Hosp Pharm. 2021 Oct;56(5):592-596. doi: 10.1177/0018578720931756. Epub 2020 Jun 2.

ABSTRACT

Background: Diazepam is one of the most widely prescribed tranquilizers for the therapy of alcohol withdrawal syndrome (AWS), which includes the symptoms of anxiety, fear, and emotional tension. However, diazepam therapy often turns out to be ineffective, and some patients experience dose-dependent adverse drug reactions, reducing the efficacy of therapy. Aim: The purpose of our study was to investigate the effects of CYP2C19*17 genetic polymorphisms on the steady-state concentration of diazepam in patients with AWS. Materials and Methods: The study was conducted on 50 Russian male patients suffering from the AWS. For the therapy of psychomotor agitation, anxiety, fear, and emotional tension, patients received diazepam in injections at a dosage of 30.0 mg/day for 5 days. Genotyping was performed by real-time polymerase chain reaction. The efficacy and safety assessment was performed using psychometric scales and scales for assessing the severity of adverse drug reactions. Therapeutic drug monitoring (TDM) was performed using the high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS) method. Results: Based on the results of the study, we revealed the differences in the efficacy of therapy in patients with different CYP2C19 -806C>T genotypes: (*1/*1) -12.0 [-15.0; -8.0], (*1/*17+*17/*17) -7.0 [-14.0; -5.0], P < .001, as well as the results of TDM: (CC) 250.70 [213.34; 308.53] ng/mL (*1/*17+*17/*17) 89.12 [53.26; 178.07] ng/mL, P < .001. Conclusion: Thus, our study enrolling 50 patients with AWS, showed the effects of CYP2C19*17 genetic polymorphisms on the efficacy and safety rates of diazepam. Furthermore, we revealed the statistically significant difference in the levels of plasma steady-state concentrations of diazepam in patients carrying different genotypes.

PMID:34720165 | PMC:PMC8554590 | DOI:10.1177/0018578720931756

Pharmacogenomics. 2021 Nov 1. doi: 10.2217/pgs-2021-0008. Online ahead of print.

ABSTRACT

The benefit of personalized medicine is that it allows the customization of drug therapy - maximizing efficacy while avoiding side effects. Genetic polymorphisms are one of the major contributors to interindividual variability. Currently, the only gold standard for applying personalized medicine is dose titration. Because of technological advancements, converting genotypic data into an optimum dose has become easier than in earlier years. However, for many medications, determining a personalized dose may be difficult, leading to a trial-and-error method. On the other hand, the technologically oriented pharmaceutical industry has a plethora of smart drug delivery methods that are underutilized in customized medicine. This article elaborates the genetic polymorphisms of tacrolimus as case study, and extensively covers the diagnostic and therapeutic technologies which aid in the delivery of personalized tacrolimus treatment for better clinical outcomes, thereby providing a new strategy for implementing personalized medicine.

PMID:34719935 | DOI:10.2217/pgs-2021-0008

Clin Transl Sci. 2021 Oct 31. doi: 10.1111/cts.13168. Online ahead of print.

ABSTRACT

On October 2020, the US Food and Drug Administration (FDA) approved remdesivir as the first drug for the treatment of coronavirus disease 2019 (COVID-19), increasing remdesivir prescriptions worldwide. However, potential cardiovascular (CV) toxicities associated with remdesivir remain unknown. We aimed to characterize the CV adverse drug reactions (ADRs) associated with remdesivir using VigiBase, an individual case safety report database of the World Health Organization (WHO). Disproportionality analyses of CV-ADRs associated with remdesivir were performed using reported odds ratios and information components. We conducted in vitro experiments using cardiomyocytes derived from human pluripotent stem cell cardiomyocytes (hPSC-CMs) to confirm cardiotoxicity of remdesivir. To distinguish drug-induced CV-ADRs from COVID-19 effects, we restricted analyses to patients with COVID-19 and found that, after adjusting for multiple confounders, cardiac arrest (adjusted odds ratio [aOR]: 1.88, 95% confidence interval [CI]: 1.08-3.29), bradycardia (aOR: 2.09, 95% CI: 1.24-3.53), and hypotension (aOR: 1.67, 95% CI: 1.03-2.73) were associated with remdesivir. In vitro data demonstrated that remdesivir reduced the cell viability of hPSC-CMs in time- and dose-dependent manners. Physicians should be aware of potential CV consequences following remdesivir use and implement adequate CV monitoring to maintain a tolerable safety margin.

PMID:34719115 | DOI:10.1111/cts.13168

Respir Physiol Neurobiol. 2021 Oct 27:103809. doi: 10.1016/j.resp.2021.103809. Online ahead of print.

ABSTRACT

BACKGROUND: Few studies have examined whether baseline spirometry and the forced oscillation technique (FOT) would predict The COPD Assessment Test (CAT) score improvement after treatment of untreated COPD patients.

METHODS: The study subjects included 65 untreated COPD patients. They underwent the CAT, spirometry, and FOT (MostGraph) before and after treatment for more than 2 months. In addition, recursive partitioning analysis was performed using spirometry and the FOT parameters to identify the predictors of CAT improvement (CAT score ≥2).

RESULTS: CAT scores and lung function significantly improved after treatment. Recursive partitioning analysis identified 3 improved classes, defined by Rrs at 20 Hz (R20), Xrs at 5 Hz (X5), and ΔX5, but not by spirometry. The accuracy of predicting CAT improvement was as follows: odds ratio, 25.3; 95% confidence interval, 6.1 to 104.1; sensitivity, 91.2%; specificity, 71.0%; positive likelihood ratio, 3.14; and negative likelihood ratio, 0.12.

CONCLUSIONS: FOT helps predict improved health status in untreated COPD patients.

PMID:34718186 | DOI:10.1016/j.resp.2021.103809

BMC Cancer. 2021 Oct 30;21(1):1165. doi: 10.1186/s12885-021-08827-z.

ABSTRACT

BACKGROUND: Early recurrence is the major cause of poor prognosis in hepatocellular carcinoma (HCC). Long non-coding RNAs (lncRNAs) are deeply involved in HCC prognosis. In this study, we aimed to establish a prognostic lncRNA signature for HCC early recurrence.

METHODS: The lncRNA expression profile and corresponding clinical data were retrieved from total 299 HCC patients in TCGA database. LncRNA candidates correlated to early recurrence were selected by differentially expressed gene (DEG), univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses. A 25-lncRNA prognostic signature was constructed according to receiver operating characteristic curve (ROC). Kaplan-Meier and multivariate Cox regression analyses were used to evaluate the performance of this signature. ROC and nomogram were used to evaluate the integrated models based on this signature with other independent clinical risk factors. Gene set enrichment analysis (GSEA) was used to reveal enriched gene sets in the high-risk group. Tumor infiltrating lymphocytes (TILs) levels were analyzed with single sample Gene Set Enrichment Analysis (ssGSEA). Immune therapy response prediction was performed with TIDE and SubMap. Chemotherapeutic response prediction was conducted by using Genomics of Drug Sensitivity in Cancer (GDSC) pharmacogenomics database.

RESULTS: Compared to low-risk group, patients in high-risk group showed reduced disease-free survival (DFS) in the training (p < 0.0001) and validation cohort (p = 0.0132). The 25-lncRNA signature, AFP, TNM and vascular invasion could serve as independent risk factors for HCC early recurrence. Among them, the 25-lncRNA signature had the best predictive performance, and combination of those four risk factors further improves the prognostic potential. Moreover, GSEA showed significant enrichment of "E2F TARGETS", "G2M CHECKPOINT", "MYC TARGETS V1" and "DNA REPAIR" pathways in the high-risk group. In addition, increased TILs were observed in the low-risk group compared to the high-risk group. The 25-lncRNA signature negatively associates with the levels of some types of antitumor immune cells. Immunotherapies and chemotherapies prediction revealed differential responses to PD-1 inhibitor and several chemotherapeutic drugs in the low- and high-risk group.

CONCLUSIONS: Our study proposed a 25-lncRNA prognostic signature for predicting HCC early recurrence, which may guide postoperative treatment and recurrence surveillance in HCC patients.

PMID:34717566 | DOI:10.1186/s12885-021-08827-z

Mol Genet Genomic Med. 2021 Oct 30:e1841. doi: 10.1002/mgg3.1841. Online ahead of print.

ABSTRACT

Familial Progressive Hyper- and Hypopigmentation is a pigmentary disorder characterized by a mix of hypo- and hyperpigmented lesions, café-au-lait spots and hypopigmented ash-leaf macules. The disorder was previously linked to KITLG and various mutations have been reported to segregate in different families. Furthermore, association between KITLG mutations and malignancies was also suggested. Exome and SANGER sequencing were performed for identification of KITLG mutations. Functional in silico analyses were additionally performed to assess the findings. We identified a de novo mutation in exon 4 of KITLG gene causing NM_000899.4:c.[329A>T] (chr12:88912508A>T) leading to NP_000890.1:p.(Asp110Val) substitution in the 3rd alpha helix. It was predicted as pathogenic, located in a conserved region and causing an increase in hydrophobicity in the KITLG protein. Our findings clearly confirm an additional hot spot of KITLG mutations in the 3rd alpha helix, which very likely increases the risk of malignancies. To our knowledge the present study provides the strongest evidence of association of the KITLG mutation with both Familial Progressive Hyper- and Hypopigmentation and malignancy due to its' location on somatic cancer mutation locus. Additionally we also address difficulties with classification of the unique phenotype and propose a subtype within broader diagnosis.

PMID:34716665 | DOI:10.1002/mgg3.1841

J Neurosci. 2021 Oct 28:JN-RM-0564-21. doi: 10.1523/JNEUROSCI.0564-21.2021. Online ahead of print.

ABSTRACT

With the wide adoption of genomic sequencing in children having seizures, an increasing number of SCN2A genetic variants have been revealed as genetic causes of epilepsy. Voltage-gated sodium channel Nav1.2, encoded by gene SCN2A, is predominantly expressed in the pyramidal excitatory neurons and supports action potential firing. One recurrent SCN2A genetic variant is L1342P, which was identified in multiple patients with epileptic encephalopathy and intractable seizures. However, the mechanism underlying L1342P-mediated seizures and the pharmacogenetics of this variant in human neurons remain unknown. To understand the core phenotypes of the L1342P variant in human neurons, we took advantage of a reference human induced pluripotent stem cell (hiPSC) line from a male donor, in which L1342P was introduced by CRISPR/Cas9 mediated genome editing. Using patch-clamping and micro-electrode array (MEA) recordings, we revealed that cortical neurons derived from hiPSCs carrying heterozygous L1342P variant have significantly increased intrinsic excitability, higher sodium current density, and enhanced bursting and synchronous network firing, suggesting hyperexcitability phenotypes. Interestingly, L1342P neuronal culture displayed a degree of resistance to the anticonvulsant medication phenytoin, which recapitulated aspects of clinical observation of patients carrying the L1342P variant. In contrast, phrixotoxin-3 (PTx3), a Nav1.2 isoform-specific blocker, can potently alleviate spontaneous and chemically-induced hyperexcitability of neurons carrying the L1342P variant. Our results reveal a possible pathogenic underpinning of Nav1.2-L1342P mediated epileptic seizures and demonstrate the utility of genome-edited hiPSCs as an in vitro platform to advance personalized phenotyping and drug discovery.SIGNIFICANCE STATEMENTA mounting number of SCN2A genetic variants have been identified from patients with epilepsy, but how SCN2A variants affect the function of human neurons contributing to seizures is still elusive. This study investigated the functional consequences of a recurring SCN2A variant (L1342P) using human iPSC-derived neurons and revealed both intrinsic and network hyperexcitability of neurons carrying a mutant Nav1.2 channel. Importantly, this study recapitulated elements of clinical observations of drug-resistant features of the L1342P variant, and provided a platform for in vitro drug testing. Our study sheds light on cellular mechanism of seizures resulting from a recurring Nav1.2 variant, and helps to advance personalized drug discovery to treat patients carrying pathogenic SCN2A variant.

PMID:34716231 | DOI:10.1523/JNEUROSCI.0564-21.2021

Diabetes Care. 2021 Oct 29:dc211136. doi: 10.2337/dc21-1136. Online ahead of print.

ABSTRACT

OBJECTIVE: Insulin action in the human brain reduces food intake, improves whole-body insulin sensitivity, and modulates body fat mass and its distribution. Obesity and type 2 diabetes are often associated with brain insulin resistance, resulting in impaired brain-derived modulation of peripheral metabolism. So far, no pharmacological treatment for brain insulin resistance has been established. Since sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glucose levels and modulate energy metabolism, we hypothesized that SGLT2 inhibition may be a pharmacological approach to reverse brain insulin resistance.

RESEARCH DESIGN AND METHODS: In this randomized, double-blind, placebo-controlled clinical trial, 40 patients (mean ± SD; age 60 ± 9 years; BMI 31.5 ± 3.8 kg/m2) with prediabetes were randomized to receive 25 mg empagliflozin every day or placebo. Before and after 8 weeks of treatment, brain insulin sensitivity was assessed by functional MRI combined with intranasal administration of insulin to the brain.

RESULTS: We identified a significant interaction between time and treatment in the hypothalamic response to insulin. Post hoc analyses revealed that only empagliflozin-treated patients experienced increased hypothalamic insulin responsiveness. Hypothalamic insulin action significantly mediated the empagliflozin-induced decrease in fasting glucose and liver fat.

CONCLUSIONS: Our results corroborate insulin resistance of the hypothalamus in humans with prediabetes. Treatment with empagliflozin for 8 weeks was able to restore hypothalamic insulin sensitivity, a favorable response that could contribute to the beneficial effects of SGLT2 inhibitors. Our findings position SGLT2 inhibition as the first pharmacological approach to reverse brain insulin resistance, with potential benefits for adiposity and whole-body metabolism.

PMID:34716213 | DOI:10.2337/dc21-1136

Am J Pharm Educ. 2021 Oct 29:8600. doi: 10.5688/ajpe8600. Online ahead of print.

ABSTRACT

Objective Rapid changes in the current U.S. health care system, especially in the fields of pharmacy and pharmaceutical sciences, require practicing pharmacists to acquire new knowledge and skills. Despite the growth of opportunities for pharmacists within new spaces such as nanotechnology, informatics, and pharmacogenomics, those without the Doctor of Pharmacy (PharmD) could be eliminated from consideration by employers who seek new graduates with more contemporary training and skills. The purpose of this study was to determine which associations exist between student success within the Non-Traditional Doctor of Pharmacy (NTDP) program and certain demographic factors.Methods This quantitative longitudinal study was designed to determine which factors predict academic success among NTDP students entering the College of Pharmacy. Academic success was measured by cumulative graduating grade point average (GPA). Data from four cohorts of students was utilized to develop multivariate linear regression models with several predictors including age, region of residence, citizenship status, previous pharmacy work background, and ethnicity.Results. The study sample included 81 students and the mean cumulative GPA was 3.44. A foreign-born African heritage was predictive of a GPA that was significantly higher in comparison to African Americans after adjusting for other factors.Conclusion. Findings showed that international students had a higher cumulative GPA in comparison to African American students in the NTDP program.

PMID:34716132 | DOI:10.5688/ajpe8600

Genome Med. 2021 Oct 29;13(1):172. doi: 10.1186/s13073-021-00972-1.

ABSTRACT

BACKGROUND: Deletions and duplications of the multigenic 16p11.2 and 22q11.2 copy number variant (CNV) regions are associated with brain-related disorders including schizophrenia, intellectual disability, obesity, bipolar disorder, and autism spectrum disorder (ASD). The contribution of individual CNV genes to each of these identified phenotypes is unknown, as well as the contribution of these CNV genes to other potentially subtler health implications for carriers. Hypothesizing that DNA copy number exerts most effects via impacts on RNA expression, we attempted a novel in silico fine-mapping approach in non-CNV carriers using both GWAS and biobank data.

METHODS: We first asked whether gene expression level in any individual gene in the CNV region alters risk for a known CNV-associated behavioral phenotype(s). Using transcriptomic imputation, we performed association testing for CNV genes within large genotyped cohorts for schizophrenia, IQ, BMI, bipolar disorder, and ASD. Second, we used a biobank containing electronic health data to compare the medical phenome of CNV carriers to controls within 700,000 individuals in order to investigate the full spectrum of health effects of the CNVs. Third, we used genotypes for over 48,000 individuals within the biobank to perform phenome-wide association studies between imputed expressions of individual 16p11.2 and 22q11.2 genes and over 1500 health traits.

RESULTS: Using large genotyped cohorts, we found individual genes within 16p11.2 associated with schizophrenia (TMEM219, INO80E, YPEL3), BMI (TMEM219, SPN, TAOK2, INO80E), and IQ (SPN), using conditional analysis to identify upregulation of INO80E as the driver of schizophrenia, and downregulation of SPN and INO80E as increasing BMI. We identified both novel and previously observed over-represented traits within the electronic health records of 16p11.2 and 22q11.2 CNV carriers. In the phenome-wide association study, we found seventeen significant gene-trait pairs, including psychosis (NPIPB11, SLX1B) and mood disorders (SCARF2), and overall enrichment of mental traits.

CONCLUSIONS: Our results demonstrate how integration of genetic and clinical data aids in understanding CNV gene function and implicates pleiotropy and multigenicity in CNV biology.

PMID:34715901 | DOI:10.1186/s13073-021-00972-1

Biochem Pharmacol. 2021 Oct 26:114794. doi: 10.1016/j.bcp.2021.114794. Online ahead of print.

ABSTRACT

Androgen is beneficial for the prostate with normal functions but creates a risk for prostate cancer progression. How androgen receptor (AR) mediates these various actions of androgen remains elusive. AR conserves a phosphorylation motif within its ligand-binding domain throughout species. Here, we have found AR phosphorylated at Ser815 (P-AR) is expressed in normal tissues of both human and mouse prostates. P-AR begins being expressed in association with prostatic development and decreases its expression levels by castration in the mouse prostate. Functional analysis of AR in the prostate cancer PC-3 cells showed ligand-induced AR nuclear translocation and transactivation were disturbed by its phosphorylation at Ser815. Moreover, P-AR suppressed oncogenic AKT signaling suggesting AR has a suppression function for prostate cancer development. In fact, AR phosphorylation levels progressively decrease in human prostates as cancer worsens. These findings showed androgen might utilize P-AR to self-antagonize oncogenic signals and cancer progression believed to be regulated by non-phosphorylated AR (NonP-AR). By differing its target genes and signal regulations from those of NonP-AR, P-AR co-expression with NonP-AR may be the molecular basis for androgen to balance its actions and to control disease developments.

PMID:34715066 | DOI:10.1016/j.bcp.2021.114794

J Palliat Med. 2021 Oct 28. doi: 10.1089/jpm.2021.0270. Online ahead of print.

ABSTRACT

Context: Pharmacogenomic analysis may improve the efficacy or safety of the drugs used in palliative care. Decision support systems may promote clinical integration of this information. Objectives: To determine the feasibility and acceptability of a pharmacist-directed pharmacogenomic decision support system in the care of patients with advanced illness and explore the drug-gene and drug-drug interactions that occur in this population. Methods: Physicians or nurse practitioners from two U.S. hospice agencies identified opioid-treated patients receiving multiple other drugs. Buccal samples and clinical data were obtained from consenting patients. A pharmacist used the proprietary MedWise™ platform to evaluate the current medications in terms of genotype and phenotype, created a standardized report describing potential interactions and recommended actions that may reduce the associated risk. Clinicians could access the report online and completed Likert-type scales to assess use and satisfaction with the system. Results: Twenty clinicians and 100 patients participated. The reports revealed that 74 drugs were subject to 462 drug-gene interactions and 77 were involved in 691 drug-drug interactions; only 4 and 16 patients, respectively, had no drug-gene or drug-drug interactions. Clinicians routinely checked the reports and used the information to change ≥1 treatments in 55 (55%) patients. Almost all clinicians rated the system likely to improve the quality of care and all "agreed" or "strongly agreed" to recommend the system to colleagues. Conclusion: This pharmacist-directed pharmacogenomic decision support system was perceived positively and was integrated into practice. Further studies are warranted to its clinical integration and its outcomes.

PMID:34714127 | DOI:10.1089/jpm.2021.0270

Clin Transl Sci. 2021 Oct 29. doi: 10.1111/cts.13178. Online ahead of print.

ABSTRACT

Junctional ectopic tachycardia (JET) is a potentially life-threatening postoperative arrhythmia in children with specific congenital heart defects and can contribute significantly to postoperative morbidity for at-risk populations. In adults, β1-adrenergic receptor (ADRB1) and β2-adrenergic receptor (ADRB2) genotypes have been associated with increased risk for arrhythmias. However, their association with arrhythmia risk in children is unknown. We aimed to test associations between ADRB1 and ADRB2 genotypes and postoperative JET inpatients with congenital heart defects. Children who underwent cardiac surgery were genotyped for the ADRB1 p.Ser49Gly (rs1801252; c.145A>G) and p.Arg389Gly (rs1801253; c.1165C>G) and ADRB2 p.Arg16Gly (rs1042713; c.46A>G) and p.Glu27Gln (rs1042714; c.79C>G) polymorphisms. The occurrence of postoperative JET was assessed via cardiologist-interpreted electrocardiograms. Genotype associations with JET were analyzed via logistic regression, adjusted for clinical variables associated with JET, with separate analysis in patients not on a β-blocker. Of the 343 children included (median age 8 months, 53% male, 69% European ancestry), 45 (13%) developed JET. The Arg389Arg genotype was not significantly associated with JET in the overall population (OR=1.96; 95% CI=0.96-4.03; p=0.064), but was nominally associated in patients not taking a β-blocker (n=324; OR=2.25; 95% CI=1.05-4.80; p=0.034). None of the other variants were associated with JET. These data suggest that the ADRB1 Arg389Arg genotype may predict risk for JET following cardiac surgery in pediatric patients in the absence of β-blockade. Whether treatment with a β-blocker ameliorates this association requires further research.

PMID:34713976 | DOI:10.1111/cts.13178

Front Digit Health. 2021 Feb 9;2:567656. doi: 10.3389/fdgth.2020.567656. eCollection 2020.

ABSTRACT

Background: The integration of genetic testing into eHealth applications holds great promise for the personalization of disease prevention guidelines. However, relatively little is known about the impact of eHealth applications on an individual's behavior. Aim: The aim of the pilot study was to investigate the effect of the personalized eHealth application approach to behavior change in a 1-month follow-up period on groups with previously known and unknown caffeine impacts. Method: We created a direct-to-consumer approach that includes providing relevant information and personalized reminders and goals on the digital device regarding the caffeine intake for two groups of individuals: the intervention group (IG) with the genetic raw data available and the control group (CG) to test the impact of the same content (article about caffeine metabolism) on participants without the genetic test. Study participants were all Estonians (n = 160). Results: The study suggests that eHealth applications work for short-term behavior change. Participants in the genetic IG tended to increase caffeine intake if they were informed about caffeine not being harmful. They reported feeling better physically and/or mentally after their behavioral change decision during the period of the study. Conclusions: Our pilot study revealed that eHealth applications may have a positive effect for short-term behavior change, regardless of a prior genetic test. Further studies among larger study groups are required to achieve a better understanding about behavior change of individuals in the field of personalized medicine and eHealth interventions.

PMID:34713041 | PMC:PMC8521856 | DOI:10.3389/fdgth.2020.567656

Toxicol Rep. 2021 Oct 12;8:1762-1768. doi: 10.1016/j.toxrep.2021.10.008. eCollection 2021.

ABSTRACT

INTRODUCTION: Parkinson's disease is a neurodegenerative disorder with a complex etiology coming from interactions between genetic and environmental factors. Research on Parkinson's disease genetics has been an effortful struggle, while new technologies and novel study designs served as indispensable boosters. Until now, 90 loci and 20 disease-causing gene mutations have been identified. In this study we describe a novel non-parametric approach to GWAS meta-analysis and its application in PD genetics.

METHODS: A literature search was conducted to identify Genome-Wide Association Studies (GWAS) regarding Parkinson's disease. We applied predefined inclusion criteria and extracted the reported SNPs and their respective position and statistical significance. We divided all chromosomes in approximately equal genetic distance segments called bins and recorded the most significant SNP from each bin and each study and ranked them in terms of their p-value. Ranks from each bin were summed, averaged and added in a heterogeneity-based analysis using the METRADISC-XL software. Weighted and unweighted analysis was performed.

RESULTS: Five-hundred and forty-three SNPs and their respective p-values from 15 studies were matched in their corresponding bins. The METRADISC-XL analysis resulted in 7 bins with a significant p-value. A bin on chromosome 4 where the SNCA gene is located found with genome-wide significant association with Parkinson's Disease.

CONCLUSION: This is the first time a non-parametric method is applied in GWAS meta-analysis. The results add some insight on the overall understanding of Parkinson's disease genetics and serve as a first step of further convergent analysis with Genome-wide linkage studies.

PMID:34712594 | PMC:PMC8528647 | DOI:10.1016/j.toxrep.2021.10.008

Pharmacogenomics J. 2021 Oct 28. doi: 10.1038/s41397-021-00251-7. Online ahead of print.

ABSTRACT

Acute Graft versus Host Disease (aGvHD) grades 2-4 occurs in 15-60% of pediatric patients undergoing allogeneic haematopoietic stem-cell transplantation (allo-HSCT). The collateral damage to normal tissue by conditioning regimens administered prior to allo-HSCT serve as an initial trigger for aGvHD. DNA-repair mechanisms may play an important role in mitigating this initial damage, and so the variants in corresponding DNA-repair protein-coding genes via affecting their quantity and/or function. We explored 51 variants within 17 DNA-repair genes for their association with aGvHD grades 2-4 in 60 pediatric patients. The cumulative incidence of aGvHD 2-4 was 12% (n = 7) in the exploratory cohort. MGMT rs10764881 (G>A) and EXO rs9350 (c.2270C>T) variants were associated with aGvHD 2-4 [Odds ratios = 14.8 (0 events out of 40 in rs10764881 GG group) and 11.5 (95% CI: 2.3-191.8), respectively, multiple testing corrected p ≤ 0.001]. Upon evaluation in an extended cohort (n = 182) with an incidence of aGvHD 2-4 of 22% (n = 40), only MGMT rs10764881 (G>A) remained significant (adjusted HR = 2.05 [95% CI: 1.06-3.94]; p = 0.03) in the presence of other clinical risk factors. Higher MGMT expression was seen in GG carriers for rs10764881 and was associated with higher IC50 of Busulfan in lymphoblastoid cells. MGMT rs10764881 carrier status could predict aGvHD occurrence in pediatric patients undergoing allo-HSCT.

PMID:34711928 | DOI:10.1038/s41397-021-00251-7

NPJ Precis Oncol. 2021 Oct 28;5(1):96. doi: 10.1038/s41698-021-00235-7.

ABSTRACT

MI-773 is a recently developed small-molecule inhibitor of the mouse double minute 2 (MDM2) proto-oncogene. Preclinical data on the anti-tumour activity of MI-773 are limited and indicate that tumour cell lines (CLs) with mutated TP53 are more resistant to MI-773 than wild type TP53. Here, we explored the compound's therapeutic potential in vitro using a panel of 274 annotated CLs derived from a diversity of tumours. MI-773 exhibited a pronounced selectivity and moderate potency, with anti-tumour activity in the sub-micromolar range in about 15% of the CLs. The most sensitive tumour types were melanoma, sarcoma, renal and gastric cancers, leukaemia, and lymphoma. A COMPARE analysis showed that the profile of MI-773 was similar to that of Nutlin-3a, the first potent inhibitor of p53-MDM2 interactions, and, in addition, had a superior potency. In contrast, it poorly correlates with profiles of compounds targeting the p53 pathway with another mechanism of action. OMICS analyses confirmed that MI-773 was primarily active in CLs with wild type TP53. In silico biomarker investigations revealed that the TP53 mutation status plus the aggregated expression levels of 11 genes involved in the p53 signalling pathway predicted sensitivity or resistance of CLs to inhibitors of p53-MDM2 interactions reliably. The results obtained for MI-773 could help to refine the selection of cancer patients for therapy.

PMID:34711913 | DOI:10.1038/s41698-021-00235-7

PeerJ. 2021 Oct 5;9:e12073. doi: 10.7717/peerj.12073. eCollection 2021.

ABSTRACT

The coronavirus disease (COVID-19) pandemic has caused havoc worldwide. The tests currently used to diagnose COVID-19 are based on real time reverse transcription polymerase chain reaction (RT-PCR), computed tomography medical imaging techniques and immunoassays. It takes 2 days to obtain results from the RT-PCR test and also shortage of test kits creating a requirement for alternate and rapid methods to accurately diagnose COVID-19. Application of artificial intelligence technologies such as the Internet of Things, machine learning tools and big data analysis to COVID-19 diagnosis could yield rapid and accurate results. The neural networks and machine learning tools can also be used to develop potential drug molecules. Pharmaceutical companies face challenges linked to the costs of drug molecules, research and development efforts, reduced efficiency of drugs, safety concerns and the conduct of clinical trials. In this review, relevant features of artificial intelligence and their potential applications in COVID-19 diagnosis and drug development are highlighted.

PMID:34707924 | PMC:PMC8500072 | DOI:10.7717/peerj.12073

Hered Cancer Clin Pract. 2021 Oct 27;19(1):45. doi: 10.1186/s13053-021-00199-6.

ABSTRACT

BACKGROUND AND AIM: The BRCA 1 and BRCA 2 genes are associated with an inherited susceptibility to breast cancer with a cumulative risk of 60% in BRCA 1 mutation carriers and of 30% in BRCA 2 mutation carriers. Several lifestyle factors could play a role in determining an individual's risk of breast cancer. Obesity, changes in body size or unhealthy lifestyle habits such as smoking, alcohol consumption and physical inactivity have been evaluated as possible determinants of breast cancer risk. The aim of this study was to explore the current understanding of the role of harmful lifestyle and obesity or weight change in the development of breast cancer in female carriers of BRCA 1/2 mutations.

METHODS: Articles were identified from MEDLINE in October 2020 utilizing related keywords; they were then read and notes, study participants, measures, data analysis and results were used to write this review.

RESULTS: Studies with very large case series have been carried out but only few of them have shown consistent results. Additional research would be beneficial to better determine the actual role and impact of such factors.

PMID:34706754 | DOI:10.1186/s13053-021-00199-6

Br J Clin Pharmacol. 2021 Oct 27. doi: 10.1111/bcp.15127. Online ahead of print.

ABSTRACT

Aspirin has known effects beyond inhibiting platelet cyclooxygenase-1 (COX1) that have been incompletely characterized. Transcriptomics can comprehensively characterize the on- and off-target effects of medications. We used a systems pharmacogenomics approach of aspirin exposure in volunteers coupled with serial platelet function and purified platelet mRNA sequencing to test the hypothesis that aspirin's effects on the platelet transcriptome are associated with platelet function. We prospectively recruited 74 adult volunteers for a randomized cross over study of 81- vs. 325 mg/day, each for 4 weeks. Using mRNA sequencing of purified platelets collected before and after each 4-week exposure, we identified 208 aspirin-responsive genes with no evidence for dosage effects. In independent cohorts of healthy volunteers and patients with diabetes we validated aspirin's effects on five genes: EIF2S3, CHRNB1, EPAS1, SLC9A3R2, and HLA-DRA. Functional characterization of the effects of aspirin on mRNA as well as platelet ribosomal RNA demonstrated that aspirin may act as an inhibitor of protein synthesis. Database searches for small molecules that mimicked the effects of aspirin on platelet gene expression in vitro identified aspirin but no other molecules that share aspirin's known mechanisms of action. The effects of aspirin on platelet mRNA were correlated with higher levels of platelet function both at baseline and after aspirin exposure - an effect that counteracts aspirin's known antiplatelet effect. In summary, this work collectively demonstrates a dose-independent effect of aspirin on the platelet transcriptome that counteracts the well-known antiplatelet effects of aspirin.

PMID:34705291 | DOI:10.1111/bcp.15127