Eur Rev Med Pharmacol Sci. 2022 Oct;26(20):7580-7593. doi: 10.26355/eurrev_202210_30033.

ABSTRACT

OBJECTIVE: Polymerase ε exonuclease (POLE) is an enzyme involved in DNA replication and may be an attractive therapeutic target in various cancers. Here we sought to model the impact of specific POLE mutations on protein function. Due to the lack of a crystal structure, the tertiary structures of the wild type and four common mutants were modeled using I-Tasser server.

MATERIALS AND METHODS: Molecular docking and dynamic simulation studies were performed, and the structure and function of the mutants analyzed through residue conservation analysis and protein folding energy changes.

RESULTS: All mutants of POLE gene had favorable binding affinities compared with their wild type of counterpart. The P286R variant, but not the other variants, disrupted cladribine binding to the protein. Similarly, dynamics studies revealed instability of the P286R mutant, while V411L, L424V, and L424F appeared to favor cladribine binding.

CONCLUSIONS: Since P286R is a hotspot mutation in endometrioid carcinomas, patients with this variant may not respond to cladribine. Population-based pharmacogenomics studies will be required to validate our results.

PMID:36314330 | DOI:10.26355/eurrev_202210_30033

Pharmacogenomics. 2022 Oct 31. doi: 10.2217/pgs-2022-0094. Online ahead of print.

ABSTRACT

Aims: To assess knowledge and attitudes toward pharmacogenomics (PGx) of incoming doctoral pharmacy students, to evaluate the internal structure and reliability of the PGx survey and to identify variables associated with the different responses. Methods: A PGx survey based on the core pharmacist competencies in PGx was created. Results: Of 83.2% analyzable responses, 91% believed PGx is a useful tool and relevant to future practice but over 70% stated they lack confidence in clinical PGx knowledge. This 38-item PGx survey included three factors showing high reliability. Prior genetic/PGx testing and unsatisfactory medication experiences were associated with a more positive attitude toward PGx. Conclusion: The majority of students have positive attitudes toward PGx, but lack knowledge in genetic concepts and clinical PGx.

PMID:36314296 | DOI:10.2217/pgs-2022-0094

J Int Med Res. 2022 Oct;50(10):3000605221133173. doi: 10.1177/03000605221133173.

ABSTRACT

OBJECTIVE: The TP73 G4C14-A4T14 variant has been associated with elevated cancer risk, but the evidence is inconclusive. We performed a meta-analysis to clarify the role of this variant in cancer development.

METHODS: Eligible literature was selected by searching PubMed, Google Scholar, Cochrane Library, and Embase. The meta-analysis was performed using Review Manager 5.4.

RESULTS: A meta-analysis of 55 case-control studies showed that the G4C14-A4T14 variant was significantly associated with overall cancer development in five genetic models, including the allele model (AM), codominant model 1 (COD1), COD2, dominant model (DM), and over-dominant model (OD). Sub-group analysis based on ethnicity showed significantly higher risks in Africans in COD2 and RM and in Whites in AM, COD2, DM, and recessive model (RM). Cancer-specific subgroup analysis identified significant risks of gynecological (ovarian, cervical, and endometrial cancer), colorectal, oral, head and neck, and other cancers. Moreover, hospital-based controls revealed significant cancer risks in the AM, COD1, COD2, DM, and RM genetic models. Our findings were confirmed by trial sequential analysis.

CONCLUSION: This meta-analysis confirmed that TP73 G4C14-A4T14 significantly elevates the overall cancer risk, especially in White, African, and hospital-based populations, and specifically predisposes individuals to gynecological, colorectal, oral, and head and neck cancers.This meta-analysis was registered at INPLASY (registration number: INPLASY202210070).

PMID:36314251 | DOI:10.1177/03000605221133173

EJIFCC. 2022 Aug 8;33(2):79. eCollection 2022 Aug.

NO ABSTRACT

PMID:36313913 | PMC:PMC9562485

Front Genet. 2022 Oct 13;13:1016416. doi: 10.3389/fgene.2022.1016416. eCollection 2022.

ABSTRACT

The enzyme cytochrome P450 2D6 (CYP2D6) metabolises approximately 25% of commonly prescribed drugs, including analgesics, anti-hypertensives, and anti-depressants, among many others. Genetic variation in drug metabolising genes can alter how an individual responds to prescribed drugs, including predisposing to adverse drug reactions. The majority of research on the CYP2D6 gene has been carried out in European and East Asian populations, with many Indigenous and minority populations, such as those from Oceania, greatly underrepresented. However, genetic variation is often population specific and analysis of diverse ethnic groups can reveal differences in alleles that may be of clinical significance. For this reason, we set out to examine the range and frequency of CYP2D6 variants in a sample of 202 Māori and Pacific people living in Aotearoa (New Zealand). We carried out long PCR to isolate the CYP2D6 region before performing nanopore sequencing to identify all variants and alleles in these samples. We identified twelve variants which have previously not been reported in the PharmVar CYP2D6 database, three of which were exonic missense variations. Six of these occurred in single samples and one was found in 19 samples (9.4% of the cohort). The remaining five variants were identified in two samples each. Identified variants formed twelve new CYP2D6 suballeles and four new star alleles, now recorded in the PharmVar database. One striking finding was that CYP2D6*71, an allele of uncertain functional status which has been rarely observed in previous studies, occurs at a relatively high frequency (8.9%) within this cohort. These data will help to ensure that CYP2D6 genetic analysis for pharmacogenetic purposes can be carried out accurately and effectively in this population group.

PMID:36313436 | PMC:PMC9606245 | DOI:10.3389/fgene.2022.1016416

Front Pharmacol. 2022 Oct 14;13:1016669. doi: 10.3389/fphar.2022.1016669. eCollection 2022.

ABSTRACT

The identification of pharmacogenetic factors that increase the susceptibility to clozapine-induced agranulocytosis or granulocytopenia (CIAG) has received increasing interest. The SLCO1B3-SCLO1B7 variant (rs149104283) and single amino acid changes in human leukocyte antigen (HLA) HLA-DQB1 (126Q) and HLA-B (158T) were associated with an increased risk of CIAG. In this study, we evaluated the effectiveness and cost-effectiveness of adding the SLCO1B3-SCLO1B7 to HLA variants as a new pharmacogenomic (PGx) approach and explored the evolution of a cohort of schizophrenic patients taking long-term clozapine as a third-line antipsychotic medication. The decision model included probabilistic and deterministic sensitivity analyses to assess the expected costs and quality-adjusted life-years (QALYs). The current monitoring scheme was compared with the PGx-guided strategy, where all patients underwent pre-emptively a genetic test before taking clozapine, over 10 years. By adding the SLCO1B3-SCLO1B7 variant into HLA variants, CIAG sensitivity increased from 36.0% to 43.0%, the specificity decreased from 89.0% to 86.9%, and the probability of cost-effectiveness improved from 74.1% to 87.8%. The incremental cost-effectiveness ratio was £16,215 per QALY and remained below the conventional decision threshold (£30,000 or US$50,000 per QALY). Therefore, the SLCO1B3-SCLO1B7 variant, as an additional risk allele to HLA variants, increases preemptive test sensitivity and improves the effectiveness and cost-effectiveness of PGx-guided clozapine administration.

PMID:36313369 | PMC:PMC9614368 | DOI:10.3389/fphar.2022.1016669

Front Pharmacol. 2022 Oct 12;13:1015338. doi: 10.3389/fphar.2022.1015338. eCollection 2022.

ABSTRACT

Glaucoma is the main cause of irreversible visual loss worldwide, and comprises a group of progressive, age-related, and chronic optic neuropathies. Prostaglandin analogs are considered a first-line treatment in the management of glaucoma and have the best efficacy in reducing intraocular pressure. When comparing these therapeutic agents between them, long-term therapy with 0.03% bimatoprost is the most effective followed by treatment with 0.005% latanoprost and 0.004% travoprost. The prevalence of adverse events is lower for latanoprost than for other prostaglandin analogs. However, some patients do not respond to the treatment with prostaglandin analogs (non-responders). Intraocular pressure-lowering efficacy differs significantly between individuals partly owing to genetic factors. Rs1045642 in ABCB1, rs4241366 in SLCO2A1, rs9503012 in GMDS, rs10306114 in PTGS1, rs11568658 in MRP4, rs10786455 and rs6686438 in PTGFR were reported to be positive with the response to prostaglandin analogs in patients with glaucoma. A negative association was found between single nucleotide polymorphisms of PTGFR (rs11578155 and rs6672484) and the response to prostaglandin analogs in patients with glaucoma. The current review is an analysis of the information relevant to prostaglandin analog treatments based on previous literatures. It describes in detail the clinical pharmacology and pharmacogenetics of drugs belonging to this therapeutical class to provide a sound pharmacological basis for their proper use in ophthalmological clinical practice.

PMID:36313286 | PMC:PMC9596770 | DOI:10.3389/fphar.2022.1015338

JHEP Rep. 2022 Sep 25;4(12):100598. doi: 10.1016/j.jhepr.2022.100598. eCollection 2022 Dec.

ABSTRACT

BACKGROUND & AIMS: The aim of this study was to examine the determinants of the interplay between liver damage and the coagulation balance in individuals at risk of non-alcoholic fatty liver disease (NAFLD).

METHODS: We considered 581 healthy participants with ≥3 metabolic alterations undergoing clinical and genomic evaluation, measurement of liver stiffness (LSM) and controlled attenuation parameter (CAP) by Fibroscan, Pro-C3, coagulation balance (von Willebrand factor [vWF], factor VIII/protein C ratio [F8/PC] as the main outcome, D-dimer as marker of coagulation/fibrinolysis activation).

RESULTS: Liver fibrosis indices (both Fibrosis-4 [FIB-4] and liver stiffness measurement [LSM]), but not liver fat (CAP), were independently associated with higher F8/PC ratio (p <0.01), triggering D-dimer formation (p = 2E-21). In keeping with a causal role of liver damage in determining a procoagulant status, the main fatty liver inherited risk variant PNPLA3 p.I148M was independently associated with the F8/PC ratio (p = 0.048). Vice versa, the main determinant of the coagulation balance was ABO locus variation (p = 1E-16), through the impact on vWF (p = 8E-26). Both rs687289 ABO and factor V Leiden were independently associated with higher Pro-C3 (p <0.025), with the effect of ABO being mediated by the impact on vWF (p = 5E-10 for association with Pro-C3). Mendelian randomisation analysis was consistent with a causal association of procoagulant imbalance with heightened fibrogenesis (p = 0.001 at robust MR-Egger for Pro-C3), but not with fibrosis (for LSM; p = not significant).

CONCLUSIONS: In individuals with metabolic dysfunction, liver damage severity and possibly the PNPLA3 p.I148M variant were associated with procoagulant status. Vice versa, evaluation of inherited variants in ABO and other genes influencing coagulation was consistent with a causal role of procoagulant imbalance in activation of early stages of fibrogenesis.

LAY SUMMARY: In individuals with metabolic alterations at risk of metabolic fatty liver disease, there is a tendency toward heightened blood coagulation (clotting), but the cause and the impact on the progression of liver disease remain unclear. Here we show that liver damage severity and metabolic alterations, but not hepatic fat, are mainly responsible for heightened coagulation in patients with metabolic fatty liver disease. By using genetic approaches, we showed that hepatic inflammation due to lipotoxicity may favour heightened coagulation, which in turn can trigger liver fibrosis, igniting a vicious cycle that leads to progressive liver disease.

PMID:36313186 | PMC:PMC9597122 | DOI:10.1016/j.jhepr.2022.100598

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