Simultaneous formation of Bi2O2(OH)(NO3)/BiOBr ultrathin hierarchical microspheres for effectively promoting visible-light-driven photocatalytic activity in environmental remediation.

Chemosphere. 2020 Nov;258:127384

Authors: Lee GY, Cho EC, Lo PY, Zheng JH, Huang JH, Chen YL, Lee KC

Abstract
As a two-dimensional nanomaterial, bismuth oxybromide (BiOBr) have attracted tremendous interest in the area of visible-light photocatalysis since it can provide the internal electric field (IEF) through z-axis through its unique electronic band structure. However, the insufficient active sites and rapid recombination rate of charged carriers hamper the efficiency of the photocatalysis. To address these two major obstacles, an enticing strategy of constructing heterojunction was established by introducing Bi2O2(OH)(NO3) (BiON) in BiOBr with the same precursor. Through a facile one-pot hydrothermal synthesis, two Sillén-type layered photocatalysts, with intimately constructed ultrathin heterostructure, was synthesized by the co-precipitation method. In this work, the formation of Bismuth-based heterojunction for charge separation is established by the excessive bismuth nitrate, which subsequently participates with the in situ growth of ultrathin hierarchical microspheres. By attenuating the thickness of BiOBr from 20 nm to 8 nm with the aid of BiON, the photogenerated charges could migrate to the active sites through shorter charge diffusion pathway. Also, the BiOBr and BiON act as an active bridge to promote the separation of electron-hole pairs, which also brings out more active sites due to its increased specific surface area. BiON/BiOBr ultrathin hierarchical microspheres exhibited enhanced visible-light photocatalytic activity for decontaminating several types of pollutants. Besides, the activity of as-prepared BiON/BiOBr was further evaluated by inhibiting the growth of kanamycin-resistant bacteria strains. This study presents a novel strategy to incorporate the crystalline bismuth hydrate nitrate into BiOBr to form ultrathin hierarchical microspheres with high surface area for environmental remediation.

PMID: 32947660 [PubMed - as supplied by publisher]

Renal function is associated with plasma trimethylamine-N-oxide, choline, L-carnitine and betaine: a pilot study.

Int Urol Nephrol. 2020 Sep 18;:

Authors: Guo F, Dai Q, Zeng X, Liu Y, Tan Z, Zhang H, Ouyang D

Abstract
INTRODUCTION: Chronic kidney disease (CKD) is characterized by decreased glomerular filtration rate (GFR) due to a variety of causes. Most patients remain undiagnosed at early stage of CKD and proceed to end stage CKD due to unawareness and lacking of efficient biomarkers. Trimethylamine-N-oxide (TMAO) and its predecessor products: choline, L-carnitine and betaine are associated with reduced renal function. However, whether the combined variation of the four metabolites could contribute in prediction and stratification of impaired glomerular function in Chinese CKD patients is unknown. Our aim is to investigate the associations of plasma TMAO, choline, L-carnitine and betaine with glomerular filtration in CKD patients.
MATERIALS AND METHODS: A total of 65 CKD patients and 64 healthy controls were enrolled in this study. Fasting plasma metabolites were detected using liquid chromatography-based method.
RESULTS: Plasma TMAO, choline, betaine and L-carnitine levels were differentially correlated with eGFR. The four metabolites were independently associated with CKD after adjustment for multiple traditional risk factors. The combination of the four metabolites had good performance at discriminating CKD from healthy controls (AUC = 0.96) as well as discriminating low eGFR from high eGFR in CKD (AUC = 0.96).
CONCLUSION: Combinations of TMAO and its precursors were associated with glomerular function and might be utilized in evaluation of CKD.

PMID: 32945995 [PubMed - as supplied by publisher]

CYP17A1 polymorphism c.-362T>C predicts clinical outcome in metastatic castration-resistance prostate cancer patients treated with abiraterone.

Cancer Chemother Pharmacol. 2020 Sep 18;:

Authors: Crucitta S, Del Re M, Paolieri F, Bloise F, Sbrana A, Sammarco E, Mercinelli C, Cucchiara F, Fontanelli L, Galli L, Danesi R

Abstract
BACKGROUND: Abiraterone became a standard hormonal therapy for patients with metastatic castration-resistance prostate cancer (mCRPC). However, patients may experience primary resistance to treatment. To date, few predictive biomarkers of efficacy have been identified. Our aim was to investigate the association between the single nucleotide polymorphism (SNP) c.-362T>C in the CYP17A1 gene, and clinical outcome in mCRPC patients treated with abiraterone.
PATIENTS AND METHODS: mCRPC patients candidate to receive abiraterone were enrolled in the present retrospective pharmacogenetic study. Based on a literature selection, CYP17A1 rs2486758 (c.-362T > C) was selected and analysed by real-time PCR on genomic DNA extracted from whole blood. Univariate analysis was performed to test the association between the SNP and treatment-related clinical outcomes.
RESULTS: Sixty mCRPC patients were enrolled in the present study. Patients carrying the mutant CYP17A1 c.-362CT/CC genotypes showed a shorter median progression-free survival (PFS) and prostate-specific antigen-PFS (PSA-PFS) compared to patients carrying the TT genotype (10.7 vs 14.2 months and 8 vs 16 months, respectively; p = 0.04). No association between the selected SNP and the overall survival was found.
CONCLUSIONS: These findings suggest an association between CYP17A1 c.-362T>C polymorphism and poorer clinical outcome with abiraterone for mCRPC patients. However, further validations on larger cohort of patients are needed to confirm its role as a predictive biomarker for abiraterone resistance.

PMID: 32945940 [PubMed - as supplied by publisher]

Correction to: One-pot fabrication of dual-emission and single-emission biomass carbon dots for Cu2+ and tetracycline sensing and multicolor cellular imaging.

Anal Bioanal Chem. 2020 Sep 18;:

Authors: Wu L, Long R, Li T, Tang C, Tong X, Guo Y, Shi S, Xiang H, Tong C

Abstract
The authors would like to call the reader's attention to the fact that unfortunately the wrong file was published as Fig. 2.

PMID: 32944810 [PubMed - as supplied by publisher]

Investigating an in silico approach for prioritizing antidepressant drug prescription based on drug-induced expression profiles and predicted gene expression.

Pharmacogenomics J. 2020 Sep 17;:

Authors: Shoaib M, Giacopuzzi E, Pain O, Fabbri C, Magri C, Minelli A, Lewis CM, Gennarelli M

Abstract
In clinical practice, an antidepressant prescription is a trial and error approach, which is time consuming and discomforting for patients. This study investigated an in silico approach for ranking antidepressants based on their hypothetical likelihood of efficacy. We predicted the transcriptomic profile of citalopram remitters by performing an in silico transcriptomic-wide association study on STAR*D GWAS data (N = 1163). The transcriptional profile of remitters was compared with 21 antidepressant-induced gene expression profiles in five human cell lines available in the connectivity-map database. Spearman correlation, Pearson correlation, and the Kolmogorov-Smirnov test were used to determine the similarity between antidepressant-induced profiles and remitter profiles, subsequently calculating the average rank of antidepressants across the three methods and a p value for each rank by using a permutation procedure. The drugs with the top ranks were those having a high positive correlation with the expression profiles of remitters and that may have higher chances of efficacy in the tested patients. In MCF7 (breast cancer cell line), escitalopram had the highest average rank, with an average rank higher than expected by chance (p = 0.0014). In A375 (human melanoma) and PC3 (prostate cancer) cell lines, escitalopram and citalopram emerged as the second-highest ranked antidepressants, respectively (p = 0.0310 and 0.0276, respectively). In HA1E (kidney) and HT29 (colon cancer) cell types, citalopram and escitalopram did not fall among top antidepressants. The correlation between citalopram remitters' and (es)citalopram-induced expression profiles in three cell lines suggests that our approach may be useful and with future improvements, it can be applicable at the individual level to tailor treatment prescription.

PMID: 32943772 [PubMed - as supplied by publisher]

A two-tiered in vitro approach to de-risk drug candidates for potential bile salt export pump inhibition liabilities in drug discovery.

Drug Metab Dispos. 2020 Sep 17;:

Authors: Hafey MJ, Houle R, Tanis KQ, Knemeyer I, Shang J, Chen Q, Baudy A, Monroe J, Sistare FD, Evers R

Abstract
Hepatocellular accumulation of bile salts by inhibition of bile salt export pump (BSEP/ABCB11) may result in cholestasis and is one proposed mechanism of drug induced liver injury (DILI). To understand the relationship between BSEP inhibition and DILI, we evaluated 64 DILI positive and 57 DILI negative compounds in BSEP, multidrug resistance protein 2 (MRP2), MRP3, and MRP4 vesicular inhibition assays. An empirical cutoff (5 μM) for BSEP inhibition was established based on a relationship between BSEP IC50 values and the calculated maximal unbound concentration at the inlet of the human liver (fu*Iin,max, assay specificity = 98%). Including inhibition of MRP2-4 did not increase DILI predictivity. To further understand the potential to inhibit bile salt transport, a selected subset of 30 compounds were tested for inhibition of taurocholate (TCA) transport in a long-term human hepatocyte micropatterned co-culture (MPCC) system. The resulting IC50 for TCA in vitro biliary clearance (Clbiliary) and biliary excretion index (BEI) in MPCCs were compared to the compound's fu*Iin,max to assess potential risk for bile salt transport perturbation. The data show high specificity (89%). Nine out of 15 compounds showed an IC50 value in the BSEP vesicular assay of <5μM, but the BEI IC50 was greater than 10-fold the fu*Iin,max, suggesting that inhibition of BSEP in vivo is unlikely. The data indicate that although BSEP inhibition measured in membrane vesicles correlates with DILI risk, that measurement of this assay activity is insufficient. A two-tiered strategy incorporating MPCCs is presented to reduce BSEP inhibition potential and improve DILI risk. Significance Statement This work describes a two-tiered in vitro approach to de-risk compounds for potential bile salt export pump inhibition liabilities in drug discovery utilizing membrane vesicles and a long-term human hepatocyte micropatterned co-culture (MPCC) system. Cutoffs to maximize specificity were established based on in vitro data from a set of 121 DILI positive and negative compounds and associated calculated maximal unbound concentration at the inlet of the human liver (fu*Iin,max) based on the highest clinical dose.

PMID: 32943412 [PubMed - as supplied by publisher]

COVID-19 Pandemic: Implications on Interventional Pain Practice-a Narrative Review.

Pain Physician. 2020 Aug;23(4S):S311-S318

Authors: Gharaei H, Diwan S

Abstract
BACKGROUND: The COVID-19 pandemic has emerged and has challenged us to look for alternatives to bring about a paradigm shift in interventional chronic pain management. As the disease lowers the body's immune system, the use of medications that suppress the immune system are not recommended during the COVID-19 pandemic.
OBJECTIVE: The purpose of this study was to review medications other than steroids used for interventional pain management and the emphasis on mitigation of the untoward consequences of steroid injections on the immune system during the COVID-19 pandemic.
LITERATURE SEARCH: The literature was searched for articles in English with key words COVID-19, immunity, steroid for pain management injections with steroid, local anesthetics, dextrose water, normal saline, pain and genetic medicine, pain, and regenerative medicine. The sources of articles were PubMed, Embase, and open Google search.
LITERATURE REVIEW: The medications used for interventional pain management include steroids and opioids. The side effects of these medications are well known but have never been looked at as critically as they are now. Many other medications have been used for interventional pain procedures to relieve pain, such as dextrose water, normal saline solution, local anesthetics, and many adjuvants. Regarding regenerative therapy, despite plenty of evidence in literature, we have not yet considered it as a routine therapy for chronic pain injections. It is now time to move on beyond steroids and consider other types of medications and treatment options.The use of these medications in clinical practice is less auspicious, and thus more research is needed on the practical applications. Further areas for research include studies to determine definitive efficacy and safety assessment and determine whether or not the analgesic effects of these drugs are duration or dose-dependent. The optimal identification of candidates, volume, concentration, and intervals of injection are essential for routine application in interventional chronic pain practice.
CONCLUSIONS: The future of interventional pain practice is trending toward regenerative medicine and genetic research. Numerous scientific studies have been conducted to investigate the genetic basis of phenotypic variability in individuals with different ethnic groups in terms of susceptibility to chronic pain, as well as response to treatment for the personalized medicine model. Despite the preliminary data on genetic variations, there is no evidence for the use of a pharmacogenomics-based approach to personalized medicine for patients with chronic pain. The field of medicine therefore needs further research in pharmacogenetics, including large-scale prospective studies that focus on pain pathways. However, recent research, including larger studies and larger-scale genomic perspectives, may yield more promising findings in the future. The COVID-19 pandemic proved the need for medications with the most impact and least complications.

PMID: 32942791 [PubMed - in process]

Association of candidate pharmacogenetic markers with platinum-induced ototoxicity: PanCareLIFE dataset.

Data Brief. 2020 Oct;32:106227

Authors: Langer T, Clemens E, Broer L, Maier L, Uitterlinden AG, de Vries ACH, van Grotel M, Pluijm SFM, Binder H, Mayer B, von dem Knesebeck A, Byrne J, van Dulmen-den Broeder E, Crocco M, Grabow D, Kaatsch P, Kaiser M, Spix C, Kenborg L, Winther JF, Rechnitzer C, Hasle H, Kepak T, van der Kooi AF, Kremer LC, Kruseova J, Bielack S, Sorg B, Hecker-Nolting S, Kuehni CE, Ansari M, Kompis M, van der Pal HJ, Parfitt R, Deuster D, Matulat P, Tillmanns A, Tissing WJE, Beck JD, Elsner S, Am Zehnhoff-Dinnesen A, van den Heuvel-Eibrink MM, Zolk O, PanCareLIFE consortium

Abstract
Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The PanCareLIFE cross-sectional cohort study evaluated the genetic associations in a large pan-European population and assessed the diagnostic accuracy of the genetic markers. 1,112 pediatric cancer survivors who had provided biomaterial for genotyping were screened for participation in the pharmacogenetic association study. 900 participants qualified for inclusion. Based on the assessment of original audiograms, patients were assigned to three phenotype categories: no, minor, and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1, and ACYP2) were genotyped. The genotype and phenotype data represent a resource for conducting meta-analyses to derive a more precise pooled estimate of the effects of genes on the risk of hearing loss due to platinum treatment.

PMID: 32939381 [PubMed]

Race and smoking status associated with paclitaxel drug response in patient-derived lymphoblastoid cell lines.

Pharmacogenet Genomics. 2020 Sep 15;:

Authors: Akhtari FS, Havener TM, Hertz DL, Ash J, Larson A, Carey LA, McLeod HL, Motsinger-Reif AA

Abstract
The use of ex-vivo model systems to provide a level of forecasting for in-vivo characteristics remains an important need for cancer therapeutics. The use of lymphoblastoid cell lines (LCLs) is an attractive approach for pharmacogenomics and toxicogenomics, due to their scalability, efficiency, and cost-effectiveness. There is little data on the impact of demographic or clinical covariates on LCL response to chemotherapy. Paclitaxel sensitivity was determined in LCLs from 93 breast cancer patients from the University of North Carolina Lineberger Comprehensive Cancer Center Breast Cancer Database to test for potential associations and/or confounders in paclitaxel dose-response assays. Measures of paclitaxel cell viability were associated with patient data included treatment regimens, cancer status, demographic and environmental variables, and clinical outcomes. We used multivariate analysis of variance to identify the in-vivo variables associated with ex-vivo dose-response. In this unique dataset that includes both in-vivo and ex-vivo data from breast cancer patients, race (P = 0.0049) and smoking status (P = 0.0050) were found to be significantly associated with ex-vivo dose-response in LCLs. Racial differences in clinical dose-response have been previously described, but the smoking association has not been reported. Our results indicate that in-vivo smoking status can influence ex-vivo dose-response in LCLs, and more precise measures of covariates may allow for more precise forecasting of clinical effect. In addition, understanding the mechanism by which exposure to smoking in-vivo effects ex-vivo dose-response in LCLs may open up new avenues in the quest for better therapeutic prediction.

PMID: 32941389 [PubMed - as supplied by publisher]

Evaluation of Voriconazole CYP2C19 Phenotype-Guided Dose Adjustments by Physiologically Based Pharmacokinetic Modeling.

Clin Pharmacokinet. 2020 Sep 17;:

Authors: Zubiaur P, Kneller LA, Ochoa D, Mejía G, Saiz-Rodríguez M, Borobia AM, Koller D, García IG, Navares-Gómez M, Hempel G, Abad-Santos F

Abstract
BACKGROUND AND OBJECTIVES: Controversy exists regarding dose adjustment in patients treated with voriconazole due to the severity of the infections for which it is prescribed. The Dutch Pharmacogenetics Working Group (DPWG) recommends a 50% dose increase or decrease for cytochrome P450 (CYP) 2C19 ultrarapid (UM) or poor (PM) metabolizers, respectively. In contrast, for the previous phenotypes, the Clinical Pharmacogenetics Implementation Consortium (CPIC) voriconazole guideline only recommends a change of treatment. Based on observed data from single-dose bioequivalence studies and steady-state observed concentrations, we aimed to investigate voriconazole dose adjustments by means of physiologically based pharmacokinetic (PBPK) modeling.
METHODS: PBPK modeling was used to optimize voriconazole single-dose models for each CYP2C19 phenotype, which were extrapolated to steady state and evaluated for concordance with the therapeutic range of voriconazole. Based on optimized models, dose adjustments were evaluated for better adjustment to the therapeutic range.
RESULTS: Our models suggest that the standard dose may only be appropriate for normal metabolizers (NM), although they would benefit from a 50-100% loading dose increase. Intermediate metabolizers (IMs) and PMs required a daily dose reduction of 50 and 75%, respectively. Rapid metabolizers (RMs) and UMs required a daily dose increase of 100% and 300%, respectively.
CONCLUSION: The prescription of voriconazole in clinical practice should be personalized according to the CYP2C19 phenotype, followed by therapeutic drug monitoring of plasma concentrations to guide dose adjustment.

PMID: 32939689 [PubMed - as supplied by publisher]

Broad host range of SARS-CoV-2 predicted by comparative and structural analysis of ACE2 in vertebrates.

Proc Natl Acad Sci U S A. 2020 09 08;117(36):22311-22322

Authors: Damas J, Hughes GM, Keough KC, Painter CA, Persky NS, Corbo M, Hiller M, Koepfli KP, Pfenning AR, Zhao H, Genereux DP, Swofford R, Pollard KS, Ryder OA, Nweeia MT, Lindblad-Toh K, Teeling EC, Karlsson EK, Lewin HA

Abstract
The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19. The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of ACE2 sequences from 410 vertebrate species, including 252 mammals, to study the conservation of ACE2 and its potential to be used as a receptor by SARS-CoV-2. We designed a five-category binding score based on the conservation properties of 25 amino acids important for the binding between ACE2 and the SARS-CoV-2 spike protein. Only mammals fell into the medium to very high categories and only catarrhine primates into the very high category, suggesting that they are at high risk for SARS-CoV-2 infection. We employed a protein structural analysis to qualitatively assess whether amino acid changes at variable residues would be likely to disrupt ACE2/SARS-CoV-2 spike protein binding and found the number of predicted unfavorable changes significantly correlated with the binding score. Extending this analysis to human population data, we found only rare (frequency <0.001) variants in 10/25 binding sites. In addition, we found significant signals of selection and accelerated evolution in the ACE2 coding sequence across all mammals, and specific to the bat lineage. Our results, if confirmed by additional experimental data, may lead to the identification of intermediate host species for SARS-CoV-2, guide the selection of animal models of COVID-19, and assist the conservation of animals both in native habitats and in human care.

PMID: 32826334 [PubMed - indexed for MEDLINE]

Potential drug-drug interactions associated with drugs currently proposed for COVID-19 treatment in patients receiving other treatments.

Fundam Clin Pharmacol. 2020 Oct;34(5):530-547

Authors: Lemaitre F, Solas C, Grégoire M, Lagarce L, Elens L, Polard E, Saint-Salvi B, Sommet A, Tod M, Barin-Le Guellec C, French Society of Pharmacology, Therapeutics (SFPT), the International Association of Therapeutic Drug Monitoring, Clinical Toxicology (IATDMCT)

Abstract
Patients with COVID-19 are sometimes already being treated for one or more other chronic conditions, especially if they are elderly. Introducing a treatment against COVID-19, either on an outpatient basis or during hospitalization for more severe cases, raises the question of potential drug-drug interactions. Here, we analyzed the potential or proven risk of the co-administration of drugs used for the most common chronic diseases and those currently offered as treatment or undergoing therapeutic trials for COVID-19. Practical recommendations are offered, where possible.

PMID: 32603486 [PubMed - indexed for MEDLINE]

A new threat from an old enemy: Re‑emergence of coronavirus (Review).

Int J Mol Med. 2020 Jun;45(6):1631-1643

Authors: Docea AO, Tsatsakis A, Albulescu D, Cristea O, Zlatian O, Vinceti M, Moschos SA, Tsoukalas D, Goumenou M, Drakoulis N, Dumanov JM, Tutelyan VA, Onischenko GG, Aschner M, Spandidos DA, Calina D

Abstract
The new outbreak of coronavirus from December 2019 has brought attention to an old viral enemy and has raised concerns as to the ability of current protection measures and the healthcare system to handle such a threat. It has been known since the 1960s that coronaviruses can cause respiratory infections in humans; however, their epidemic potential was understood only during the past two decades. In the present review, we address current knowledge on coronaviruses from a short history to epidemiology, pathogenesis, clinical manifestation of the disease, as well as treatment and prevention strategies. Although a great amount of research and efforts have been made worldwide to prevent further outbreaks of coronavirus‑associated disease, the spread and lethality of the 2019 outbreak (COVID‑19) is proving to be higher than previous epidemics on account of international travel density and immune naivety of the population. Only strong, joint and coordinated efforts of worldwide healthcare systems, researchers, and pharmaceutical companies and receptive national leaders will succeed in suppressing an outbreak of this scale.

PMID: 32236624 [PubMed - indexed for MEDLINE]

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pharmacogenomics

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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 2020/09/17

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.

Early administration of steroids in the ambulance setting: Protocol for a type I hybrid effectiveness-implementation trial with a stepped wedge design.

Contemp Clin Trials. 2020 Sep 12;:106141

Authors: Fishe JN, Hendry P, Brailsford J, Salloum RG, Vogel B, Finlay E, Palmer S, Datta S, Hendeles L, Blake K

Abstract
BACKGROUND: Pediatric asthma exacerbations are a frequent reason for emergency care. Early administration of oral systemic corticosteroids (OCS) in the emergency department (ED) decreases hospitalization rates and ED length-of-stay (LOS). However, it is unknown whether even earlier OCS administration by emergency medical services (EMS) in the prehospital setting further improves outcomes.
PURPOSE: To describe the background and methods of a type 1 hybrid effectiveness-implementation trial of EMS-administered OCS for pediatric asthma patients incorporating a stepped wedge design and the RE-AIM framework.
METHODS: The study employs a non-randomized stepped wedge design where multiple EMS agencies adopt OCS as a treatment for pediatric asthma exacerbations at varying times. This design accommodates ethical considerations of studying pediatric subjects in the prehospital setting where informed consent is not feasible. We will compare hospitalization rates, ED LOS, and short-term healthcare costs between pediatric asthma patients who do and do not receive OCS from EMS. Using geographic information systems (GIS), we will measure how differences in outcomes scale with increasing EMS transport time. We will use the RE-AIM framework to guide a mixed methods analysis of barriers and enablers to EMS administration of OCS for pediatric asthma patients, including quantitative measures of adoption and uptake and qualitative EMS provider focus group data.
CONCLUSION: This trial will determine if earlier EMS administration of OCS to pediatric asthma patients decreases hospitalizations, ED LOS, and short-term healthcare costs, and if those outcomes scale with longer EMS transport times. We will identify barriers and enablers to implementing EMS-administered OCS for pediatric asthma patients.

PMID: 32931918 [PubMed - as supplied by publisher]

Genetic inhibition of NFATC2 attenuates asparaginase hypersensitivity in mice.

Blood Adv. 2020 Sep 22;4(18):4406-4416

Authors: Rathod S, Ramsey M, Finkelman FD, Fernandez CA

Abstract
The family of nuclear factor of activated T cells (NFAT) transcription factors plays a critical role in mediating immune responses. Our previous clinical pharmacogenetic studies suggested that NFATC2 is associated with the risk of hypersensitivity reactions to the chemotherapeutic agent L-asparaginase (ASNase) that worsen outcomes during the treatment of pediatric acute lymphoblastic leukemia. We therefore hypothesized that the genetic inhibition of NFATC2 would protect against the development of anti-ASNase antibodies and ASNase hypersensitivity. Our study demonstrates that ASNase-immunized NFATC2-deficient mice are protected against ASNase hypersensitivity and develop lower antigen-specific and total immunoglobulin E (IgE) levels compared with wild-type (WT) controls. Furthermore, ASNase-immunized NFATC2-deficient mice develop more CD4+ regulatory T cells, fewer CD4+ interleukin-4-positive (IL-4+) cells, higher IL-10/TGF-β1 levels, and lower IL-4/IL-13 levels relative to WT mice. Basophils and peritoneal mast cells from ASNase-immunized, but not naïve, NFATC2-deficient mice had lower FcεRI expression and decreased IgE-mediated mast cell activation than WT mice. Furthermore, ASNase-immunized, but not naïve, NFATC2-deficient mice developed less severe shock than WT mice after induction of passive anaphylaxis or direct histamine administration. Thus, inhibition of NFATC2 protects against ASNase hypersensitivity by impairing T helper 2 responses, which may provide a novel strategy for attenuating hypersensitivity and the development of antidrug antibodies, including to ASNase.

PMID: 32931581 [PubMed - in process]

Development and Analytical Validation of a 29 Gene Clinical Pharmacogenetic Genotyping Panel: Multi-Ethnic Allele and Copy Number Variant Detection.

Clin Transl Sci. 2020 Jul 23;:

Authors: Scott SA, Scott ER, Seki Y, Chen AJ, Wallsten R, Owusu Obeng A, Botton MR, Cody N, Shi H, Zhao G, Brake P, Nicoletti P, Yang Y, Delio M, Shi L, Kornreich R, Schadt EE, Edelmann L

Abstract
To develop a novel pharmacogenetic genotyping panel, a multidisciplinary team evaluated available evidence and selected 29 genes implicated in interindividual drug response variability, including 130 sequence variants and additional copy number variants (CNVs). Of the 29 genes, 11 had guidelines published by the Clinical Pharmacogenetics Implementation Consortium. Targeted genotyping and CNV interrogation were accomplished by multiplex single-base extension using the MassARRAY platform (Agena Biosciences) and multiplex ligation-dependent probe amplification (MRC Holland), respectively. Analytical validation of the panel was accomplished by a strategic combination of > 500 independent tests performed on 170 unique reference material DNA samples, which included sequence variant and CNV accuracy, reproducibility, and specimen (blood, saliva, and buccal swab) controls. Among the accuracy controls were 32 samples from the 1000 Genomes Project that were selected based on their enrichment of sequence variants included in the pharmacogenetic panel (VarCover.org). Coupled with publicly available samples from the Genetic Testing Reference Materials Coordination Program (GeT-RM), accuracy validation material was available for the majority (77%) of interrogated sequence variants (100% with average allele frequencies > 0.1%), as well as additional structural alleles with unique copy number signatures (e.g., CYP2D6*5, *13, *36, *68; CYP2B6*29; and CYP2C19*36). Accuracy and reproducibility for both genotyping and copy number were > 99.9%, indicating that the optimized panel platforms were precise and robust. Importantly, multi-ethnic allele frequencies of the interrogated variants indicate that the vast majority of the general population carries at least one of these clinically relevant pharmacogenetic variants, supporting the implementation of this panel for pharmacogenetic research and/or clinical implementation programs.

PMID: 32931151 [PubMed - as supplied by publisher]

Pharmacogenomic Studies of Current Antidiabetic Agents and Potential New Drug Targets for Precision Medicine of Diabetes.

Diabetes Ther. 2020 Sep 15;:

Authors: Zeng Z, Huang SY, Sun T

Abstract
Diabetes is a major threat to people's health and has become a burden worldwide. Current drugs for diabetes have limitations, such as different drug responses among individuals, failure to achieve glycemic control, and adverse effects. Exploring more effective therapeutic strategies for patients with diabetes is crucial. Currently pharmacogenomics has provided potential for individualized drug therapy based on genetic and genomic information of patients, and has made precision medicine possible. Responses and adverse effects to antidiabetic drugs are significantly associated with gene polymorphisms in patients. Many new targets for diabetes also have been discovered and developed, and even entered clinical trial phases. This review summarizes pharmacogenomic evidence of some current antidiabetic agents applied in clinical settings, and highlights potential drugs with new targets for diabetes, which represent a more effective treatment in the future.

PMID: 32930968 [PubMed - as supplied by publisher]

Newborn screening and single nucleotide variation profiling of TSHR, TPO, TG and DUOX2 candidate genes for congenital hypothyroidism.

Mol Biol Rep. 2020 Sep 15;:

Authors: Kollati Y, Akella RRD, Naushad SM, Borkar D, Thalla M, Nagalingam S, Lingappa L, Patel RK, Reddy GB, Dirisala VR

Abstract
High prevalence of congenital hypothyroidism (CH) among Indian newborns prompted us to establish population-specific reference ranges of TSH and to explore the contribution of the common genetic variants in TSHR, TPO, TG and DUOX2 genes towards CH. A total of 1144 newborns (593 males and 551 females) were screened for CH. SNV profiling (n = 22) spanning three candidate genes, i.e. TSHR, TPO and TG was carried out in confirmed CH cases (n = 45). In screen negative cases (n = 700), ten TSHR variants were explored to establish association with CH. No mutation found in DUOX2. The 2.5th to 97.5th percentiles of TSH in these newborns were 0.5 to 12.2 mU/L. In newborns with optimal birth weight, the cut-off was 10 mU/L. Lower or higher birth weight resulted in slightly higher TSH. Two TSHR variants, i.e. rs7144481 and rs17630128 were associated with agenesis, hypoplasia and goiter. The rs2268477 was associated with agenesis and hypoplasia. The rs1991517, rs2075176 and rs2241119 were associated with agenesis only. The rs7144481, rs17630128, rs1991517 and rs2268477 were associated with 2.17, 4.62, 2.91 and 2.29-fold increased risk for CH, respectively. Among the TPO variants, rs867983 and rs2175977 were associated with agenesis and goiter, respectively. Among the TG variants, rs2076740 showed association with agenesis and goiter. Two rare variants i.e. TPO g.IVS14-19 G>C and TG c.1262 C>T were observed in CH cases. No genetic variant identified in the two exons of DUOX2. To conclude, the current study established Indian population-specific normative values for TSH and demonstrates specific genotype-phenotype correlations among three candidate genes.

PMID: 32930933 [PubMed - as supplied by publisher]