoJ14) within the amphiphilic structure of nanoparticles. The only difference between them was one of the nanoparticles vaccines received additional surface coating with poly (I:C). The formulated vaccines exhibited nanosized particles within the range of 220-240 nm. Cellular uptake study showed that nanoparticles vaccine without additional poly (I:C) coating has greater uptake by dendritic cells and macrophages compared to nanoparticles vaccine that was functionalized with poly (I:C). Both vaccines were found to be safe in mice and showed negligible cytotoxicity against HEK293 cells. Upon immunization in mice, both nanoparticle vaccines produced high antigen-specific antibodies titres that were regulated by a balanced Th1 and Th2 response compared to physical mixture. These antibodies elicited high opsonic activity against the tested GAS strains. Overall, our data demonstrated that amphiphilic chitosan nanoparticles platform induced a potent immune response even without additional inclusion of poly (I:C).

PMID:35782331 | PMC:PMC9237632 | DOI:10.1016/j.ajps.2022.04.002

Pharmacogenomics J. 2022 Jul 2. doi: 10.1038/s41397-022-00284-6. Online ahead of print.

ABSTRACT

Genetic variation in genes encoding cytochrome P450 enzymes influences the metabolism of drugs and endogenous compounds. The locus containing the cytochrome genes CYP2C8 and CYP2C9 on chromosome 10 exhibits linkage disequilibrium between the CYP2C8*3 and CYP2C9*2 alleles, forming a haplotype of ~300 kilobases. This haplotype is associated with altered metabolism of several drugs, most notably reduced metabolism of warfarin and phenytoin, leading to toxicity at otherwise therapeutic doses. Here we show that this haplotype is inherited from Neandertals.

PMID:35780191 | DOI:10.1038/s41397-022-00284-6

J Adv Res. 2022 Jul;39:319-332. doi: 10.1016/j.jare.2021.10.004. Epub 2021 Oct 18.

ABSTRACT

INTRODUCTION: Pharmacokinetic variability in disease state is common in clinical practice, but its underlying mechanism remains unclear. Recently, gut microbiota has been considered to be pharmacokinetically equivalent to the host liver. Although some studies have explored the roles of gut microbiota and host Cyp450s in drug pharmacokinetics, few have explored their effects on pharmacokinetic variability, especially in disease states.

OBJECTIVES: In this study, we aim to investigate the effects of gut microbiota and host Cyp450s on pharmacokinetic variability in mice with non-alcoholic steatohepatitis (NASH), and to elucidate the contribution of gut microbiota and host Cyp450s to pharmacokinetic variability in this setting.

METHODS: The pharmacokinetic variability of mice with NASH was explored under intragastric and intravenous administrations of a cocktail mixture of omeprazole, phenacetin, midazolam, tolbutamide, chlorzoxazone, and metoprolol, after which the results were compared with those obtained from the control group. Thereafter, the pharmacokinetic variabilities of all drugs and their relations to the changes in gut microbiota and host Cyp450s were compared and analyzed.

RESULTS: The exposures of all drugs, except metoprolol, significantly increased in the NASH group under intragastric administration. However, no significant increase in the exposure of all drugs, except tolbutamide, was observed in the NASH group under intravenous administration. The pharmacokinetic variabilities of phenacetin, midazolam, omeprazole, and chlorzoxazone were mainly associated with decreased elimination activity in the gut microbiota. By contrast, the pharmacokinetic variability of tolbutamide was mainly related to the change in the host Cyp2c65. Notably, gut microbiota and host Cyp450s exerted minimal effects on the pharmacokinetic variability of metoprolol.

CONCLUSION: Gut microbiota and host Cyp450s co-contribute to the pharmacokinetic variability in mice with NASH, and the degree of contribution varies from drug to drug. The present findings provide new insights into the explanation of pharmacokinetic variability in disease states.

PMID:35777915 | DOI:10.1016/j.jare.2021.10.004

Drug Deliv Transl Res. 2022 Jul 1. doi: 10.1007/s13346-022-01198-3. Online ahead of print.

ABSTRACT

Pharmacotherapy has become more focused on the personalized treatment of patients with various diseases. This field of pharmacology and pharmacogenomics focuses on developing drug delivery systems designed to address the unique characteristics of individual patients. Three-dimensional printing technology can be used to fabricate personalized drug delivery systems with desired release properties according to patient needs. Norfloxacin (NOR)-loaded micropellets (MPs) were fabricated and filled inside a stereolithography (SLA) 3D printing technology-mediated hollow capsular device in accordance with a standard size of 09 (8.4 mm length × 2.70 mm diameter). The prepared 3D-printed hollow capsular device filled with pristine NOR and NOR-loaded MPs were characterized in terms of both in vitro and in vivo means. MPs with the particle size distribution of 1540.0 ± 26 µm showed 95.63 ± 2.0% NOR content with pellet-shaped surface morphology. The in vitro release profile showed an initial lag phase of approximately 30 min, followed by the sustained release of NOR from MPs from the 3D-printed hollow capsular device. The pharmacokinetic profile showed prolonged Tmax, AUC, and evidence of good RBA of NOR compared to pure NOR after a single oral administration in the experimental animal model. The overall results confirm the feasibility of SLA-mediated 3D printing technology for preparing customized solid oral unit dosage carriers that can be filled with pure NOR- and NOR-loaded MPs with controlled-release delivery features.

PMID:35776385 | DOI:10.1007/s13346-022-01198-3

Support Care Cancer. 2022 Jul 1. doi: 10.1007/s00520-022-07243-8. Online ahead of print.

ABSTRACT

OBJECTIVE: Aromatase inhibitors (AIs) are commonly used to treat hormone receptor positive (HR +) breast cancer. AI-induced musculoskeletal syndrome (AIMSS) is a common toxicity that causes AI treatment discontinuation. The objective of this genome-wide association study (GWAS) was to identify genetic variants associated with discontinuation of AI therapy due to AIMSS and attempt to replicate previously reported associations.

METHODS: In the Exemestane and Letrozole Pharmacogenetics (ELPh) study, postmenopausal patients with HR + non-metastatic breast cancer were randomized to letrozole or exemestane. Genome-wide genotyping of germline DNA was conducted followed by imputation. Each imputed variant was tested for association with time-to-treatment discontinuation due to AIMSS using a Cox proportional hazards model assuming additive genetic effects and adjusting for age, baseline pain score, prior taxane treatment, and AI arm. Secondary analyses were conducted within each AI arm and analyses of candidate variants previously reported to be associated with AIMSS risk.

RESULTS: Four hundred ELPh participants were included in the combined analysis. Two variants surpassed the genome-wide significance level in the primary analysis (p value < 5 × 10-8), an intronic variant (rs79048288) within CCDC148 (HR = 4.42, 95% CI: 2.67-7.33) and an intergenic variant (rs912571) upstream of PPP1R14C (HR = 0.30, 95% CI: 0.20-0.47). In the secondary analysis, rs74418677, which is known to be associated with expression of SUPT20H, was significantly associated with discontinuation of letrozole therapy due to AIMSS (HR = 5.91, 95% CI: 3.16-11.06). We were able to replicate associations for candidate variants previously reported to be associated with AIMSS in this cohort, but were not able to replicate associations for any other variants previously reported in other patient cohorts.

CONCLUSIONS: Our GWAS findings identify several candidate variants that may be associated with AIMSS risk from AI generally or letrozole specifically. Validation of these associations in independent cohorts is needed before translating these findings into clinical practice to improve treatment outcomes in patients with HR + breast cancer.

PMID:35776183 | DOI:10.1007/s00520-022-07243-8

Pharmacogenomics. 2022 Jul 1. doi: 10.2217/pgs-2022-0055. Online ahead of print.

ABSTRACT

Background: Statins are among the most commonly prescribed medications, and improve patient outcomes by lowering cholesterol levels, but also have side effects. Variations in statin response can be attributed to a handful of factors that include pharmacogenetics. Methods: While not a true review article, this work was written using various search engines and terms and previous and newly published Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for statins to provide a historical perspective in addition to the current status of statin-related pharmacogenetics and future perspectives. Results: This article provides historical background on statins and associated adverse effects, reviews pharmacogenetic implications, applies clinical-decision support, incorporates the latest CPIC guidelines and addresses future implications. Conclusion: Statins are a beneficial medication, but not without risk. Pharmacogenomics can help mitigate some risk factors. Clinical-decision support, implementation, research and guidelines will continue to influence statin prescribing.

PMID:35775396 | DOI:10.2217/pgs-2022-0055

Sci Rep. 2022 Jun 30;12(1):11100. doi: 10.1038/s41598-022-15246-y.

ABSTRACT

Many primary-tumor subregions exhibit low levels of molecular oxygen and restricted access to nutrients due to poor vascularization in the tissue, phenomenon known as hypoxia. Hypoxic tumors are able to regulate the expression of certain genes and signaling molecules in the microenvironment that shift it towards a more aggressive phenotype. The transcriptional landscape of the tumor favors malignant transformation of neighboring cells and their migration to distant sites. Herein, we focused on identifying key proteins that participate in the signaling crossroads between hypoxic environment and metastasis progression that remain poorly defined. To shed light on these mechanisms, we performed an integrated multi-omics analysis encompassing genomic/transcriptomic alterations of hypoxia-related genes and Buffa hypoxia scores across 17 pancarcinomas taken from the PanCancer Atlas project from The Cancer Genome Atlas consortium, protein-protein interactome network, shortest paths from hypoxia-related proteins to metastatic and angiogenic phenotypes, and drugs involved in current clinical trials to treat the metastatic disease. As results, we identified 30 hypoxia-related proteins highly involved in metastasis and angiogenesis. This set of proteins, validated with the MSK-MET Project, could represent key targets for developing therapies. The upregulation of mRNA was the most prevalent alteration in all cancer types. The highest frequencies of genomic/transcriptomic alterations and hypoxia score belonged to tumor stage 4 and positive metastatic status in all pancarcinomas. The most significantly associated signaling pathways were HIF-1, PI3K-Akt, thyroid hormone, ErbB, FoxO, mTOR, insulin, MAPK, Ras, AMPK, and VEGF. The interactome network revealed high-confidence interactions among hypoxic and metastatic proteins. The analysis of shortest paths revealed several ways to spread metastasis and angiogenesis from hypoxic proteins. Lastly, we identified 23 drugs enrolled in clinical trials focused on metastatic disease treatment. Six of them were involved in advanced-stage clinical trials: aflibercept, bevacizumab, cetuximab, erlotinib, ipatasertib, and panitumumab.

PMID:35773405 | DOI:10.1038/s41598-022-15246-y

J Clin Psychiatry. 2022 Jun 27;83(4):21m14239. doi: 10.4088/JCP.21m14239.

ABSTRACT

Background: Many patients with major depressive disorder (MDD) who experience no meaningful benefit (NMB) from antidepressive treatment go undetected. However, there is a lack of consensus on the definition of NMB from antidepressants.

Methods: Equipercentile linking was used to identify a threshold for percent change in 17-item Hamilton Depression Rating Scale (HDRS-17) scores that equated with a Clinical Global Impressions-Improvement (CGI-I) score of 3 (minimally improved), a proxy for NMB, after 4 and 8 weeks of citalopram or escitalopram treatment, using data from the Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS). The NMB threshold for the HDRS-17 was validated by equating a CGI-I rating of 3 with percent change values from the clinician- and patient-rated versions of the Quick Inventory of Depressive Symptomatology (QIDS-C and QIDS-SR) using data from PGRN-AMPS and phase 1 of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. This study was conducted between June 2021 and September 2021.

Results: In PGRN-AMPS, a 30% improvement in HDRS-17 score corresponded to a CGI-I rating of 3 at 4 and 8 weeks. The 30% improvement threshold was also observed for QIDS-C and QIDS-SR scores in both PGRN-AMPS and STAR*D. Similar results were observed for percent change in HDRS-17 and QIDS-based measures in lower- and higher-severity groups based on a median split of baseline total scores.

Conclusions: Improvement in depressive severity of ≤ 30%, as assessed using the HDRS-17, QIDS-C, and QIDS-SR, may validly define NMB from antidepressants during short-term treatment.

PMID:35771974 | DOI:10.4088/JCP.21m14239

Per Med. 2022 Jun 30. doi: 10.2217/pme-2021-0092. Online ahead of print.

ABSTRACT

Aim: The effects of variants in IMPDH, UGT1A9, UGT1A8, UGT2B7 and SLCO1B1 genes on the efficacy and safety of mycophenolate mofetil (MMF) in the Tunisian population were investigated. Materials & methods: A total of 245 kidney transplant patients being treated with MMF were recruited and cotreated with cyclosporine or tacrolimus. Genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism method. MMF, cyclosporine and tacrolimus trough levels were measured by immunoassay. The AUC (AUC0-12hMPA) was estimated by a Bayesian method. Results: In the tacrolimus-treated group, anemia and diarrhea were associated with the UGT1A9-98C and UGT1A9-275T alleles, respectively (p < 0.05). In the cyclosporine-treated group, leukopenia was associated with the SLCO1B1-521T allele (p < 0.05). Both groups had an increased risk of rejection (p < 0.05) associated with the variant alleles of IMPDH2-3757T>C, UGT1A9-2152C>T and UGT1A9-275C>A and the common allele of SLCO1B1-388A>G. However, no significant association was found between the studied genotypes and AUC0-12hMPA or cotreatment levels. Conclusion: The results constitute preliminary evidence for the inclusion of the pharmacogenetics of MMF in kidney pretransplantation evaluations.

PMID:35770851 | DOI:10.2217/pme-2021-0092

Technol Cancer Res Treat. 2022 Jan-Dec;21:15330338221109798. doi: 10.1177/15330338221109798.

ABSTRACT

Background: MiR-196a2 rs11614913 polymorphism has been studied in a wide range of cancers throughout the years. Despite a large number of epidemiological studies performed in almost all ethnic populations, the contribution of this polymorphism to cancer risk is still inconclusive. Therefore, this updated meta-analysis was performed to estimate a meticulous correlation between miR-196a2 rs11614913 variant and cancer susceptibility. Methods: A systematic study search was carried out using PubMed, ScienceDirect, CNKI, EMBASE, Scopus, and Google Scholar databases following PRISMA guidelines to find necessary literature up to December 15, 2021. Pooled odds ratios with corresponding 95% confidence intervals were estimated using RevMan 5.4 based on ethnicities, cancer types, control sources, and genotyping methods. Results: A total of 152 studies, including 120 135 subjects (53 818 patients and 66 317 controls; 140 studies, after removing studies that deviated from HWE: 51 459 cases and 62 588 controls), were included in this meta-analysis. Quantitative synthesis suggests that the miR-196a2 rs11614913 genetic variant is significantly correlated with the reduced risk of overall cancer in CDM2, CDM3, RM, and AM (odds ratio < 1 and P < .05). It is also observed from ethnicity-based subgroup analysis that rs11614913 polymorphism is significantly (P < .05) linked with cancer in the Asian (in CDM2, CDM3, RM, AM) and the African population (in CDM1, CDM3, ODM). Stratified analysis based on the cancer types demonstrated a significantly decreased correlation for breast, hepatocellular, lung, and gynecological cancer and an increased association for oral and renal cell cancer. Again, the control population-based subgroup analysis reported a strongly reduced correlation for HB population in CDM2, RM, and AM. A substantially decreased risk was also observed for other genotyping methods in multiple genetic models. Conclusions: MiR-196a2 rs11614913 variant is significantly correlated with overall cancer susceptibility. Besides, rs11614913 is correlated with cancer in Asians and Africans. It is also correlated with breast, gynecological, hepatocellular, lung, oral, and renal cell cancer.

PMID:35770306 | DOI:10.1177/15330338221109798

Front Genet. 2022 Jun 13;13:839154. doi: 10.3389/fgene.2022.839154. eCollection 2022.

ABSTRACT

Background: Allopurinol is the most commonly used drug for the treatment of gout arthritis. However, the use of allopurinol is associated with severe cutaneous adverse reactions (SCARs) and life-threatening immune-mediated reactions that include Stevens-Johnson syndrome (SJS). SJS induced by allopurinol is strongly linked with the presence of HLA-B*58:01 in the Asian population. Such a study has not been conducted in Indonesia. We present two cases with clinical diagnosis of SJS. These patients had Javanese ethnicity, for which evidence on the genetic predisposition of allopurinol-induced SJS/TEN had not been established. Testing for the presence of the HLA-B∗58:01 allele was positive in both cases. Our case report confirms findings from studies in Asian countries that link HLA-B*58:01 and allopurinol-induced SJS/TEN. A larger study is needed to elicit evidence that the HLA-B*58:01 allele can potentially be used as a genetic marker for allopurinol-induced SCARs among different ethnicities in Indonesia.

PMID:35769987 | PMC:PMC9234807 | DOI:10.3389/fgene.2022.839154

Aliment Pharmacol Ther. 2022 Jun 29. doi: 10.1111/apt.17089. Online ahead of print.

ABSTRACT

BACKGROUND: During illness, adaptations of the hypothalamic-pituitary-thyroid axis reduce energy expenditure, protein catabolism and modulate immune responses to promote survival. Lower serum free triiodothyronine-to-thyroxine (fT3/fT4) ratio has been linked to non-response to treatment in a range of diseases, including in biologic-treated patients with inflammatory bowel disease.

AIM: To assess whether baseline serum fT3/fT4 ratio predicted primary non-response (PNR) and non-remission to infliximab and adalimumab in patients with Crohn's disease METHODS: Thyroid function tests were undertaken in stored serum from biologic-naïve adult patients with active luminal Crohn's disease immediately prior to treatment with infliximab (427 originator; 122 biosimilar) or adalimumab (448) in the Personalised Anti-TNF Therapy in Crohn's Disease study (PANTS).

RESULTS: Baseline median [IQR] fT3/fT4 ratios were lower in women than men (0.30 [0.27-0.34] vs 0.32 [0.28-0.36], p < 0.001), in patients with more severe inflammatory disease, and in patients receiving corticosteroids (0.28 [0.25-0.33] vs. 0.32 [0.29-0.36], p < 0.001). Multivariable logistic regression analysis demonstrated that fT3/fT4 ratio was independently associated with PNR at week 14 (odds ratio [OR] 0.51, 95% confidence interval [CI] 0.31-0.85, p = 0.009), but not non-remission or changes in faecal calprotectin concentrations at week 54. The optimal threshold to determine PNR was 0.31 (area under the curve 0.57 [95% CI 0.54-0.61], sensitivity 0.62 [95% CI 0.41-0.74], and specificity 0.53 [95% CI 0.42-0.73]).

CONCLUSIONS: Lower baseline serum fT3/fT4 ratio was associated with female sex, corticosteroid use and disease activity. It predicted PNR to anti-TNF treatment at week 14, but not non-remission at week 54.

PMID:35768996 | DOI:10.1111/apt.17089

Drug Metab Dispos. 2022 Jun 29:DMD-MR-2021-000706. doi: 10.1124/dmd.121.000706. Online ahead of print.

ABSTRACT

Transporters govern the access of molecules to cells or their exit from cells, thereby controlling the overall distribution of drugs to their intracellular site of action. Clinically relevant drug-drug interactions mediated by transporters are of increasing interest in drug development. Drug transporters, acting alone or in concert with drug metabolizing enzymes, can play an important role in modulating drug absorption, distribution, metabolism, and excretion, thus affecting the pharmacokinetics and/or pharmacodynamics of a drug. Dr. Kathy Giacomini from the University of California, San Francisco is one of the world leaders in transporters and pharmacogenetics with key contributions to transporter science. Her contributions to transporter science are noteworthy. This review paper will summarize Dr. Giacomini's key contributions and influence on transporters in regulatory science in the past two decades. Regulatory science research highlighted in this review covers various aspects of transporter science including understanding the effect of renal impairment on transporters, transporter ontogeny, biomarkers for transporters, and interactions of excipients with transporters affecting drug absorption. Significance Statement This review paper highlights Dr. Giacomini's key contributions and influence on transporters in regulatory science in the past two decades. She has been at the cutting edge of science pertaining to drug transport, drug disposition, and regulatory science, leading to new era of translational sciences pertaining to drug disposition and transporter biology. Her research has and will continue to bring enormous impact on gaining new knowledge in guiding drug development and inspire scientists from all sectors in the field.

PMID:35768075 | DOI:10.1124/dmd.121.000706

J Clin Lab Anal. 2022 Jun 29:e24578. doi: 10.1002/jcla.24578. Online ahead of print.

ABSTRACT

BACKGROUND: Determination of UGT1A1 (TA)n polymorphism prior to irinotecan therapy is necessary to avoid severe adverse drug effects. Thus, accurate and reliable genotyping methods for (TA)n polymorphism are highly desired. Here, we present a new method for polymerase chain reaction (PCR) melting curve analysis using one fluorescent probe to discriminate the UGT1A1*1 [(TA)6 ] and *28 [(TA)7 ] genotypes.

METHODS: After protocol optimization, this technique was applied for genotyping of 64 patients (including 23 with UGT1A1*1/*1, 22 with *1/*28, and 19 with *28/*28) recruited between 2016 and 2021 in China-Japan Friendship Hospital. The accuracy of the method was evaluated by comparing the results with those of direct sequencing and fragment analysis. The intra- and inter-run precision of the melting temperatures (Tm s) were calculated to assess the reliability, and the limit of detection was examined to assess the sensitivity.

RESULTS: All genotypes were correctly identified with the new method, and its accuracy was higher than that of fragment analysis. The intra- and inter-run coefficients of variation for the Tm s were both ≤0.27%, with standard deviations ≤0.14°C. The limit of detection was 0.2 ng of input genomic DNA.

CONCLUSION: The developed PCR melting curve analysis using one fluorescent probe can provide accurate, reliable, rapid, simple, and low-cost detection of UGT1A1 (TA)n polymorphism, and its use can be easily generalized in clinical laboratories with a fluorescent PCR platform.

PMID:35766440 | DOI:10.1002/jcla.24578

Pharmacol Ther. 2022 Jun 25:108236. doi: 10.1016/j.pharmthera.2022.108236. Online ahead of print.

ABSTRACT

Almost fifty years after its first introduction into clinical care, clozapine remains the only evidence-based pharmacological option for treatment-resistant schizophrenia (TRS), which affects approximately 30% of patients with schizophrenia. Despite the long-time experience with clozapine, the specific mechanism of action (MOA) responsible for its superior efficacy among antipsychotics is still elusive, both at the receptor and intracellular signaling level. This systematic review is aimed at critically assessing the role and specific relevance of clozapine's multimodal actions, dissecting those mechanisms that under a translational perspective could shed light on molecular targets worth to be considered for further innovative antipsychotic development. In vivo and in vitro preclinical findings, supported by innovative techniques and methods, together with pharmacogenomic and in vivo functional studies, point to multiple and possibly overlapping MOAs. To better explore this crucial issue, the specific affinity for 5-HT2R, D1R, α2c, and muscarinic receptors, the relatively low occupancy at dopamine D2R, the interaction with receptor dimers, as well as the potential confounder effects resulting in biased ligand action, and lastly, the role of the moiety responsible for lipophilic and alkaline features of clozapine are highlighted. Finally, the role of transcription and protein changes at the synaptic level, and the possibility that clozapine can directly impact synaptic architecture are addressed. Although clozapine's exact MOAs that contribute to its unique efficacy and some of its severe adverse effects have not been fully understood, relevant information can be gleaned from recent mechanistic understandings that may help design much needed additional therapeutic strategies for TRS.

PMID:35764175 | DOI:10.1016/j.pharmthera.2022.108236