J Pers Med. 2022 Aug 28;12(9):1399. doi: 10.3390/jpm12091399.

ABSTRACT

Thiopurine methyltransferase (TPMT) is the rate-limiting enzyme in Azathioprine (AZA) metabolization. Although studies have discussed the association between the TPMT polymorphisms and myelosuppression, the data about the relationship between TPMT genotypes and hepatoxicity in Asian patients remain limited. This study investigated the correlation between TPMT polymorphisms and AZA-related hepatotoxicity. This study enrolled the patients who had prior exposure to AZA from the Taichung Veterans General Hospital (TCVGH)-Taiwan Precision Medicine Initiative (TPMI) cohort. Genetic variants were determined using a single nucleotide polymorphism (SNP) array. Participants were accordingly categorized into normal metabolizer (NM) and non-normal metabolizer (non-NM) groups. From the TCVGH-TPMI cohort, we included 50 TPMT non-NM patients, including 1 poor metabolizer (PM), 49 intermediate metabolizers (IMs), and 1000 NM patients. The non-NM genotype was associated with hepatotoxicity compared with the NM genotype (hazard ratio (HR): 3.85, 95% confidence interval (CI): 1.83-8.10). In the non-NM group, the 3-year cumulative incidence of hepatotoxicity was higher than that in the NM group at 8.5% in the first year and 18.6% in the second and third years (p < 0.001). A TPMT non-NM genotype was associated with the occurrence of hepatotoxicity following AZA therapy. Preemptive testing helps individualize AZA therapy by minimizing the risk of hepatotoxicity.

PMID:36143183 | DOI:10.3390/jpm12091399

J Pers Med. 2022 Aug 27;12(9):1394. doi: 10.3390/jpm12091394.

ABSTRACT

Polygenic models have emerged as promising prediction tools for the prediction of complex traits. Currently, the majority of polygenic models are developed in the context of predicting disease risk, but polygenic models may also prove useful in predicting drug outcomes. This study sought to understand how polygenic models incorporating pharmacogenetic variants are being used in the prediction of drug outcomes. A systematic review was conducted with the aim of gaining insights into the methods used to construct polygenic models, as well as their performance in drug outcome prediction. The search uncovered 89 papers that incorporated pharmacogenetic variants in the development of polygenic models. It was found that the most common polygenic models were constructed for drug dosing predictions in anticoagulant therapies (n = 27). While nearly all studies found a significant association with their polygenic model and the investigated drug outcome (93.3%), less than half (47.2%) compared the performance of the polygenic model against clinical predictors, and even fewer (40.4%) sought to validate model predictions in an independent cohort. Additionally, the heterogeneity of reported performance measures makes the comparison of models across studies challenging. These findings highlight key considerations for future work in developing polygenic models in pharmacogenomic research.

PMID:36143179 | DOI:10.3390/jpm12091394

J Pers Med. 2022 Aug 26;12(9):1387. doi: 10.3390/jpm12091387.

ABSTRACT

Human papilloma virus (HPV) infection could be considered a social disease, both for its high incidence, especially in younger subjects, and for the risk of neoplastic evolution linked to viral infection. Therefore, the National Health System, in collaboration with the state, must help women to understand the oncological risk of HPV and suitable methods of prevention. We conducted an Italian monocentric survey on HPV risk information as part of cervical cancer screening. An anonymous questionnaire was administered to 200 women with high-risk positive HPV and low-grade cervical lesions during second-level cervical cancer screening at the Gynecology and Obstetrics Unit of the "San Paolo" Hospital. From this survey, the need to improve communication for patients has emerged, as currently it is not exhaustive. In response to this need, organizational changes have been implemented to centralize the moment of counseling in the second levels of screening and to improve the training of health workers in level I as well as family doctors. In addition, psychological support was also proposed to patients who requested it, as was the dissemination of material such as that produced by GISCI (Italian Cervico-Carcinoma Screening Group) and updated in May 2018, which provides 100 answers to questions on HPV in order to achieve effective and comprehensive communication. This investigation requires further development, and the expansion of this investigation to the multicenter level is already underway. Therefore, this survey will represent a cornerstone for further discussion on the topic considering the necessity of appropriate communication in the oncological context.

PMID:36143172 | DOI:10.3390/jpm12091387

Int J Mol Sci. 2022 Sep 19;23(18):10960. doi: 10.3390/ijms231810960.

ABSTRACT

In the presence of established atherosclerosis, estrogens are potentially harmful. MMP-2 and MMP-9, their inhibitors (TIMP-2 and TIMP-1), RANK, RANKL, OPG, MCP-1, lysyl oxidase (LOX), PDGF-β, and ADAMTS-4 play critical roles in plaque instability/rupture. We aimed to investigate (i) the effect of estradiol on the expression of the abovementioned molecules in endothelial cells, (ii) which type(s) of estrogen receptors mediate these effects, and (iii) the role of p21 in the estrogen-mediated regulation of the aforementioned factors. Human aortic endothelial cells (HAECs) were cultured with estradiol in the presence or absence of TNF-α. The expression of the aforementioned molecules was assessed by qRT-PCR and ELISA. Zymography was also performed. The experiments were repeated in either ERα- or ERβ-transfected HAECs and after silencing p21. HAECs expressed only the GPR-30 estrogen receptor. Estradiol, at low concentrations, decreased MMP-2 activity by 15-fold, increased LOX expression by 2-fold via GPR-30, and reduced MCP-1 expression by 3.5-fold via ERβ. The overexpression of ERα increased MCP-1 mRNA expression by 2.5-fold. In a low-grade inflammation state, lower concentrations of estradiol induced the mRNA expression of MCP-1 (3.4-fold) and MMP-9 (7.5-fold) and increased the activity of MMP-2 (1.7-fold) via GPR-30. Moreover, p21 silencing resulted in equivocal effects on the expression of the abovementioned molecules. Estradiol induced different effects regarding atherogenic plaque instability through different ERs. The balance of the expression of the various ER subtypes may play an important role in the paradoxical characterization of estrogens as both beneficial and harmful.

PMID:36142876 | DOI:10.3390/ijms231810960

Genes (Basel). 2022 Sep 2;13(9):1575. doi: 10.3390/genes13091575.

ABSTRACT

Since the beginning of pharmacology, several variations in responses to drugs have been recorded [...].

PMID:36140743 | DOI:10.3390/genes13091575

Antibiotics (Basel). 2022 Sep 17;11(9):1263. doi: 10.3390/antibiotics11091263.

ABSTRACT

Antimicrobial resistance represents a serious threat for global health, causing an unacceptable burden in terms of morbidity, mortality and healthcare costs. In particular, in 2017, carbapenem-resistant organisms were listed by the WHO among the group of pathogens for which novel treatment strategies are urgently needed. Fortunately, several drugs and combinations have been introduced in recent years to treat multi-drug-resistant (MDR) bacteria. However, a correct use of these molecules is needed to preserve their efficacy. In the present paper, we will provide an overview on the epidemiology and mechanisms of resistance of the most common MDR Gram-negative bacteria, proposing a treatment algorithm for the management of infections due to carbapenem-resistant bacteria based on the most recent clinical evidence.

PMID:36140042 | DOI:10.3390/antibiotics11091263

Cancers (Basel). 2022 Sep 8;14(18):4365. doi: 10.3390/cancers14184365.

ABSTRACT

Radiotherapy (RT) for breast cancer significantly impacts patient survival and causes adverse events. Double-strand breaks are the most harmful type of DNA damage associated with RT, which is repaired through homologous recombination (HRR). As genetic variability of DNA repair genes could affect response to RT, we aimed to evaluate the association of polymorphisms in HRR genes with tumor characteristics and the occurrence of RT adverse events in early HER2-positive breast cancer. Our study included 101 breast cancer patients treated with adjuvant RT and trastuzumab. All patients were genotyped for eight single nucleotide polymorphisms in NBN, RAD51 and XRCC3 using competitive allele-specific PCR. Carriers of XRCC3 rs1799794 GG genotype were less likely to have higher tumor differentiation grade (OR = 0.05, 95% CI = 0.01-0.44, p = 0.007). Carriers of RAD51 rs1801321 TT genotype were more likely to have higher NYHA class in univariable (OR = 10.0; 95% CI = 1.63-61.33; p = 0.013) and multivariable (OR = 9.27; 95% CI = 1.28-67.02; p = 0.027) analysis. Carriers of RAD51 rs12593359 GG genotype were less likely to have higher NYHA class in univariable (OR = 0.09; 95% CI = 0.01-0.79; p = 0.030) and multivariable (OR = 0.07; 95% CI = 0.01-0.81; p = 0.034) analysis. Carriers of XRCC3 rs1799794 GG genotypes experienced more skin adverse events based on LENT-SOMA scale in univariable (OR = 5.83; 95% CI = 1.22-28.00; p = 0.028) and multivariable (OR = 10.90; 95% CI = 1.61-73.72; p = 0.014) analysis. In conclusion, XRCC3 and RAD51 polymorphisms might contribute to RT adverse events in early HER2-positive breast cancer patients.

PMID:36139526 | DOI:10.3390/cancers14184365

Biomolecules. 2022 Sep 16;12(9):1307. doi: 10.3390/biom12091307.

ABSTRACT

Human diseases are generally influenced by SNPs (single nucleotide polymorphisms). The mutations in amino acid residues generated by deleterious SNPs contribute to the structural and functional diversity of the encoded protein. Tumor necrosis factor-α (TNF-α), Glucocorticoid receptor gene (NR3C1), and Cytochrome P450 3A5 (CYP3A5) play a key role in glucocorticoid resistance susceptibility in humans. Possible causative mutations could be used as therapeutic targets and diagnostic markers for glucocorticoid resistance. This study evaluated the missense SNPs of TNF-α, NR3C1, and CYP3A5 to predict their impact on amino acid changes, protein interaction, and functional stability. The protein sequence of dbSNP was obtained and used online in silico method to screen deleterious mutants for the in silico analysis. In the coding regions of TNF-α, NR3C1, and CYP3A5, 14 deleterious mutations were discovered. The protein functional and stability changes in the amino acid between native and mutant energy were identified by analyzing the changes in the hydrogen bonding of these mutants from native, which were all measured using Swiss PDB and PyMOL. F446S and R439K had the highest root-mean-square deviation (RMSD) values among the 14 deleterious mutants. Additionally, the conserved region of amino acid protein interaction was analyzed. This study could aid in the discovery of new detrimental mutations in TNF-α, NR3C1, and CYP3A5, as well as the development of long-term therapy for corticosteroid resistance in several inflammatory diseases. However, more research into the deleterious mutations of the TNF-α, NR3C1, and CYP3A5 genes is needed to determine their role in corticosteroid resistance.

PMID:36139147 | DOI:10.3390/biom12091307

Biomolecules. 2022 Sep 2;12(9):1226. doi: 10.3390/biom12091226.

ABSTRACT

Immune dysfunction and pro-oncogenic inflammation play critical roles in malignant progression and non-response to immunotherapy for hepatocellular carcinoma (HCC). In particular, PD-1/PD-L1 blockade therapy could induce durable tumor remissions and improve the prognosis of patients to a certain extent. However, PD-L1, as a promising biomarker, has limited knowledge about its relevance to tumor microenvironment (TME) characterization and endogenous inflammatory immune responses. In this study, we systematically investigated and characterized the important intercommunication of PD-L1 with immunosuppressive TME and inflammatory response activity in HCC and predicted promising therapeutic drugs to improve the current therapeutic strategy for specific patients. We identified aberrant expression patterns of PD-L1 in HCC and completely different clinical and molecular characteristics among the PD-L1 subgroups. PD-L1 positively associated with immunosuppressive macrophages and macrophage-derived cytokines, which may contribute to the polarization of macrophages. Moreover, inflammatory response activity exhibited significant differences between high and low PD-L1 expression groups and had robust positive correlativity of the infiltration level of tumor-associated macrophages. Notably, given the immunosuppressive and inflammatory microenvironment in HCC, we screened four candidate drugs, including dasatinib, vemurafenib, topotecan and AZD6482, and corroborated in two pharmacogenomics databases, which might have potential therapeutic implications in specific HCC patients. Our results enhanced the understanding of linkage in PD-L1 expression patterns with macrophages and inflammation, which may provide new insight into the pathogenic mechanisms and potential therapeutic strategy for HCC.

PMID:36139065 | DOI:10.3390/biom12091226

Biomolecules. 2022 Aug 31;12(9):1206. doi: 10.3390/biom12091206.

ABSTRACT

Cisplatin (cis-diamminedichloroplatinum (II), DDP) is an antineoplastic agent widely used in the treatment of solid tumors because of its extensive cytotoxic activity. However, the main limiting side effect of DDP use is nephrotoxicity, a rapid deterioration in kidney function due to toxic chemicals. Several studies have shown that epigenetic processes are involved in DDP-induced nephrotoxicity. Noncoding RNAs (ncRNAs), a class of epigenetic processes, are molecules that regulate gene expression under physiological and pathological conditions. MicroRNAs (miRNAs) are the most characterized class of ncRNAs and are engaged in many cellular processes. In this review, we describe how different miRNAs regulate some pathways leading to cell death by apoptosis, specifically the intrinsic apoptosis pathway. Accordingly, many classes of natural products have been tested for their ability to prevent DDP-induced apoptosis. The study of epigenetic regulation for underlying cell death is still being studied, which will allow new strategies for the diagnosis and therapy of this unwanted disease, which is presented as a side effect of antineoplastic treatment.

PMID:36139046 | DOI:10.3390/biom12091206

Brain Sci. 2022 Sep 3;12(9):1189. doi: 10.3390/brainsci12091189.

ABSTRACT

Genetic influences on acute responses to psychoactive drugs may contribute to individual variability in addiction risk. ABCB1 is a human gene that encodes P-glycoprotein, an ATP-dependent efflux pump that may influence the pharmacokinetics of delta-9-tetrahydrocannabinol (THC), the primary psychoactive component of cannabis. Using data from 48 young adults (aged 19-25 years) reporting 1-4 days of cannabis use per week who completed a placebo-controlled human laboratory experiment, we tested the hypothesis that the rs2235048 polymorphism of ABCB1 would influence acute responses to smoked cannabis. C-allele carriers reported on average greater frequency of weekly cannabis use compared to the TT genotype carriers (TC/CC mean ± SEM = 2.74 ± 0.14, TT = 1.85 ± 0.24, p = 0.004). After smoking a single cannabis cigarette to their desired high, C-allele carriers had higher area-under-the-curve (AUC) of both THC metabolites (11-OH-THC TC/CC = 7.18 ± 9.64, TT = 3.28 ± 3.40, p = 0.05; THC-COOH TC/CC = 95.21 ± 116.12, TT = 45.92 ± 42.38, p = 0.043), and these results were impact by self-reported ethnicity. There were no significant differences in self-reported subjective drug effects except for a greater AUC of visual analogue scale rating of drug liking (TC/CC = 35,398.33 ± 37,233.72, TT = 15,895.56 ± 13,200.68, p = 0.017). Our preliminary findings suggest that further work in a larger sample should investigate whether human ABCB1 influences cannabis-related phenotypes and plays a role in the risk of developing a cannabis use disorder.

PMID:36138925 | DOI:10.3390/brainsci12091189

J Chemother. 2022 Sep 22:1-10. doi: 10.1080/1120009X.2022.2125736. Online ahead of print.

ABSTRACT

Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer death. 5-Fluorouracil (5-FU) is an essential component of systemic chemotherapy for CRC. Our objective was to determine the genotypic frequency of polymorphisms affecting dihydropyrimidine dehydrogenase (DPYD) and thymidylate synthetase (TYMS) genes and to correlate the genetic profile with the toxicity due to 5-FU, also considering nongenetic factors. This is a prospective study that involved 66 patients. We extracted DNA by salting out methods. We carried out the genotyping of the different polymorphisms by simple PCR for the TYMS 5'UTR and by PCR-RFLP for DPYD: 1905 + 1 G > A, 85 T > C, 496 A > G, 1679 T > G, c.483 + 18G > A and the TYMS: 5'UTR VNTR, 5'UTR G > C and 3'UTR. The study of the association of DPYD and TYMS polymorphisms with the various signs of toxicity under 5-FU revealed that the polymorphisms 496 A > G were significantly associated with hepatotoxicity: OR = 3.85 (p = 0.04). In addition, 85 T > C was significantly associated with mucositis and neurotoxicity: OR = 4.35 (p = 0.03), OR = 3.79 (p = 0.02). For TYMS, the only significant association we observed for 5'UTR with vomiting: OR = 3.34 (p = 0.04). The incidence of adverse reactions related to 5-FU appears to be influenced in patients with CRC by the identified DPYD and TYMS gene polymorphisms in the Tunisian population.

PMID:36137946 | DOI:10.1080/1120009X.2022.2125736

Chem Res Toxicol. 2022 Sep 22. doi: 10.1021/acs.chemrestox.2c00231. Online ahead of print.

ABSTRACT

β-Lactamase inhibitors such as clavulanic acid and tazobactam were developed to overcome β-lactam antibiotic resistance. Hypersensitivity reactions to these drugs have not been studied in detail, and the antigenic determinants that activate T-cells have not been defined. The objectives of this study were to (i) characterize clavulanate- and tazobactam-responsive T-cells from hypersensitive patients, (ii) explore clavulanate and tazobactam T-cell crossreactivity, and (iii) define the antigenic determinants that contribute to T-cell reactivity. Antigen specificity, pathways of T-cell activation, and crossreactivity with clavulanate- and tazobactam-specific T-cell clones were assessed by proliferation and cytokine release assays. Antigenic determinants were analyzed by mass spectrometry-based proteomics methods. Clavulanate- and tazobactam-responsive CD4+ T-cell clones were stimulated to proliferate and secrete IFN-γ in an MHC class II-restricted and dose-dependent manner. T-cell activation with clavulanate- and tazobactam was dependent on antigen presenting cells because their fixation prevented the T-cell response. Strong crossreactivity was observed between clavulanate- and tazobactam-T-cells; however, neither drug activated β-lactam antibiotic-responsive T-cells. Mass spectrometric analysis revealed that both compounds form multiple antigenic determinants with lysine residues on proteins, including an overlapping aldehyde and hydrated aldehyde adduct with mass additions of 70 and 88 Da, respectively. Collectively, these data show that although clavulanate and tazobactam are structurally distinct, the antigenic determinants formed by both drugs overlap, which explains the observed T-cell cross-reactivity.

PMID:36137197 | DOI:10.1021/acs.chemrestox.2c00231

OMICS. 2022 Sep 22. doi: 10.1089/omi.2022.0121. Online ahead of print.

NO ABSTRACT

PMID:36137061 | DOI:10.1089/omi.2022.0121

JCI Insight. 2022 Sep 22:e162695. doi: 10.1172/jci.insight.162695. Online ahead of print.

ABSTRACT

Primary immune regulatory disorders (PIRD) are a group of disorders characterized by immune dysregulation, presenting with a wide range of clinical disease including autoimmunity, autoinflammation, or lymphoproliferation. Autosomal dominant germline gain-of-function (GOF) variants in STAT3 result in a PIRD with a broad clinical spectrum. Studies in patients have documented a decreased frequency of FOXP3+ regulatory T (Treg) cells and an increased frequency of Th17 cells in some patients with active disease. However, the mechanisms of disease pathogenesis in STAT3 GOF syndrome remain largely unknown, and treatment is challenging. We developed a knock-in mouse model harboring a de novo pathogenic human STAT3 variant (p.G421R) and found these mice developed T cell dysregulation, lymphoproliferation and CD4+ Th1 cell skewing. Surprisingly, Treg cell numbers, phenotype, and function remained largely intact, however mice had a selective deficiency in the generation of iTreg cells. In parallel, we performed single-cell RNA-sequencing on T cells from STAT3 GOF patients. We demonstrate only minor changes in the Treg cell transcriptional signature and an expanded, effector CD8+ T cell population. Together, these findings suggest Treg cells are not the primary driver of disease and highlight the importance of preclinical models in the study of disease mechanisms in rare PIRD.

PMID:36136607 | DOI:10.1172/jci.insight.162695

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