Drugs Repurposing Using QSAR, Docking and Molecular Dynamics for Possible Inhibitors of the SARS-CoV-2 Mpro Protease.

Molecules. 2020 Nov 06;25(21):

Authors: Tejera E, Munteanu CR, López-Cortés A, Cabrera-Andrade A, Pérez-Castillo Y

Abstract
Wuhan, China was the epicenter of the first zoonotic transmission of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2) in December 2019 and it is the causative agent of the novel human coronavirus disease 2019 (COVID-19). Almost from the beginning of the COVID-19 outbreak several attempts were made to predict possible drugs capable of inhibiting the virus replication. In the present work a drug repurposing study is performed to identify potential SARS-CoV-2 protease inhibitors. We created a Quantitative Structure-Activity Relationship (QSAR) model based on a machine learning strategy using hundreds of inhibitor molecules of the main protease (Mpro) of the SARS-CoV coronavirus. The QSAR model was used for virtual screening of a large list of drugs from the DrugBank database. The best 20 candidates were then evaluated in-silico against the Mpro of SARS-CoV-2 by using docking and molecular dynamics analyses. Docking was done by using the Gold software, and the free energies of binding were predicted with the MM-PBSA method as implemented in AMBER. Our results indicate that levothyroxine, amobarbital and ABP-700 are the best potential inhibitors of the SARS-CoV-2 virus through their binding to the Mpro enzyme. Five other compounds showed also a negative but small free energy of binding: nikethamide, nifurtimox, rebimastat, apomine and rebastinib.

PMID: 33172092 [PubMed - in process]

Association of UBE3C Variants with Reduced Kidney Function in Patients with Diabetic Kidney Disease.

J Pers Med. 2020 Nov 06;10(4):

Authors: Chen YC, Wu MY, Yu ZL, Chou WH, Lai YT, Kao CC, Faridah IN, Wu MS, Chang WC

Abstract
Diabetic kidney disease (DKD) is the leading cause of morbidity and mortality in patients with diabetes mellitus (DM) and the most common variant of end-stage renal disease (ESRD) globally. The economic burden of ESRD treatment with dialysis is substantial. The incidence and prevalence of ESRD in Taiwan remain the highest worldwide. Therefore, identifying genetic factors affecting kidney function would have valuable clinical implications. We performed microarray experiments and identified that ubiquitin protein ligase E3C (UBE3C) is differentially expressed in two DKD patient groups with extreme (low and high) urine protein-to-creatinine ratios. A follow-up genotyping study was performed in a larger group to investigate any specific variants of UBE3C associated with DKD. A total of 263 patients were included in the study, comprising 172 patients with DKD and 91 control subjects (patients with DM without chronic kidney disease (CKD)). Two UBE3C variants (rs3802129(AA) and rs7807(CC)) were determined to be associated with reduced kidney function. The haplotype analysis revealed that rs3802129/rs3815217 (block 1) with A/G haplotype and rs8101/rs7807 (block 2) with T/C haplotype were associated with higher risks of CKD phenotypes. These findings suggest a clinical role of UBE3C variants in DKD risk.

PMID: 33171965 [PubMed]

Genome Wide Epistasis Study of On-Statin Cardiovascular Events with Iterative Feature Reduction and Selection.

J Pers Med. 2020 Nov 07;10(4):

Authors: Adams SM, Feroze H, Nguyen T, Eum S, Cornelio C, Harralson AF

Abstract
Predicting risk for major adverse cardiovascular events (MACE) is an evidence-based practice that incorporates lifestyle, history, and other risk factors. Statins reduce risk for MACE by decreasing lipids, but it is difficult to stratify risk following initiation of a statin. Genetic risk determinants for on-statin MACE are low-effect size and impossible to generalize. Our objective was to determine high-level epistatic risk factors for on-statin MACE with GWAS-scale data. Controlled-access data for 5890 subjects taking a statin collected from Vanderbilt University Medical Center's BioVU were obtained from dbGaP. We used Random Forest Iterative Feature Reduction and Selection (RF-IFRS) to select highly informative genetic and environmental features from a GWAS-scale dataset of patients taking statin medications. Variant-pairs were distilled into overlapping networks and assembled into individual decision trees to provide an interpretable set of variants and associated risk. 1718 cases who suffered MACE and 4172 controls were obtained from dbGaP. Pathway analysis showed that variants in genes related to vasculogenesis (FDR = 0.024), angiogenesis (FDR = 0.019), and carotid artery disease (FDR = 0.034) were related to risk for on-statin MACE. We identified six gene-variant networks that predicted odds of on-statin MACE. The most elevated risk was found in a small subset of patients carrying variants in COL4A2, TMEM178B, SZT2, and TBXAS1 (OR = 4.53, p < 0.001). The RF-IFRS method is a viable method for interpreting complex "black-box" findings from machine-learning. In this study, it identified epistatic networks that could be applied to risk estimation for on-statin MACE. Further study will seek to replicate these findings in other populations.

PMID: 33171725 [PubMed]

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pharmacogenomics

These pubmed results were generated on 2020/11/11

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2020/11/11

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

12 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2020/11/10

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Pharmacogenetic profile and the development of the dyskinesia induced by levodopa-therapy in Parkinson's disease patients: a population-based cohort study.

Mol Biol Rep. 2020 Nov 05;:

Authors: Dos Santos EUD, da Silva IIFG, Asano AGC, Asano NMJ, De Mascena Diniz Maia M, de Souza PRE

Abstract
Levodopa-induced dyskinesia (LID) is an adverse effect that negatively impacts the quality of life of patients with Parkinson's disease (PD). Studies report that genetic variations in the genes of the pharmacogenetic pathway of the levodopa (L-DOPA) might be associated with LID development. The goal of the present study was to investigate a possible influence of functional genetic variants in the DRD1 (rs4532), DRD2 (rs1800497), DAT1 (rs28363170), and COMT (rs4680) genes with LID development. A total of 220 patients with idiopathic PD were enrolled. The genotyping for DRD1 (rs4532), DRD2 (rs1800497), DAT1 (rs28363170), and COMT (rs4680) polymorphisms were performed using Restriction Fragment Length Polymorphism (PCR-RFLP). Univariate and multivariate analyses were performed to assess the association of these polymorphisms and risk factors with LID development. Multivariate Cox regression analysis showed increased risk to LID development for both Levodopa Dose Equivalency (LED) (Hazard ratios (HR) = 1.001; 95% CI 1.00-1.01; p = 0.009) and individuals carrying the COMT L/L genotype (HR = 2.974; 95% CI 1.12-7.83; p = 0.010). Furthermore, when performed a Cox regression analysis adjusted for a total LED, we observed that the genotype COMT L/L had a 3.84-fold increased risk for LID development (HR = 3.841; 95% CI 1.29-11.37; p = 0.012). Our results suggest that before treating LID in PD patients, it is important to take into consideration genetic variant in the COMT gene, since COMT LL genotype may increase the risk for LID development.

PMID: 33151475 [PubMed - as supplied by publisher]

Targeting the TGFβ pathway in uterine carcinosarcoma.

Cell Stress. 2020 Aug 25;4(11):252-260

Authors: Dwivedi SKD, Rao G, Dey A, Buechel M, Zhang Y, Zhang M, Yang D, Mukherjee P, Bhattacharya R

Abstract
Uterine carcinosarcoma (UCS) is a relatively infrequent, but extremely aggressive endometrial malignancy. Although surgery and chemotherapy have improved outcomes, overall survival (OS) remains dismal due to the lack of targeted therapy and biphasic (epithelial and mesenchymal) nature that renders the tumor aggressive and difficult to manage. Here we report a role of transforming growth factor-β (TGFβ) in maintaining epithelial to mesenchymal transition (EMT) phenotype and aggressiveness in UCS. Using a 3D-culture system, we evaluated the efficacy of the transforming growth factor-β receptor-I (TGFβR1) kinase inhibitor Galunisertib (GLT), alone and in combination with standard chemotherapeutic drugs used for the management of UCS. We demonstrate that GLT by inhibiting canonical and non-canonical signaling emanating from transforming growth factor-β1 (TGFβ1) reduces cellular viability, invasion, clonal growth and differentiation. Interestingly, GLT sensitizes UCS cells to chemotherapy both in vitro and in in vivo preclinical tumor model. Hence, targeting TGFβ signaling, in combination with standard chemotherapy, may be exploited as an important strategy to manage the clinically challenging UCS.

PMID: 33150300 [PubMed]

The Research Progression and Clinical Significance of Circular RNAs in Head and Neck Cancers.

Biomed Res Int. 2020;2020:2712310

Authors: Wang D, Li Z, Wu Y

Abstract
With rapid development of science technique and molecular research, a large number of circular RNAs (circRNAs) were discovered. CircRNAs that are a heterogeneous endogenous group of non-coding RNA not only are abundantly and diffusely expressed in mammals but also participate in many biological processes, such as in tumor ingenuity and progress. CircRNAs have rarely open reports in the head and neck cancers (HNC), which are an aggressive malignant tumor with unsatisfactory overall survival rates. The diagnostics and treatments continue to improve while the survival rate of HNC patients has no more obvious improvement. Recent studies that are aimed at exploring the molecular mechanisms of occurrence and progression of circRNAs in HNC provide a valuable insight into potential novel diagnostic and therapeutic approaches. In this review, we summarize the increasing number of published researches on the research progression of circRNAs in HNC, as well as their possible clinical implications on HNC.

PMID: 33150169 [PubMed - in process]

Medical Costs and Productivity Loss Due to Mild, Moderate, and Severe Asthma in the United States.

J Asthma Allergy. 2020;13:545-555

Authors: Song HJ, Blake KV, Wilson DL, Winterstein AG, Park H

Abstract
Background: Little is known about economic and productivity loss by severity of asthma. We investigate health-care utilization, direct medical costs, and indirect costs due to productivity loss from asthma by severity.
Methods: We conducted a cross-sectional analysis of the Medical Expenditure Panel Survey database (2010-2017) of patients with asthma aged ≥12 years and categorized them into mild, moderate, and severe asthma groups based on symptom control medications. Study outcomes included health-care utilization, direct medical costs, and indirect costs of asthma-related absenteeism. We used zero-inflated Poisson regression models to estimate incremental health-care utilization and generalized linear models to estimate incremental annual direct medical costs compared to patients without asthma.
Results: An estimated 139 million persons had an asthma diagnosis. Of patients with asthma, 77.1%, 22.2%, and 0.7% had mild, moderate, and severe asthma, respectively. Compared to patients without asthma, patients with asthma had incremental mean differences of 4.16 outpatient visits, 0.18 emergency department visits, and 0.07 hospitalizations per year. Annual direct medical costs were significantly associated with asthma severity ($3305 in mild, $7250 in moderate, and $9175 in severe asthma) (P < 0.05). Patients with mild, moderate, and severe asthma reported 0.76, 2.31, and 7.19 missed work or school days, resulting in $106, $321, and $1000 indirect costs per person per year, respectively.
Conclusion: Asthma-related direct and indirect costs are significantly associated with asthma severity, with severe asthma medical costs being about three times higher than mild. Controlling asthma symptoms is important to reduce the economic and social burden of asthma.

PMID: 33149626 [PubMed]

Tacrolimus Bayesian dose adjustment in pediatric renal transplant recipients.

Ther Drug Monit. 2020 Oct 30;:

Authors: Marquet P, Cros F, Micallef L, Jacqz-Aigrain E, Woillard JB, Monchaud C, Saint-Marcoux F, Debord J

Abstract
BACKGROUND: Immunosuppressant Bayesian Dose Adjustment (ISBA) is an online expert system that estimates the area under the curve (AUC) of immunosuppressive drugs through pharmacokinetic modelling and Bayesian estimation to propose dose adjustments to reach predefined exposure targets. The ISBA database was retrospectively analyzed to describe tacrolimus pharmacokinetics and exposure, evaluate the efficiency of ISBA dose recommendations, and propose tacrolimus AUC0-12h target ranges for pediatric renal allograft recipients treated with immediate release tacrolimus.
METHODS: The database included 1935 tacrolimus dose adjustment requests from 419 patients <19 years old who were treated with immediate-release tacrolimus and followed in 21 French hospitals. The tacrolimus exposure evolution with patient age and post-transplantation time, the correlation between trough tacrolimus concentration (C0) and AUC0-12h at different periods post-transplantation, the efficiency of dose recommendations to avoid underexposure and overexposure and to decrease between-patient AUC variability were investigated.
RESULTS: Tacrolimus AUC showed large between-patient variability (CV%=40%) but moderate within-patient variability (median=24.3% over a three-month time period). Dose-standardized exposure but not the AUC/C0 ratio significantly decreased with time post-transplantation and patient age. We derived AUC0-12h ranges from the consensual C0 ranges using linear regression equations. When the ISBA recommended dose was applied, the AUC distribution was narrower and a significantly higher proportion was within the targets (p<0.0001).
CONCLUSION: ISBA efficiently reduced tacrolimus under- and overexposure. The AUC0-12h target ranges for pediatric patients derived from the database were similar to those previously reported for adults. Estimating the AUC/C0 ratio could help determine personalized C0 targets.

PMID: 33149055 [PubMed - as supplied by publisher]

Human Aortic Valve Interstitial Cells Display Proangiogenic Properties During Calcific Aortic Valve Disease.

Arterioscler Thromb Vasc Biol. 2020 Nov 05;:ATVBAHA120314287

Authors: Gendron N, Rosa M, Blandinieres A, Sottejeau Y, Rossi E, Van Belle E, Idelcadi S, Lecourt S, Vincentelli A, Cras A, Jashari R, Chocron R, Baudouin Y, Pamart T, Bièche I, Nevo N, Cholley B, Rancic J, Staels B, Gaussem P, Dupont A, Carpentier A, Susen S, Smadja DM

Abstract
OBJECTIVE: The study's aim was to analyze the capacity of human valve interstitial cells (VICs) to participate in aortic valve angiogenesis. Approach and Results: VICs were isolated from human aortic valves obtained after surgery for calcific aortic valve disease and from normal aortic valves unsuitable for grafting (control VICs). We examined VIC in vitro and in vivo potential to differentiate in endothelial and perivascular lineages. VIC paracrine effect was also examined on human endothelial colony-forming cells. A pathological VIC (VICp) mesenchymal-like phenotype was confirmed by CD90+/CD73+/CD44+ expression and multipotent-like differentiation ability. When VICp were cocultured with endothelial colony-forming cells, they formed microvessels by differentiating into perivascular cells both in vivo and in vitro. VICp and control VIC conditioned media were compared using serial ELISA regarding quantification of endothelial and angiogenic factors. Higher expression of VEGF (vascular endothelial growth factor)-A was observed at the protein level in VICp-conditioned media and confirmed at the mRNA level in VICp compared with control VIC. Conditioned media from VICp induced in vitro a significant increase in endothelial colony-forming cell proliferation, migration, and sprouting compared with conditioned media from control VIC. These effects were inhibited by blocking VEGF-A with blocking antibody or siRNA approach, confirming VICp involvement in angiogenesis by a VEGF-A dependent mechanism.
CONCLUSIONS: We provide here the first proof of an angiogenic potential of human VICs isolated from patients with calcific aortic valve disease. These results point to a novel function of VICp in valve vascularization during calcific aortic valve disease, with a perivascular differentiation ability and a VEGF-A paracrine effect. Targeting perivascular differentiation and VEGF-A to slow calcific aortic valve disease progression warrants further investigation.

PMID: 33147990 [PubMed - as supplied by publisher]

Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling to Predict the Impact of CYP2C9 Genetic Polymorphisms, Co-Medication and Formulation on the Pharmacokinetics and Pharmacodynamics of Flurbiprofen.

Pharmaceutics. 2020 Nov 02;12(11):

Authors: Loisios-Konstantinidis I, Cristofoletti R, Jamei M, Turner D, Dressman J

Abstract
Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models can serve as a powerful framework for predicting the influence as well as the interaction of formulation, genetic polymorphism and co-medication on the pharmacokinetics and pharmacodynamics of drug substances. In this study, flurbiprofen, a potent non-steroid anti-inflammatory drug, was chosen as a model drug. Flurbiprofen has absolute bioavailability of ~95% and linear pharmacokinetics in the dose range of 50-300 mg. Its absorption is considered variable and complex, often associated with double peak phenomena, and its pharmacokinetics are characterized by high inter-subject variability, mainly due to its metabolism by the polymorphic CYP2C9 (fmCYP2C9 ≥ 0.71). In this study, by leveraging in vitro, in silico and in vivo data, an integrated PBPK/PD model with mechanistic absorption was developed and evaluated against clinical data from PK, PD, drug-drug and gene-drug interaction studies. The PBPK model successfully predicted (within 2-fold) 36 out of 38 observed concentration-time profiles of flurbiprofen as well as the CYP2C9 genetic effects after administration of different intravenous and oral dosage forms over a dose range of 40-300 mg in both Caucasian and Chinese healthy volunteers. All model predictions for Cmax, AUCinf and CL/F were within two-fold of their respective mean or geometric mean values, while 90% of the predictions of Cmax, 81% of the predictions of AUCinf and 74% of the predictions of Cl/F were within 1.25 fold. In addition, the drug-drug and drug-gene interactions were predicted within 1.5-fold of the observed interaction ratios (AUC, Cmax ratios). The validated PBPK model was further expanded by linking it to an inhibitory Emax model describing the analgesic efficacy of flurbiprofen and applying it to explore the effect of formulation and genetic polymorphisms on the onset and duration of pain relief. This comprehensive PBPK/PD analysis, along with a detailed translational biopharmaceutic framework including appropriately designed biorelevant in vitro experiments and in vitro-in vivo extrapolation, provided mechanistic insight on the impact of formulation and genetic variations, two major determinants of the population variability, on the PK/PD of flurbiprofen. Clinically relevant specifications and potential dose adjustments were also proposed. Overall, the present work highlights the value of a translational PBPK/PD approach, tailored to target populations and genotypes, as an approach towards achieving personalized medicine.

PMID: 33147873 [PubMed]

13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2020/11/05

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2020/11/05

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Genetic Variability in Antioxidative and Inflammatory Pathways Modifies the Risk for PCOS and Influences Metabolic Profile of the Syndrome.

Metabolites. 2020 Oct 29;10(11):

Authors: Herman R, Jensterle M, Janež A, Goričar K, Dolžan V

Abstract
Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder of multifactorial etiopathology likely to involve the interactions between genetics and lifestyle. Chronic inflammation and oxidative stress (OS) may participate in the pathophysiology of the syndrome. The question of the extent to which OS and inflammation are causally related to the development of the syndrome and metabolic complications remains unanswered. By our knowledge, the role of the NLR family pyrin domain containing 3 (NLRP3) inflammasome as an important trigger of inflammatory pathways and NLRP3 and CARD8 polymorphisms has never been addressed in PCOS yet. We conducted a case-control study conducting of total 169 Slovenian PCOS patients and 83 healthy blood donors. They were genotyped for polymorphisms in antioxidative (SOD2 rs4880, CAT rs1001179, PON1 rs854560, and rs662) and inflammatory pathways genes (NLRP3 rs35829419, CARD8 rs2043211, TNF rs1800629, IL1B rs1143623, and rs16944, IL6 rs1800795) using competitive allele-specific polymerase chain reaction (PCR). Logistic regression and the Mann-Whitney test were used in the statistical analysis. SOD2 rs4880, CARD8 rs2043211, and IL1B rs16944 were associated with the risk of developing PCOS. Furthermore, the interactions between CARD8 rs2043211 and IL6 rs1800795 and between IL1B rs1143623 and IL6 rs1800795 also significantly affected the risk for PCOS. With regard to glucose homeostasis, CAT rs1001179, SOD2 rs4880, PON1 rs854560, NLRP3 rs35829419, and TNF rs1800629 were significantly associated with response to the glycemic load. Our data indicate that the genetic variability in the antioxidative and inflammatory pathways influences the development of PCOS and glucose homeostasis in PCOS patients.

PMID: 33138337 [PubMed]

Optimizing Precision of Hypertension Care to Maximize Blood Pressure Control (OPTI-BP): A Pilot Study Utilizing a Smartphone App to Incorporate Plasma Renin Activity Testing.

Clin Transl Sci. 2020 Nov 03;:

Authors: Mehanna M, Chen YE, Gong Y, Handberg E, Roth B, De Leon J, Smith SM, Harrell JG, Cooper-DeHoff RM

Abstract
Only half of hypertensive patients respond to any given antihypertensive. Heterogeneity in pathophysiologic pathways underlying hypertension (HTN) is a major contributor. Personalizing antihypertensive therapy could improve blood pressure (BP) reduction. The objective of this study was to assess the effect of pragmatic implementation of a personalized plasma renin activity (PRA)-based smartphone app on improving BP reduction. Patients with untreated or treated but uncontrolled HTN were recruited. BP and PRA were measured at baseline with final BP measured at 6 months. Patient's information was entered into the app and treatment recommendations were returned. Clinicians were at liberty to follow or disregard the app recommendations. BP levels and percent BP control among patients whose clinicians did and did not follow the app recommendations were compared using independent t-test and Fisher's exact test, respectively. Twenty-nine European-American (EA) patients were included (38% women) with mean age of 52±9 years and median PRA of 1.3 ng/ml/hr (IQR 0.5-3.1 ng/ml/hr). Participants whose clinicians followed the app recommendations (n=16, 55%) as compared to those whose clinicians did not (n=13, 45%), had a greater reduction in 6-month systolic-BP (-15±21 vs. -3±21 mm Hg; adjusted-P=0.1) and diastolic-BP (-8±8 vs. -1±8 mm Hg; adjusted-P=0.04). BP control at 6 months tended to be greater among patients whose clinicians accepted the app recommendations versus those whose clinicians did not (63% vs. 23%, P=0.06). This pilot study demonstrates that acceptance of the app recommendations was associated with a greater BP reduction. Future studies to confirm these pilot findings are warranted.

PMID: 33142006 [PubMed - as supplied by publisher]

Genome-Wide Association Study of Metamizole-Induced Agranulocytosis in European Populations.

Genes (Basel). 2020 Oct 29;11(11):

Authors: Cismaru AL, Rudin D, Ibañez L, Liakoni E, Bonadies N, Kreutz R, Carvajal A, Lucena MI, Martin J, Sancho Ponce E, Molokhia M, Eriksson N, EuDAC Collaborators, Krähenbühl S, Largiadèr CR, Haschke M, Hallberg P, Wadelius M, Amstutz U

Abstract
Agranulocytosis is a rare yet severe idiosyncratic adverse drug reaction to metamizole, an analgesic widely used in countries such as Switzerland and Germany. Notably, an underlying mechanism has not yet been fully elucidated and no predictive factors are known to identify at-risk patients. With the aim to identify genetic susceptibility variants to metamizole-induced agranulocytosis (MIA) and neutropenia (MIN), we conducted a retrospective multi-center collaboration including cases and controls from three European populations. Association analyses were performed using genome-wide genotyping data from a Swiss cohort (45 cases, 191 controls) followed by replication in two independent European cohorts (41 cases, 273 controls) and a joint discovery meta-analysis. No genome-wide significant associations (p < 1 × 10-7) were observed in the Swiss cohort or in the joint meta-analysis, and no candidate genes suggesting an immune-mediated mechanism were identified. In the joint meta-analysis of MIA cases across all cohorts, two candidate loci on chromosome 9 were identified, rs55898176 (OR = 4.01, 95%CI: 2.41-6.68, p = 1.01 × 10-7) and rs4427239 (OR = 5.47, 95%CI: 2.81-10.65, p = 5.75 × 10-7), of which the latter is located in the SVEP1 gene previously implicated in hematopoiesis. This first genome-wide association study for MIA identified suggestive associations with biological plausibility that may be used as a stepping-stone for post-GWAS analyses to gain further insight into the mechanism underlying MIA.

PMID: 33138277 [PubMed - in process]

Determination of the activity of γ-glutamyl transpeptidase and of its inhibitors by using the inner filter effect on the fluorescence of nitrogen-doped carbon dots.

Mikrochim Acta. 2020 02 21;187(3):182

Authors: Tong X, Li T, Long R, Guo Y, Wu L, Shi S

Abstract
A fluorescence (FL) probe for determination of γ-glutamyl transpeptidase (GGT) activity and evaluation of inhibitors was developed based on the inner filter effect (IFE) of nitrogen-doped carbon dots (N-CDs). Bright green emissive N-CDs were synthesized by one-step hydrothermal technique with catechol and ethylenediamine. The excitation and emission wavelengths for N-CDs were 408 and 510 nm, respectively. γ-L-Glutamyl-4-nitroanilide (γ-G4NA) was employed as the substrate of GGT. The absorption spectrum of GGT catalytic product (4-nitroaniline, 4-NA) overlapped greatly with the excitation spectrum of N-CDs. 4-NA acted as the absorber in IFE to quench the FL of N-CDs. Thus, the FL quenching of N-CDs was closely related to GGT activity. The established FL method offered good linear relationship within 2.0-10.0 U L-1 (R2, 0.982) and 10.0-110.0 U L-1 (R2, 0.998) with a low detection limit of 0.6 U L-1. The method was successfully applied to investigate GGT activity in human serum samples with acceptable recoveries (99.1-105.0%). The approach was also employed for screening GGT inhibitors from different polar extracts of Schisandra chinensis. Results indicated that this strategy presents superior characteristics for GGT sensing. This method has great potential as a candidate for diagnosis of GGT-related diseases and high-throughput drug discovery. Graphical abstract.

PMID: 32086563 [PubMed - indexed for MEDLINE]

Blood-based PD-L1 analysis in tumor-derived extracellular vesicles: Applications for optimal use of anti-PD-1/PD-L1 axis inhibitors.

Biochim Biophys Acta Rev Cancer. 2020 Oct 30;:188463

Authors: Del Re M, van Schaik RHN, Fogli S, Mathijssen RHJ, Cucchiara F, Capuano A, Scavone C, Jenster GW, Danesi R

Abstract
Monoclonal antibodies that inhibit the programmed cell death protein 1 axis (anti-PD-1/PD-L1) are part of a new pharmacological strategy aimed at reinforcing the immune response to cancer. Despite the success in several cancer types, a significant percentage of patients do not benefit from treatment with these drugs due to intrinsic or acquired resistance or the occurrence of immune-related adverse reactions. Assessment of PD-L1 expression in tumor tissues is currently used to predict drug response in the clinics; however, there is a growing interest in identifying blood-based biomarkers that, owing to the minimally-invasive nature, can allow a dynamic monitoring of drug response in daily clinical practice. In the current review article, we discuss whether the assessment of PD-L1 mRNA and protein levels in circulating extracellular vesicles may have the potential to predict the likelihood of tumor response to anti-PD-1/PD-L1 antibodies.

PMID: 33137405 [PubMed - as supplied by publisher]