Toxics. 2022 Aug 27;10(9):497. doi: 10.3390/toxics10090497.

ABSTRACT

The particulate matter present in air pollution is a complex mixture of solid and liquid particles that vary in size, origin, and composition, among which are polycyclic aromatic hydrocarbons (PAHs). Although exposure to PAHs has become an important risk factor for cardiovascular disease, the mechanisms by which these compounds contribute to increased cardiovascular risk have not been fully explored. The aim of the present study was to evaluate the effects of PAH exposure on systemic pro-inflammatory cytokines and markers of endothelial dysfunction. An intervention was designed using a murine model composed of twenty BALB/c male mice separated into controls and three groups exposed to a mixture of phenanthrene, fluoranthene, and pyrene using three different concentrations. The serum levels of the inflammatory cytokines and gene expression of adhesion molecules located on endothelial cells along with inflammatory markers related to PAH exposure in aortic tissue were determined. Furthermore, the expression of the ICAM-1 and VCAM-1 proteins was evaluated. The data showed significant differences in IL-6 and IFN-γ in the serum. In the gene expression, significant differences for ICAM-1, VCAM-1, and E-Selectin were observed. The results suggest that phenanthrene, fluoranthene, and pyrene, present in air pollution, stimulate the increase in serum inflammatory cytokines and the expression of markers of endothelial dysfunction in the murine model studied, both relevant characteristics associated with the onset of disease atherosclerosis and cardiovascular disease.

PMID:36136462 | DOI:10.3390/toxics10090497

Bioengineering (Basel). 2022 Sep 15;9(9):475. doi: 10.3390/bioengineering9090475.

ABSTRACT

Nuclei identification is a fundamental task in many areas of biomedical image analysis related to computational pathology applications. Nowadays, deep learning is the primary approach by which to segment the nuclei, but accuracy is closely linked to the amount of histological ground truth data for training. In addition, it is known that most of the hematoxylin and eosin (H&E)-stained microscopy nuclei images contain complex and irregular visual characteristics. Moreover, conventional semantic segmentation architectures grounded on convolutional neural networks (CNNs) are unable to recognize distinct overlapping and clustered nuclei. To overcome these problems, we present an innovative method based on gradient-weighted class activation mapping (Grad-CAM) saliency maps for image segmentation. The proposed solution is comprised of two steps. The first is the semantic segmentation obtained by the use of a CNN; then, the detection step is based on the calculation of local maxima of the Grad-CAM analysis evaluated on the nucleus class, allowing us to determine the positions of the nuclei centroids. This approach, which we denote as NDG-CAM, has performance in line with state-of-the-art methods, especially in isolating the different nuclei instances, and can be generalized for different organs and tissues. Experimental results demonstrated a precision of 0.833, recall of 0.815 and a Dice coefficient of 0.824 on the publicly available validation set. When used in combined mode with instance segmentation architectures such as Mask R-CNN, the method manages to surpass state-of-the-art approaches, with precision of 0.838, recall of 0.934 and a Dice coefficient of 0.884. Furthermore, performance on the external, locally collected validation set, with a Dice coefficient of 0.914 for the combined model, shows the generalization capability of the implemented pipeline, which has the ability to detect nuclei not only related to tumor or normal epithelium but also to other cytotypes.

PMID:36135021 | DOI:10.3390/bioengineering9090475

Br J Clin Pharmacol. 2022 Sep 22. doi: 10.1111/bcp.15541. Online ahead of print.

ABSTRACT

BACKGROUND: Pharmacogenetic variants impact dihydropyridine calcium channel blockers (dCCB) (i.e. amlodipine) treatment efficacy, yet evidence on clinical outcomes in routine primary care is limited. Reported associations in PharmGKB have weak supporting evidence. We aimed to estimate associations between reported pharmacogenetic variants and incident adverse events in a community-based cohort prescribed dCCB.

METHODS: We analyzed up to 32,360 UK Biobank participants prescribed dCCB in primary care (from UK General Practices, 1990-2017). We investigated 23 genetic variants. Outcomes were incident diagnosis of coronary heart disease (CHD), heart failure (HF), chronic kidney disease (CKD), edema, and switching antihypertensive medication.

RESULTS: Participants were aged 40 to 79 years at first dCCB prescription. Carriers of rs877087 T allele in RYR3 had increased risk of HF (Hazard Ratio 1.13: 95% Confidence Intervals 1.02 to 1.25, p=0.02). Though non-significant after multiple testing correction, the association is consistent with prior evidence. We estimated that if rs877087 T allele could experience the same treatment effect as non-carriers, the incidence of HF in patients prescribed dCCB would reduce by 9.2% (95%CI 3.1 to 15.4). In patients with a history of heart disease prior to dCCB (N=2,296), rs877087 homozygotes had increased risk of new CHD or HF compared to CC variant. rs10898815 in NUMA1 and rs776746 in CYP3A5 increased likelihood of switching to an alternate antihypertensive. The remaining variants were not strongly or consistently associated with studied outcomes.

CONCLUSIONS: Patients with common genetic variants in NUMA1, CYP3A5 and RYR3 had increased adverse clinical outcomes. Work is needed to establish whether outcomes of dCCB prescribing could be improved by prior knowledge of pharmacogenetics variants supported by clinical evidence of association with adverse events.

PMID:36134646 | DOI:10.1111/bcp.15541

Eur Heart J. 2022 Sep 20:ehac534. doi: 10.1093/eurheartj/ehac534. Online ahead of print.

NO ABSTRACT

PMID:36130114 | DOI:10.1093/eurheartj/ehac534

Bioinformatics. 2022 Sep 20:btac642. doi: 10.1093/bioinformatics/btac642. Online ahead of print.

ABSTRACT

MOTIVATION: Multiomic profiling data, such as The Cancer Genome Atlas (TCGA) and pharmacogenomic data, facilitate research into cancer mechanisms and drug development. However, it is not easy for researchers to connect, integrate, and analyze huge and heterogeneous data, which is a major obstacle to the utilization of cancer genomic data.

RESULTS: We developed Cancer Genome Viewer (CGV), a user-friendly web service that provides functions to integrate and visualize cancer genome data and pharmacogenomic data. Users can easily select and customize the samples to be analyzed with the pre-defined selection options for patients' clinic-pathological features from multiple data sets. Using the customized data set, users can perform subsequent data analyses comprehensively, including gene set analysis, clustering, or survival analysis. CGV also provides pre-calculated drug response scores from pharmacogenomic data, which may facilitate the discovery of new cancer targets and therapeutics.

AVAILABILITY AND IMPLEMENTATION: CGV web service is implemented with the R Shiny application at http://cgv.sysmed.kr and the source code is freely available at https://git.sysmed.kr/sysmed_public/cgv.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:36130060 | DOI:10.1093/bioinformatics/btac642

Clin Transl Sci. 2022 Sep 20. doi: 10.1111/cts.13402. Online ahead of print.

ABSTRACT

Alternative polyadenylation (APA) is a common genetic regulatory mechanism that generates distinct 3' ends for RNA transcripts. Changes in APA have been associated with multiple biological processes and disease phenotypes. However, the role of hormones and their drug analogs in APA remains largely unknown. In this study, we investigated transcriptome-wide the impact of glucocorticoids on APA in 30 human B-lymphoblastoid cell lines. We found that glucocorticoids could regulate APA for a subset of genes, possibly by changing the expression of 142 RNA-binding proteins, some with known APA-regulating properties. Interestingly, genes with glucocorticoid-mediated APA were enriched in viral translation-related pathways, while genes with glucocorticoid-mediated expression were enriched in interferon and interleukin pathways, suggesting that glucocorticoid-mediated APA might result in functional consequences distinct from gene expression. For example, glucocorticoids, a pharmacotherapy for severe COVID-19, were found to change the APA but not the expression of LY6E, an important antiviral inhibitor in coronavirus diseases. Glucocorticoid-mediated APA was also cell-type-specific, suggesting an action of glucocorticoids that may be unique to immune regulation. We also observed evidence for genotype-dependent glucocorticoid-mediated APA (referred to as pharmacogenomic-alterative polyadenylation quantitative trait loci), providing potential functional mechanisms for a series of common genetic variants that had previously been associated with immune disorders, but without a clear mechanism. In summary, this study reports a series of observations regarding the impact of glucocorticoids on APA, raising the possibility that this mechanism might have implications for both disease pathophysiology and drug therapy.

PMID:36128656 | DOI:10.1111/cts.13402

BMC Cancer. 2022 Sep 19;22(1):996. doi: 10.1186/s12885-022-10077-6.

ABSTRACT

BACKGROUND: Breast cancer patients undergoing chemotherapy treatment are at particular risk of experiencing acute cognitive impairment leading to daily challenges in decision-making and reduced quality of life and functional autonomy. The aim was to assess the relationship between clinical and genetic factors and cognitive function in a sample of patients with breast cancer undergoing chemotherapy.

METHODS: A cross-sectional study was carried out between November 2017 and June 2019 on women (N = 112) treated for breast cancer by intravenous chemotherapy at the oncology outpatient unit of Hôtel-Dieu de France Hospital, Beirut. Patients were evaluated with the 37-item Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog). Other validated scales were also used to assess depression, anxiety, sleep disorders, pain, and fatigue. DNA was obtained by a buccal swab (FTA®technology) for genotyping of different genes (ABCB1, COMT, DRD2, OPRM1, CLOCK, CRY2, and PER2) using the Lightcycler®(Roche).

RESULTS: The mean age of participants was 56.04 years. Multivariable analysis, taking the four FACT-Cog subscores as the dependent variables, showed that the mean cognitive score decreased with higher depression, anxiety, and insomnia scores. Patients with university education levels had better perceived cognitive abilities than those with primary education. Moreover, carrying the G allele for the OPRM1 polymorphism (c.118A > G;rs197791) was significantly associated with a better cognitive function compared to AA patients (B = 2.05; p = 0.038).

CONCLUSIONS: A comprehensive oncological care plan should include a personalized assessment of all factors related to cognitive functioning in cancer patients, particularly anxiety and depression, to achieve an optimal patient outcome.

PMID:36123640 | DOI:10.1186/s12885-022-10077-6

Drugs. 2022 Sep 19. doi: 10.1007/s40265-022-01774-4. Online ahead of print.

ABSTRACT

The epidemic of type 2 diabetes (T2D) is a significant global public health challenge and a major cause of morbidity and mortality. Despite the recent proliferation of pharmacological agents for the treatment of T2D, current therapies simply treat the symptom, i.e. hyperglycemia, and do not directly address the underlying disease process or modify the disease course. This article summarizes how genomic discovery has contributed to unraveling the heterogeneity in T2D, reviews relevant discoveries in the pharmacogenetics of five commonly prescribed glucose-lowering agents, presents evidence supporting how pharmacogenetics can be leveraged to advance precision medicine, and calls attention to important research gaps to its implementation to guide treatment choices.

PMID:36123514 | DOI:10.1007/s40265-022-01774-4

Nat Med. 2022 Sep 19. doi: 10.1038/s41591-022-01963-4. Online ahead of print.

NO ABSTRACT

PMID:36123428 | DOI:10.1038/s41591-022-01963-4

Ann Intern Med. 2022 Sep 20. doi: 10.7326/M22-1603. Online ahead of print.

ABSTRACT

DESCRIPTION: In February 2022, the U.S. Department of Veterans Affairs (VA) and U.S. Department of Defense (DoD) approved a joint clinical practice guideline (CPG) for the management of major depressive disorder (MDD). This synopsis summarizes key recommendations.

METHODS: Senior leaders within the VA and the DoD assembled a team to update the 2016 CPG for the management of MDD that included clinical stakeholders and conformed to the National Academy of Medicine's tenets for trustworthy CPGs. The guideline panel developed key questions, systematically searched and evaluated the literature, created two 1-page algorithms, and distilled 36 recommendations for care using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. Select recommendations that were identified by the authors to represent key changes from the prior CPG are presented in this synopsis.

RECOMMENDATIONS: The scope of the CPG is diverse; however, this synopsis focuses on key recommendations that the authors identified as important new evidence and changes to prior recommendations on pharmacologic management, pharmacogenomics, psychotherapy, complementary and alternative therapies, and the use of telemedicine.

PMID:36122380 | DOI:10.7326/M22-1603

Front Pharmacol. 2022 Jun 28;13:918493. doi: 10.3389/fphar.2022.918493. eCollection 2022.

ABSTRACT

Aim: Prospective studies support the clinical impact of pharmacogenomics (PGx)-guided prescribing to reduce severe and potentially fatal adverse effects. Drug-gene interactions (DGIs) preventing potential drug-related deaths have been categorized as "essential" by the Dutch Pharmacogenetics Working Group (DPWG). The collective clinical impact and cost-effectiveness of this sub-set is yet undetermined. Therefore, we aim to assess impact and cost-effectiveness of "essential" PGx tests for prevention of gene-drug-related deaths, when adopted nation-wide. Methods: We used a decision-analytic model to quantify the number and cost per gene-drug-related death prevented, from a 1-year Dutch healthcare perspective. The modelled intervention is a single gene PGx-test for CYP2C19, DPYD, TPMT or UGT1A1 to guide prescribing based on the DPWG recommendations among patients in the Netherlands initiating interacting drugs (clopidogrel, capecitabine, systemic fluorouracil, azathioprine, mercaptopurine, tioguanine or irinotecan). Results: For 148,128 patients initiating one of seven drugs in a given year, costs for PGx-testing, interpretation, and drugs would increase by €21.4 million. Of these drug initiators, 35,762 (24.1%) would require an alternative dose or drug. PGx-guided prescribing would relatively reduce gene-drug related mortality by 10.6% (range per DGI: 8.1-14.5%) and prevent 419 (0.3% of initiators) deaths a year. Cost-effectiveness is estimated at €51,000 per prevented gene-drug-related death (range per DGI: €-752,000-€633,000). Conclusion: Adoption of PGx-guided prescribing for "essential" DGIs potentially saves the lives of 0.3% of drug initiators, at reasonable costs.

PMID:36120299 | PMC:PMC9477094 | DOI:10.3389/fphar.2022.918493

Cancer Lett. 2022 Sep 15:215919. doi: 10.1016/j.canlet.2022.215919. Online ahead of print.

ABSTRACT

In cancer cells, poly(ADP-ribose) polymerase (PARP)-1 and PARP2 initiate and regulate DNA repair pathways to protect against DNA damage and cell death caused by radiotherapy or chemotherapy. Radiotherapy and PARP inhibitors (PARPis) have been combined in clinical trials, but their action mechanisms remain unclear. Here, we show that activated by ionizing radiation (IR) generated dsDNA, cyclic GMP-AMP synthase (cGAS) signaling promoted regulated cell death, specifically ferroptosis, via the activating transcription factor 3 (ATF3)-solute carrier family 7 member 11 axis and the antitumor immune response via the interferon-β-CD8+ T cell pathway. Niraparib, a widely used PARPi, augmented cGAS-mediated ferroptosis and immune activation. In colorectal cancer models, cGAS knockdown (KD) compromised IR-induced ferroptosis via downregulation of ATF3 (key ferroptosis regulator) expression. cGAS depletion reversed IR-induced infiltration of CD8+ T or CD8+GZMB+ T cells in the cGAS KD group. Survival analysis of paired tumor samples before and after standard radiotherapy revealed that high expression levels of cGAS, ATF3, and PTGS2 and high density of CD8+ T cells resulted in a significantly high disease-free survival rate in patients with rectal cancer. Therefore, PARPi treatment increases the cytoplasmic accumulation of dsDNA caused by IR, triggering the cGAS signaling-mediated tumor control in cancer cell lines and mouse xenograft models.

PMID:36116741 | DOI:10.1016/j.canlet.2022.215919

Br J Clin Pharmacol. 2022 Sep 17. doi: 10.1111/bcp.15538. Online ahead of print.

ABSTRACT

BACKGROUND: Antiretroviral (ARV) therapy reduces inflammation and immune activation in people with HIV, but not down to the levels observed in negative people. Limited drug penetration within tissues has been argued as potential mechanism of persistent inflammation. Data on the inflammation role on ARV plasma/intracellular (IC) pharmacokinetics (PK) through to expression of cytochrome P450 3A/membrane transporters are limited. Aim of this study was to investigate the correlation between inflammation markers (IM) and plasma/IC PK of ARVs regimen in HIV-positive patients.

METHODS: We included ART-experienced patients switching to 3 different ARV regimens. Plasma and IC ARV drugs concentration means at the end of dosing interval (T0), IM on samples concomitantly with ARV PK determination: sCD14, CRP, IL-6 and LPS were analysed.

RESULTS: Plasma and IC drug concentrations were measured in 60 samples. No significative differences between CRP, sCD14, IL-6 and LPS values in the 3 arms were observed. A significant inverse correlation between tenofovir plasma concentration and sCD14 (rho=-0.79, p<0.001), and between DRV IC/plasma ratio and Log10 IL-6 concentrations (rho= -0.36, p=0.040), and a borderline statistical significant positive trend between DRV plasma concentration and sCD14 (rho=0.31, p=0.070) were suggested. Furthermore, a borderline statistical significant inverse trend between DTG IC concentrations and sCD14 (rho=-0.34, p=0.090) was observed in 24 patients on DTG-based-triple therapy.

CONCLUSIONS: Our preliminary data support the hypothesis of lower DRV and DTG IC concentrations and lower TFV plasma exposure in patients with higher plasma IM suggesting an interplay between HIV drug penetration and persistent inflammation in cART-treated HIV-positive patients.

PMID:36115063 | DOI:10.1111/bcp.15538

Lancet Infect Dis. 2022 Sep 13:S1473-3099(22)00318-8. doi: 10.1016/S1473-3099(22)00318-8. Online ahead of print.

ABSTRACT

BACKGROUND: Bulevirtide is a first-in-class peptidic entry inhibitor for hepatitis B virus (HBV) and hepatitis D virus infection. In July, 2020, bulevirtide 2 mg received conditional marketing authorisation by the European Medical Agency for treatment of chronic hepatitis D virus infection. We investigated the antiviral activity of bulevirtide in patients chronically infected with HBV and hepatitis D virus.

METHODS: MYR202 (ClinicalTrials.gov, NCT03546621; EudraCT, 2016-000395-13) was a multicentre, parallel-group, randomised, open-label, phase 2 trial. Adults (aged 18-65 years) with chronic hepatitis D virus infection, including patients with cirrhosis and patients who had contraindications to PegIFNα treatment or for whom treatment did not work, were eligible and were enrolled from four hospitals in Germany and 12 hospitals in Russia. Patients were randomly assigned (1:1:1:1) to receive 2 mg (n=28), 5 mg (n=32), or 10 mg (n=30) subcutaneous bulevirtide once per day with tenofovir disoproxil fumarate (TDF; 245 mg once per day orally) or TDF alone (245 mg once per day orally; n=30) for 24 weeks. Randomisation was done using a digital block scheme with stratification, consisting of 480 randomisation numbers separated into 30 blocks. The primary endpoint was undetectable hepatitis D virus RNA or 2 log10 IU/mL or higher decline in hepatitis D virus RNA at week 24, which was analysed in the modified intention-to-treat population, including patients who received study medication at least once after randomisation. Hepatitis D virus RNA concentrations were monitored until week 48. Safety was assessed for all patients who received at least one dose of bulevirtide or TDF.

FINDINGS: Between Feb 16, 2016, and Dec 8, 2016, 171 patients with chronic hepatitis D virus infection were screened; 51 were ineligible based on the exclusion criteria and 120 patients (59 with cirrhosis) were enrolled. At week 24, 15 (54%, 95% CI 34-73) of 28 patients achieved undetectable hepatitis D virus RNA or a 2 log10 IU/mL or more decline in hepatitis D virus RNA (p<0·0001 vs TDF alone) with 2 mg bulevirtide, 16 (50%, 32-68) of 32 with 5 mg bulevirtide (p<0·0001), and 23 (77%, 58-90) of 30 with 10 mg bulevirtide (p<0·0001), versus one (4%, 0·1-18) of 28 with TDF alone. By week 48 (24 weeks after bulevirtide cessation), hepatitis D virus RNA concentrations had rebounded, with median changes from week 24 to week 48 of 1·923 log10 IU/mL (IQR 0·566-2·485) with 2 mg bulevirtide, 1·732 log10 (0·469-2·568) with 5 mg bulevirtide, and 2·030 log10 (1·262-2·903) with 10 mg bulevirtide. There were no deaths associated with treatment. Three (9%) patients in the bulevirtide 5 mg group, two (7%) patients in the bulevirtide 10 mg group, and one (4%) patient in the TDF group had serious adverse events. Common treatment-emergent adverse events included asymptomatic bile salt increases and increases in alanine aminotransferase and aspartate aminotransferase.

INTERPRETATION: Bulevirtide induced a significant decline in hepatitis D virus RNA over 24 weeks. After cessation of bulevirtide, hepatitis D virus RNA concentrations rebounded. Longer treatment durations and combination therapies should be investigated.

FUNDING: Hepatera LLC, MYR GmbH, and the German Centre for Infection Research, TTU Hepatitis.

PMID:36113537 | DOI:10.1016/S1473-3099(22)00318-8

Inflamm Bowel Dis. 2022 Sep 16:izac188. doi: 10.1093/ibd/izac188. Online ahead of print.

ABSTRACT

BACKGROUND: Multiple variables contribute to variation in patient exposure and response to tumor necrosis factor alpha antagonist biologics such as infliximab. This study aimed to assess the association between maintenance-phase infliximab concentrations and genetic variation in HLADQA1*05G>A and fragment crystallisable (Fc) fragment of IgG receptor and transporter (FCGRT) among patients with inflammatory bowel disease.

METHODS: A cross-sectional study was carried out in participants with inflammatory bowel disease prescribed infliximab who were in the maintenance phase of treatment. Participants were genotyped for the presence of the FCGRT variable number tandem repeat (VNTR) and HLADQA1*05G>A (rs74291249). A point estimate of the infliximab trough concentration during the maintenance phase was determined using a standard enzyme-linked immunosorbent assay for each patient. Other variables associated with infliximab pharmacokinetics were collected.

RESULTS: A total of 156 participants with inflammatory bowel disease were included from 2 tertiary care centers affiliated with Western University, London, Canada. Median infliximab trough concentrations were lower in participants who carried the FCGRT VNTR 2/3 or 2/2 (4.14 µg/mL; interquartile range [IQR], 6.48 µg/mL) vs wild type individuals (7.00 µg/mL; IQR, 7.66; P = .0027). Median infliximab trough concentrations were significantly lower in participants who were HLADQA1*05G>A variant carriers (4.73µg/mL; IQR, 4.79) vs wild type individuals (7.85µg/mL; IQR, 7.44; P = .0006). A significant decrease in infliximab trough concentrations was seen in individuals who were dual carriers of variant polymorphisms in HLADQA1*05G>A and FCGRT VNTR (no variants, 8.96µg/mL; IQR, 6.84 vs one variant, 4.96 µg/mL; IQR, 4.95 vs dual variants, 0.86µg/mL; IQR, 5.82).

CONCLUSION: FCGRT VNTR and HLADQA1*05G>A are associated with lower maintenance-phase infliximab concentrations, particularly among patients who carry both variants.

PMID:36112504 | DOI:10.1093/ibd/izac188

Hematology. 2022 Dec;27(1):1056-1061. doi: 10.1080/16078454.2022.2121899.

ABSTRACT

BACKGROUND: The CYP2C19 gene is highly polymorphic, and CYP2C19 is involved in the broad interindividual variability of the clinical efficacy of certain clinical medications, such as clopidogrel. However, data on the CYP2C19 genotype in the Chinese population of the Foshan area of Guangdong Province are scarce. The purpose of this study was to determine CYP2C19 genetic polymorphisms in patients in the Foshan area and to compare the CYP2C19 genotype frequencies in different populations to determine the allele distribution pattern to identify the most appropriate prescription.

METHODS: The CYP2C19 gene was detected in 1231 patients on a gene chip platform, and the genotype frequencies of CYP2C19 in Foshan populations from different populations were compared.

RESULTS: The frequencies of CYP2C19*1, *2 and *3 in the Foshan population were 63.89%, 30.46% and 5.65%, respectively. For the three metabolic types, the frequency associated with the rapid metabolism type (*1/*1) was 41.51 [95% confidence interval (CI) 40.11 to 42.91%]; that for the intermediate metabolism type (*1/*2, *1/*3) was 44.76% (95% CI 43.34 to 46.18) and that for the slow metabolism type (*2/*2, *2/*3, *3/*3) was 13.73% (95% CI 12.75 to 14.71%). In the Foshan population, the frequencies of the CYP2C19 *2 and *3 alleles were similar to those previously reported for Chinese and other Asian populations.

CONCLUSION: Our study is a report on the genetic basis of CYP2C19 polymorphism in the Foshan population. Our results will potentially contribute to the improvement of pharmacotherapy effectiveness by providing personalized medicine for the Foshan population.

PMID:36112003 | DOI:10.1080/16078454.2022.2121899

Clin Pharmacol Ther. 2022 Sep 16. doi: 10.1002/cpt.2749. Online ahead of print.

ABSTRACT

CYP2D6 is a key enzyme in drug response owing to its involvement in the metabolism of approximately 25% of clinically prescribed medications. The encoding CYP2D6 gene is highly polymorphic and many pharmacogenetics studies have been performed worldwide to investigate the distribution of CYP2D6 star alleles (haplotypes); however, African populations have been relatively understudied to date. In this study, the distributions of CYP2D6 star alleles and predicted drug metaboliser phenotypes-derived from activity scores-were examined across multiple sub-Saharan African populations based on bioinformatics analysis of 961 high-depth whole genome sequences. This was followed by characterisation of novel star alleles and suballeles in a subset of the participants via targeted high fidelity Single-Molecule Real-Time resequencing (Pacific Biosciences). This study revealed varying frequencies of known CYP2D6 alleles and predicted phenotypes across different African ethnolinguistic groups. Twenty-seven novel CYP2D6 star alleles were predicted computationally and two of them were further validated. This study highlights the importance of studying variation in key pharmacogenes such as CYP2D6 in the African context to better understand population-specific allele frequencies. This will aid in the development of better genotyping panels and star allele detection approaches with a view towards supporting effective implementation of precision medicine strategies in Africa and across the African diaspora.

PMID:36111505 | DOI:10.1002/cpt.2749

Clin Pharmacol Ther. 2022 Sep 16. doi: 10.1002/cpt.2748. Online ahead of print.

ABSTRACT

Pharmacogenomic (PGx) testing has emerged as a compelling strategy that clinicians can use to inform antidepressant medication selection and dosing, but the clinical efficacy of this strategy has been questioned. We systematically reviewed and meta-analyzed clinical trials for an association between the use of PGx-guided antidepressant therapy and depressive symptom remission in patients with major depressive disorder. We included prospective, controlled clinical trials published in English up to July 12, 2022. Data extraction and synthesis adhered to the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Each trial was assessed for risk of bias and a random-effects model was used to estimate pooled risk ratios. Thirteen trials comprising 4767 patients were analyzed, including 10 randomized controlled trials and three open label trials. Across all included trials, those that received PGx-guided antidepressant therapy (n = 2395) were 1.41 (95% CI: 1.15 - 1.74, p = 0.001) more likely to achieve remission compared to those that received unguided antidepressant therapy (n = 2372). Pooled risk ratios for randomized controlled trials and open label trials were 1.46 (95% CI: 1.13 - 1.88) and 1.26 (95% CI: 0.84-1.88), respectively. These results suggest that PGx-guided antidepressant therapy is associated with a modest but significant increase in depressive symptom remission in adults with major depressive disorder. Efforts to address the heterogeneity in PGx test composition (i.e., genes and alleles tested) and accompanying prescribing recommendations across trials will likely reduce the uncertainty about the efficacy of PGx-guided antidepressant therapy in the literature.

PMID:36111494 | DOI:10.1002/cpt.2748

Front Psychiatry. 2022 Aug 30;13:994425. doi: 10.3389/fpsyt.2022.994425. eCollection 2022.

ABSTRACT

Treatment-resistant schizophrenia is a lack of adequate response to antipsychotic medications resulting in incomplete functional and social recovery from the illness. Different definitions have been proposed for clinical practice and research work. Antipsychotics that are used in the management of schizophrenia mainly act on multiple dopaminergic pathways which are implicated in the development of symptoms of schizophrenia. Newer antipsychotics also are implicated to affect the serotonergic pathways. Clozapine is the only evidence-based treatment available for the management of treatment-resistant cases. Neurobiologically, there is a considerable overlap between treatment-resistant and treatment-responsive cases. The factors that are implicated in the evolution of treatment resistance are still not conclusive. These make the management of such patients a challenge. However, certain peculiarities of treatment-resistant schizophrenia have been identified which can guide us in the early identification and precise treatment of the treatment-resistant cases.

PMID:36111312 | PMC:PMC9468267 | DOI:10.3389/fpsyt.2022.994425

J Clin Pharmacol. 2022 Sep;62 Suppl 1:S9-S11. doi: 10.1002/jcph.2101.

NO ABSTRACT

PMID:36106787 | DOI:10.1002/jcph.2101