Front Cardiovasc Med. 2022 Oct 13;9:966261. doi: 10.3389/fcvm.2022.966261. eCollection 2022.

ABSTRACT

Drug-induced cardiotoxicity (DICT) is an important concern of drug safety in both drug development and clinical application. The clinical manifestations of DICT include cardiomyopathy, arrhythmia, myocardial ischemia, heart failure, and a series of cardiac structural and functional changes. The occurrence of DICT has negative impacts on the life quality of the patients, brings additional social and economic burden. It is important to identify the potential factors and explore the mechanisms of DICT. Traditional cardiovascular risk factors can only partially explain the risk of DICT. Pharmacogenomic studies show accumulated evidence of genetics in DICT and suggest the potential to guide precision therapy to reduce risk of cardiotoxicity. The comprehensive application of technologies such as third-generation sequencing, human induced pluripotent stem (iPS) cells and genome editing has promoted the in-depth understanding of the functional role of susceptible genes in DICT. This paper reviewed drugs that cause DICT, the clinical manifestations and laboratory tests, as well as the related content of genetic variations associated with the risk of DICT, and further discussed the implication of new technologies in pharmacogenomics of DICT.

PMID:36312261 | PMC:PMC9606405 | DOI:10.3389/fcvm.2022.966261

Front Mol Biosci. 2022 Oct 14;9:1004602. doi: 10.3389/fmolb.2022.1004602. eCollection 2022.

ABSTRACT

The combination of high-resolution LC-MS untargeted metabolomics with stable isotope-resolved tracing is a promising approach for the global exploration of metabolic pathway activities. In our established workflow we combine targeted isotopologue feature extraction with the non-targeted X13CMS routine. Metabolites, detected by X13CMS as differentially labeled between two biological conditions are subsequently integrated into the original targeted library. This strategy enables monitoring of changes in known pathways as well as the discovery of hitherto unknown metabolic alterations. Here, we demonstrate this workflow in a PTEN (phosphatase and tensin homolog) null breast cancer cell line (MDA-MB-468) exploring metabolic pathway activities in the absence and presence of the selective PI3Kβ inhibitor AZD8186. Cells were fed with [U-13C] glucose and treated for 1, 3, 6, and 24 h with 0.5 µM AZD8186 or vehicle, extracted by an optimized sample preparation protocol and analyzed by LC-QTOF-MS. Untargeted differential tracing of labels revealed 286 isotope-enriched features that were significantly altered between control and treatment conditions, of which 19 features could be attributed to known compounds from targeted pathways. Other 11 features were unambiguously identified based on data-dependent MS/MS spectra and reference substances. Notably, only a minority of the significantly altered features (11 and 16, respectively) were identified when preprocessing of the same data set (treatment vs. control in 24 h unlabeled samples) was performed with tools commonly used for label-free (i.e. w/o isotopic tracer) non-targeted metabolomics experiments (Profinder´s batch recursive feature extraction and XCMS). The structurally identified metabolites were integrated into the existing targeted isotopologue feature extraction workflow to enable natural abundance correction, evaluation of assay performance and assessment of drug-induced changes in pathway activities. Label incorporation was highly reproducible for the majority of isotopologues in technical replicates with a RSD below 10%. Furthermore, inter-day repeatability of a second label experiment showed strong correlation (Pearson R 2 > 0.99) between tracer incorporation on different days. Finally, we could identify prominent pathway activity alterations upon PI3Kβ inhibition. Besides pathways in central metabolism, known to be changed our workflow revealed additional pathways, like pyrimidine metabolism or hexosamine pathway. All pathways identified represent key metabolic processes associated with cancer metabolism and therapy.

PMID:36310598 | PMC:PMC9614656 | DOI:10.3389/fmolb.2022.1004602

Obes Facts. 2022 Oct 28:1-12. doi: 10.1159/000527138. Online ahead of print.

ABSTRACT

INTRODUCTION: Lipedema is a poorly known condition. Diagnosis is based almost exclusively on clinical criteria, which may be subjective and not always reliable. This study aimed to investigate regional body composition (BC) by dual-energy X-ray absorptiometry (DXA) in patients with lipedema and healthy controls and to determine cut-off values of fat mass (FM) indices to provide an additional tool for the diagnosis and staging of this condition.

METHODS: This study is a single-center case-control study performed at Lausanne University Hospital, Switzerland. Women with clinically diagnosed lipedema underwent regional BC assessment by DXA. The control group without clinical lipedema was matched for age and body mass index (BMI) at a ratio of 1:2 and underwent similar examination. Regional FM (legs, arms, legs and arms, trunk, android and gynoid FM) was measured in (kg) and divided by FM index (FMI) (kg/m2) and total FM (kg). The trunk/legs and android/gynoid ratios were calculated. For all indices of FM distribution showing a significant difference between cases and controls, we defined the receiver operating characteristic (ROC) curves, calculating the area under the curve (AUC), sensitivity, specificity, and Youden's index. Types and stages of lipedema were compared in terms of FM indices. Correlation analyses between all FM distribution indices and lipedema stages were performed.

RESULTS: We included 222 women (74 with lipedema and 148 controls). Overall, the mean age was 41 years (standard deviation [SD] 11), and mean BMI was 30.9 kg/m2 (SD 7.6). A statistically significant difference was observed for all DXA-derived indices of FM distribution between groups, except for arm FM indices. The ROC curve analysis of leg FM/total FM, as a potential indicator of lipedema, resulted in an AUC of 0.90 (95% confidence interval 0.86-0.94). According to Youden's index, optimal cut-off value identifying lipedema was 0.384. Sensitivity and specificity were 0.95 and 0.73, respectively. We found no significant differences between lipedema types and stages in terms of FM indices, nor significant correlations between the latter and lipedema stages.

DISCUSSION/CONCLUSION: BC assessment by DXA, and particularly calculation of the leg FM/total FM index, is a simple tool that may help clinicians rule out lipedema in doubtful cases.

PMID:36310013 | DOI:10.1159/000527138

Radiat Oncol. 2022 Oct 28;17(1):174. doi: 10.1186/s13014-022-02141-z.

ABSTRACT

OBJECTIVE: Radiotherapy is one of the effective ways to treat glioblastoma multiforme (GBM). We aimed to explore the prognostic difference between external beam radiotherapy (EBRT) and EBRT combined with brachytherapy (EBRT + BT).

METHODS: The GBM patients from the Surveillance, Epidemiology, and End Results (SEER) database were divided into two cohorts: the EBRT cohort and the EBRT + BT cohort. Kaplan-Meier (KM) analysis and Cox proportional hazards regression were used to determine the underlying risk factors for overall survival (OS) and disease-specific survival (DSS). And the competing risk model and propensity score matching (PSM) was adopted to eliminate potential biases. We also conducted subgroup analyses and interaction tests as well.

RESULTS: There was a total of 41,010 eligible GBM patients. The median OS (15 months) and DSS (17 months) of the EBRT + BT cohort were significantly longer than that of the EBRT cohort (OS = 11 months, DSS = 12 months). After using the competing risk model and PSM, we found that only advanced age was the independent risk factor, while only EBRT + BT was the independent protective factor (HR = 0.84, 95%CI [0.74,0.96], p = 0.01). EBRT had universal effects in the treatment of GBM, and EBRT + BT had a more pronounced protective effect in the subgroups of males (HR = 0.81, 95%CI [0.68,0.97], p = 0.02) and local excision (HR = 0.82, 95%CI [0.34,0.95], p = 0.01).

CONCLUSIONS: The therapeutical effect of EBRT + BT treatment is better than that of EBRT alone, especially in male patients or patients who have undergone local resection. Our findings may provide novel evidence to develop a better radiotherapy strategy for GBM patients.

PMID:36307810 | DOI:10.1186/s13014-022-02141-z

J Neurooncol. 2022 Oct 28. doi: 10.1007/s11060-022-04164-8. Online ahead of print.

ABSTRACT

PURPOSE: To investigate the efficacy and safety of adjuvant radiotherapy (RT) in patients with central neurocytoma (CN).

METHODS: The study included 68 patients with CN retrospectively, was further divided into surgery + RT group (31 patients) and surgery alone group (37 patients). Progression-free survival (PFS), overall survival (OS), and adverse reactions (AEs) were compared between the two groups.

RESULTS: The median follow-up duration was 82.2 (interquartile range, 64.7-104.5) months. Patients in the surgery + RT group tended to have longer PFS than those in the surgery alone group (5-year PFS rate: 92.7% vs. 86.3%; P = 0.074). There was no significant difference in OS between the two groups (5-year OS rate: 96.8% vs. 94.3%; P = 0.639). Subgroup analysis revealed a significant improvement in PFS in patients receiving RT after surgery in patients who underwent subtotal resection (STR) (P = 0.045). In the overall population, univariate multivariate analysis revealed that gross total resection (GTR) (P = 0.002), tumor location in the unilateral ventricle (P = 0.008), and MIB-1 (Ki-67) labeling index (LI) < 5% (P = 0.009) were favorable independent prognostic factors for PFS. Whereas tumor location in the unilateral ventricle (P = 0.043) was a favorable independent prognostic factor for OS. Moreover, RT patients experienced AEs (Grade 1-2, well-tolerated).

CONCLUSION: Adjuvant RT in the treatment of CNs showed satisfactory safety, and postoperative RT could improve PFS in STR patients. Furthermore, GTR, tumor development in the unilateral ventricle, and MIB-1 LI < 5% were found to be favorable factors affecting the prognosis of CNs.

PMID:36307664 | DOI:10.1007/s11060-022-04164-8

Biol Psychiatry. 2022 Aug 22:S0006-3223(22)01523-2. doi: 10.1016/j.biopsych.2022.08.014. Online ahead of print.

ABSTRACT

BACKGROUND: Bipolar disorder is a highly heritable neuropsychiatric condition affecting more than 1% of the human population. Lithium salts are commonly prescribed as a mood stabilizer for individuals with bipolar disorder. Lithium is clinically effective in approximately half of treated individuals, and their genetic backgrounds are known to influence treatment outcomes. While the mechanism of lithium's therapeutic action is unclear, it stimulates adult neural progenitor cell proliferation, similar to some antidepressant drugs.

METHODS: To identify common genetic variants that modulate lithium-induced proliferation, we conducted an EdU incorporation assay in a library of 80 genotyped human neural progenitor cells treated with lithium. These data were used to perform a genome-wide association study to identify common genetic variants that influence lithium-induced neural progenitor cell proliferation. We manipulated the expression of a putatively causal gene using CRISPRi/a (clustered regularly interspaced short palindromic repeats interference/activation) constructs to experimentally verify lithium-induced proliferation effects.

RESULTS: We identified a locus on chr3p21.1 associated with lithium-induced proliferation. This locus is also associated with bipolar disorder risk, schizophrenia risk, and interindividual differences in intelligence. We identified a single gene, GNL3, whose expression temporally increased in an allele-specific fashion following lithium treatment. Experimentally increasing the expression of GNL3 led to increased proliferation under baseline conditions, while experimentally decreasing GNL3 expression suppressed lithium-induced proliferation.

CONCLUSIONS: Our experiments reveal that common genetic variation modulates lithium-induced neural progenitor proliferation and that GNL3 expression is necessary for the full proliferation-stimulating effects of lithium. These results suggest that performing genome-wide associations in genetically diverse human cell lines is a useful approach to discover context-specific pharmacogenomic effects.

PMID:36307327 | DOI:10.1016/j.biopsych.2022.08.014

Trends Pharmacol Sci. 2022 Oct 25:S0165-6147(22)00207-3. doi: 10.1016/j.tips.2022.09.011. Online ahead of print.

ABSTRACT

Genetic factors can, to a certain extent, successfully predict the therapeutic effects, metabolism, and adverse reactions of drugs. This research field, pharmacogenomics, is well developed in oncology and is currently expanding in psychiatry. Here, we summarize the latest development in pharmacogenomic psychiatry, where results of several recent large studies indicate a true benefit and cost-effectiveness of pre-emptive genotyping for more successful psychotherapy. However, it is apparent that we still lack knowledge of many additional heritable genetic factors of importance for explanation of the interindividual differences in response to psychiatric drugs. Thus, more effort to further develop pharmacogenomic psychiatry should be invested to achieve a broader clinical implementation.

PMID:36307251 | DOI:10.1016/j.tips.2022.09.011

Biomaterials. 2022 Oct 18;290:121856. doi: 10.1016/j.biomaterials.2022.121856. Online ahead of print.

ABSTRACT

cGAS-STING pathway, as an essential intracellular immune response pathway, has attracted much attention in tumor immunotherapy. However, low metabolic stability of conventional STING agonists limits their clinical application. Recent study shows that chemotherapeutic drugs cisplatin and camptothecin (CPT) can activate cGAS-STING pathway and induce immune response by DNA damage. Nevertheless, the ability of chemotherapeutic drugs to activate STING is so weak that new strategies are required to improve drug delivery efficiency for enhanced DNA damage, and then efficiently activate cGAS-STING pathway. Herein, we have developed a hybrid platinum prodrug (CPT-Pt (IV)) which can be triggered to release cisplatin and CPT in tumor cells. CPT-Pt (IV) with high hydrophobicity is further self-assembled with a ROS sensitive polymer (P1) and mPEG2k-DSPE into ROS responsive nanoparticles (NPs). NPs could accumulate in the tumor site to release cisplatin and CPT, resulting in DNA double damage and finally activating cGAS-STING pathway, inducing DC cells maturation and increasing tumor infiltration of CD8+ T cells on colorectal cancer mouse model. This study showed that common DNA targeted drugs can activate the cGAS-STING pathway in situ via nano delivery system, and enhance the effect of chemotherapy and immunotherapy, which provide a new strategy for clinical antitumor therapy.

PMID:36306685 | DOI:10.1016/j.biomaterials.2022.121856

Clin Pharmacol Ther. 2022 Oct 28. doi: 10.1002/cpt.2776. Online ahead of print.

ABSTRACT

Black patients suffer worse outcomes after percutaneous coronary intervention (PCI) than White patients. Inequities in antiplatelet prescribing may contribute to this health disparity. We compared P2Y12 inhibitor prescribing by race following CYP2C19 genotyping to guide antiplatelet therapy selection after PCI. Patients from nine sites that performed clinical CYP2C19 genotyping after PCI were included. Alternative therapy (e.g., prasugrel or ticagrelor) was recommended for CYP2C19 no-function allele carriers, in whom clopidogrel is predicted to be less effective. The primary outcome was choice of P2Y12 inhibitor (clopidogrel versus alternative therapy) based on genotype. Of 3342 patients included, 2448 (73%) were White, and 659 (20%) were Black. More Black than White patients had a no-function allele (34.3% versus 29.7%, p=0.024). At hospital discharge following PCI, 44.2% of Black and 44.0% of White no-function allele carriers were prescribed alternative therapy. At the time of last follow-up within 12 months, numerically fewer Black (51.8%) than White (56.7%) no-function allele carriers were prescribed alternative therapy (p=0.190). However, the difference was not significant after accounting for other factors associated with P2Y12 inhibitor selection (odds ratio 0.79, 95% confidence interval 0.58-1.08). Alternative therapy use did not differ between Black (14.3%) and White (16.7%) patients without a no-function allele (p=0.232). Among real-world patients who received CYP2C19 testing after PCI, P2Y12 inhibitor prescribing rates did not differ between Black and White patients. Our data suggest an absence of racial disparity in genotype-guided antiplatelet prescribing among patients receiving CYP2C19 testing.

PMID:36306392 | DOI:10.1002/cpt.2776

Int J Clin Pharm. 2022 Oct 28. doi: 10.1007/s11096-022-01471-y. Online ahead of print.

ABSTRACT

BACKGROUND: Machine learning algorithms (MLAs) carry a huge potential in identifying predicting factors and are being explored for their utility in the field of personalized medicine.

AIM: We aimed to investigate MLAs for identifying predictors (clinical and genetic) of poor anticoagulation status (ACS) and stable weekly warfarin dose (SWWD).

METHOD: Clinical factors, in addition to the CYP2C9, VKORC1, and CYP4F2 genotypes, were obtained for patients receiving warfarin for at least the previous six months. The C5.0 decision tree classification algorithm was used to predict poor ACS while classification and regression tree analysis (CART), in addition to the Chi-square automatic interaction detector (CHAID), was used to predict SWWD. The percentage of patients within 20% of the actual dose, root mean squared error (RMSE), and area under the receiver-operating characteristics curve (AUROC) were identified as performance indicators of the models.

RESULTS: In the C5.0 classification decision tree, the CYP4F2 genotype was the strongest predictor of ACS (AUROC = 0.53). In the CART analysis of SWWD, VKORC1 polymorphisms were the most significant predictor, followed by the CYP2C9 genotype (percentage of patients within 20% of the actual dose = 38.2%, RMSE = 13.6). For the CHAID algorithm, the percentage of patients within 20% of the actual dose was 49%, while the RMSE was found to be 13.4.

CONCLUSION: Genetic and non-genetic predictive factors were identified by the MLAs for ACS and SWWD. Further, the need to externally validate the MLAs in a prospective study was highlighted.

PMID:36306062 | DOI:10.1007/s11096-022-01471-y

Med Res Arch. 2022 Sep;10(9). doi: 10.18103/mra.v10i9.2986. Epub 2022 Sep 20.

ABSTRACT

Fifty years ago, Richard Lewontin found that the vast majority of human genetic variation falls within (~85%) rather than between (~15%) racial groups. This result has been replicated numerous times since and is widely taken to support the notion that genetic differences between racial groups are trivial and thus irrelevant for clinical decision-making. The aim of this study was to consider how the apportionment of pharmacogenomic variation within and between racial and ethnic groups relates to risk disparities for adverse drug reactions. We confirmed that the majority of pharmacogenomic variation falls within (97.3%) rather than between (2.78%) the three largest racial and ethnic groups in the United States: Black, Hispanic, and White. Nevertheless, pharmacogenomic variants showing far greater within than between-group variation can have high predictive value for adverse drug reactions, particularly for minority racial and ethnic groups. We predicted excess adverse drug reactions for minority Black and Hispanic groups, compared to the majority White group, and considered these results in light of the apportionment of genetic variation within and between groups. For 85% within and 15% between group variation, there are 700 excess adverse drug reactions per 1,000 patients predicted for a recessive effect model and 300 for a dominant model. We found high numbers of predicted Black and Hispanic excess adverse drug reactions for widely prescribed platinum chemotherapy compounds, such as cisplatin and oxaliplatin, as well as controlled narcotics, including fentanyl and tramadol. Our results indicate that race and ethnicity, while imprecise proxies for genetic diversity, correlate with patterns of pharmacogenomic variation in a way that is clearly relevant to medical treatment decisions. The effects of this variation is particularly pronounced for Black and Hispanic minority groups, owing to genetic differences from the majority White group. Treatment decisions that are made based on (assumed) White pharmacogenomic variant frequencies can be harmful for minority groups. Ignoring clinically relevant genetic differences among racial and ethnic groups, however well-intentioned, will exacerbate rather than ameliorate health disparities.

PMID:36304842 | PMC:PMC9600569 | DOI:10.18103/mra.v10i9.2986

Front Pharmacol. 2022 Oct 11;13:1010520. doi: 10.3389/fphar.2022.1010520. eCollection 2022.

ABSTRACT

Pharmacogenomic analysis based on drug transcriptomic signatures is widely used to identify mechanisms of action and pharmacological indications. Despite accumulating reports on the efficacy of medicinal herbs, related transcriptome-level analyses are lacking. The aim of the present study was to elucidate the underlying molecular mechanisms of action of Bupleuri Radix (BR), a widely used herbal medicine, through a systematic transcriptomic analysis. We analyzed the drug-responsive transcriptome profiling of A549 lung cancer cell line after treating them with multiple doses of BR water (W-BR) and ethanol (E-BR) extracts and their phytochemicals. In vitro validation experiments were performed using both A549 and the immortalized human keratinocyte line HaCaT. Pathway enrichment analysis revealed the anti-cancer effects of BR treatment via inhibition of cell proliferation and induction of apoptosis. Enhanced cell adhesion and migration were observed with the W-BR but not with the E-BR. Comparison with a disease signature database validated an indication of the W-BR for skin disorders. Moreover, W-BR treatment showed the wound-healing effect in skin and lung cells. The main active ingredients of BR showed only the anti-cancer effect of the E-BR and not the wound healing effect of the W-BR, suggesting the need for research on minor ingredients of BR.

PMID:36304143 | PMC:PMC9592978 | DOI:10.3389/fphar.2022.1010520

Thromb J. 2022 Oct 27;20(1):65. doi: 10.1186/s12959-022-00425-8.

ABSTRACT

BACKGROUND: Warfarin is the most widely used oral anticoagulant; nevertheless, dosing of warfarin is problematic for clinicians worldwide. Inter-individual variability in response to warfarin is attributed to genetic as well as non-genetic factors. Pharmacogenomics studies have identified variants in CYP2C9 and VKORC1 genes as significant predictors of warfarin dose, however, phenotypes of rare variants are not well characterized.

CASE PRESENTATION: We report a case of hyper-responsiveness to warfarin in a 22-year-old outpatient with Crohn's disease who presented with a swollen, red, and painful left calf. Deep venous thrombosis (DVT) in the left lower extremity was confirmed via ultrasonography, and hence, anticoagulation therapy of heparin and concomitant warfarin was initiated. Warfarin dose of 7.5 mg/day was estimated by the physician based on clinical factors. Higher than the expected international normalized ratio (INR) value of 4.5 necessitated the reduction of the warfarin dose to 5 and eventually to 2.5 mg/day to reach a therapeutic INR value of 2.6. Pharmacogenetic profiling of the VKORC1 -1639G > A and CYP2C9 *2, *3, *4, *5, *8, *14, *20, *24, *26, *33, *40, *41, *42, *43, *45, *46, *55, *62, *63, *66, *68, *72, *73 and *78 revealed a VKORC1-1639GA/CYP2C9*1*46 genotype. The lower catalytic activity of the CYP2C9*46 (A149T) variant was previously reported in in vitro settings.

CONCLUSIONS: This is the first report on a case of warfarin hyper-responsive phenotype of a patient with the heterozygous CYP2C9*1*46 polymorphism.

PMID:36303140 | DOI:10.1186/s12959-022-00425-8

Pharmacogenomics J. 2022 Oct 27. doi: 10.1038/s41397-022-00292-6. Online ahead of print.

ABSTRACT

This study evaluated the timing, use, and clinical outcomes of the GeneFolio® Pharmacogenomic Panel in a healthcare setting with patients managed by primary care providers or by psychiatrists. Participants were randomized to receive a pharmacogenetics report at four weeks or 12 weeks. After DNA collection and genetic analysis, pharmacists produced a recommendation report which was given to providers at the randomization week. The four-week group decreased depression severity (PHQ-9 and BDI) faster than the 12-week group (p = 0.0196), and psychiatrists' patients decreased their depression severity faster than primary care patients (PHQ-9 p = 0.0005, BDI p = 0.0218). Mean mental quality of life increased over time (p < 0.0001), but it increased slower for patients taking drugs in the Significant drug-drug-gene interaction category (p = 0.0012). Mental quality of life, depression severity, and clinical outcomes were improved by GeneFolio® pharmacogenomic testing regardless of provider type, with earlier testing improving outcomes sooner.

PMID:36302979 | DOI:10.1038/s41397-022-00292-6

Nat Nanotechnol. 2022 Oct 27. doi: 10.1038/s41565-022-01225-x. Online ahead of print.

ABSTRACT

The clinical utility of stimulator of interferon genes (STING) agonists has been limited due to poor tumour-targeting and unwanted toxicity following systemic delivery. Here we describe a robust tumour-targeted STING agonist, ZnCDA, formed by the encapsulation of bacterial-derived cyclic dimeric adenosine monophosphate (CDA) in nanoscale coordination polymers. Intravenously injected ZnCDA prolongs CDA circulation and efficiently targets tumours, mediating robust anti-tumour effects in a diverse set of preclinical cancer models at a single dose. Our findings reveal that ZnCDA enhances tumour accumulation by disrupting endothelial cells in the tumour vasculature. ZnCDA preferentially targets tumour-associated macrophages to modulate antigen processing and presentation and subsequent priming of an anti-tumour T-cell response. ZnCDA reinvigorates the anti-tumour activity of both radiotherapy and immune checkpoint inhibitors in immunologically 'cold' pancreatic and glioma tumour models, offering a promising combination strategy for the treatment of intractable human cancers.

PMID:36302963 | DOI:10.1038/s41565-022-01225-x

J Hum Hypertens. 2022 Oct 27. doi: 10.1038/s41371-022-00765-y. Online ahead of print.

ABSTRACT

Pharmacogenetics play an important role in determining the anti-hypertensive effects of blood pressure-lowering medications and have the potential to improve future patient care. Current literature on the topic, however, has a heavy focus on Caucasians and may not be generalisable to the Asian populations. Therefore, we have conducted this systematic review to summarise and evaluate the literature of the past decade. PubMed, Embase, and the Cochrane Register of Controlled Trials were searched for relevant studies from 1 January 2011 to 23 July 2021. The outcome of interest was the response to anti-hypertensive treatment in Asians according to each genetic polymorphism. A total of 26 studies with a total of 8837 patients were included in our review, covering five classes of anti-hypertensive agents-namely, angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), beta-blockers (BB), calcium channel blockers (CCB), and thiazide-like diuretics. Response to ACEI therapy was most susceptible to genotypic variations, while the efficacy of ARB and CCB were affected by pharmacogenetic differences to varying extent. For BB, only variations in the ADRB1 genotype significantly affects therapeutic response, while the therapeutic efficacy of thiazide-like diuretics was correlated with genotypic variations in the REN and ACE. This systematic review evaluated the impact of pharmacogenetic variations on the therapeutic efficacy of anti-hypertensive treatment in Asians and has described numerous drug-gene pairs that are potentially clinically important. Future prospective studies with larger sample sizes and longer follow-up periods are needed to better elucidate the impact of these drug-gene pairs.

PMID:36302845 | DOI:10.1038/s41371-022-00765-y

Psychiatr Genet. 2022 Oct 21. doi: 10.1097/YPG.0000000000000325. Online ahead of print.

ABSTRACT

INTRODUCTION: The distribution pattern and knowledge structure of psychiatric genomics were surveyed based on literature dealing with both psychiatry and genomics/genetics. Coword analysis and bibliographic coupling of the records retrieved from Scopus and PubMed for 2016-2020 revealed the subsurface research aspects.

METHOD: The data were analyzed using coword analysis and clustering methods using Sci2 and VOSviewer.

RESULT: Analysis of ~3800 records showed that psychiatric genomics is, as expectedly, covered largely under biomedical subjects with a visible interest in other disciplines such as humanities and ethics. A coword analysis was done for all the years, followed by a year-wise analysis based on the keywords, and then a bibliographic coupling based on the cited references. This led to the generation of different clusters of prevalent research areas. The centrality values described the position of each component.

DISCUSSION: 'Schizophrenia', 'depression', 'pharmacogenomics', and 'immunopathogenesis' were the research topics of overarching interest. 'Gut-brain axis' and 'gene-environment interaction' were the emerging topics, whereas certain topics such as 'child and adolescent psychiatry' remained priorities when compared to earlier studies. The keywords and research focus were diverse. They ranged from genetics to transcriptomics and epigenetics to proteomics of psychiatric disorders. We found a stagnation of science communication in the field with only 0.2% of the articles from the entire corpus relevant to it. The research categories identified in this study reflect the current publication and research trends in psychiatric genomics.

PMID:36302202 | DOI:10.1097/YPG.0000000000000325

Eur J Dermatol. 2022 Jul 1;32(4):536-537. doi: 10.1684/ejd.2022.4279.

NO ABSTRACT

PMID:36301751 | DOI:10.1684/ejd.2022.4279

Popul Health Manag. 2022 Oct 26. doi: 10.1089/pop.2022.0075. Online ahead of print.

ABSTRACT

Rising prescription costs, poor medication adherence, and safety issues pose persistent challenges to employer-sponsored health care plans and their beneficiaries. Comprehensive medication management (CMM), a patient-centered approach to medication optimization, enriched by pharmacogenomics (PGx), has been shown to improve the efficacy and safety of pharmaceutical regimens. This has contributed to improved health care outcomes, reduced costs of treatments, better adherence, shorter durations of treatment, and fewer adverse effects from drug therapy. Despite compelling clinical and economic evidence to justify the application of CMM guided by PGx, implementation in clinical settings remains sparse; notable barriers include limited physician adoption and health insurance coverage. Ultimately, these challenges may be overcome through comprehensive programs that include clinical decision support systems and education through employer-sponsored population health management channels to the benefit of the employees, employers, health care providers, and health care systems. This article discusses benefits, considerations, and barriers of scalable PGx-enriched CMM programs in the context of self-insured employers.

PMID:36301527 | DOI:10.1089/pop.2022.0075

Expert Rev Clin Immunol. 2022 Oct 27. doi: 10.1080/1744666X.2023.2141226. Online ahead of print.

ABSTRACT

INTRODUCTION: Psoriasis is a common, chronic immune-mediated skin disease frequently associated to inflammatory and metabolic comorbidities. About 20-30% of patients are affected by moderate-to-severe psoriasis and require a systemic treatment, which include traditional and biological drugs. The objective of this manuscript is to provide criteria for a personalized biological treatment.

AREAS COVERED: Tailoring a biological treatment for patients with moderate-to-severe psoriasis needs to consider several variables related to the disease, the patient and the treatment. It is important to consider the disease severity and activity, the skin areas involved, the frequency of relapses, itch or other symptoms, and foremost the presence of comorbidities. About the patient, is important to consider age, gender, body weight, the occupation, the impact on the quality of life, the likelihood of adherence, patient expectations, the desire for remission and the fear of side effects.

EXPERT OPINION: The presence of comorbidities, which may benefit from or contraindicate a given biologic, is the main driver of a tailored therapy. A personalized treatment associates maximum efficacy and minimal risk of side effects. In addition, there is the possibility of modifying disease-course inducing long-term remission and preventing the development of psoriatic arthritis.

PMID:36300752 | DOI:10.1080/1744666X.2023.2141226