[Summary of the recommendations of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) on the therapeutic drug monitoring of tacrolimus].

Therapie. 2020 Jun 20;:

Authors: Lemaitre F, Monchaud C, Woillard JB, Picard N, Marquet P

Abstract
Recently, the International Association of Therapeutic Drug Monitoring (IATDMCT), that is the learning society for biological pharmacology and toxicology, issued recommendations on the therapeutic drug monitoring (TDM) of tacrolimus. This is the second consensus after the one issued in 2009. In this document, the role of tacrolimus TDM for the four principal transplanted organs is discussed. The analytical aspects, pharmacogenetics, TDM alternative approaches and the positioning of biomarkers are also presented. Stronger recommendations are about trough concentration targets in kidney and liver transplantation and for other indication of tacrolimus use. For the first time, an area under the curve of tacrolimus concentrations target is recommended for recipients management. Eventually, another set of recommendations are proposed for pharmacodynamic biomarkers used in patients' follow-up.

PMID: 32653093 [PubMed - as supplied by publisher]

A Genomewide Pharmacogenetic Study of Growth Hormone Responsiveness.

J Clin Endocrinol Metab. 2020 Jul 11;:

Authors: Dauber A, Meng Y, Audi L, Vedantam S, Weaver B, Carrascosa A, Albertsson-Wikland K, Ranke MB, Jorge AAL, Cara J, Wajnrajch MP, Lindberg A, Camacho-Hübner C, Hirschhorn JN

Abstract
CONTEXT: Individual patients vary in their response to growth hormone (GH). No large scale genomewide studies have looked for genetic predictors of GH responsiveness.
OBJECTIVE: To identify genetic variants associated with GH responsiveness.
DESIGN: Genomewide association study.
SETTING: Cohorts from multiple academic centers and a clinical trial.
PATIENTS: 614 individuals receiving GH from 5 short stature cohorts: 297 with idiopathic short stature, 276 with isolated GH deficiency, and 65 born small for gestational age.
INTERVENTION: Association of >2 million variants was tested.
MAIN OUTCOME MEASURES: Primary analysis: individual SNP association with 1st year change in height SDS. Secondary analyses: SNP associations in clinical subgroups adjusted for clinical variables; association of polygenic score calculated from 697 genomewide significant height SNPs with GH responsiveness.
RESULTS: No common variant associations reached genomewide significance in the primary analysis. The strongest suggestive signals were found near the B4GALT4 and TBCE genes. After meta-analysis including replication data, signals at several loci reached or retained genome-wide significance in secondary analyses, including variants near ST3GAL6. There was no significant association with variants previously reported to be associated with GH response nor with a polygenic predicted height score.
CONCLUSIONS: We performed the largest genomewide association study of GH responsiveness to date. We identified two loci with a suggestive effect on GH responsiveness in our primary analysis, and several genome-wide significant associations in secondary analyses that require further replication. Our results are consistent with a polygenic component to growth hormone responsiveness, likely distinct from the genetic regulators of adult height.

PMID: 32652002 [PubMed - as supplied by publisher]

Genetic testing in the acute setting: a round table discussion.

J Med Ethics. 2020 Jul 10;:

Authors: McDermott JH

Abstract
Genetic testing has historically been performed in the context of chronic disease and cancer diagnostics. The timelines for these tests are typically measured in days or weeks, rather than in minutes. As such, the concept that genetic information might be generated and then used to alter management in the acute setting has, thus far, not been feasible. However, recent advances in genetic technologies have the potential to allow genetic information to be generated significantly quicker. The m.1555A>G genetic variant is present in one in 500 individuals and predisposes to profound hearing loss following the administration of aminoglycoside antibiotics. These antibiotics are used frequently in cases of neonatal sepsis and it is estimated that approximately 180 neonates in the UK are at risk of antibiotic induced hearing loss each year because of this genetic change. Knowledge of this variant in the acute setting would allow clinicians to prescribe alternative antibiotics. The Pharmacogenetics to Avoid Loss of Hearing study will implement a genetic point of care test (POCT) for the m.1555A>G variant within two major UK based neonatal intensive care units. This represents the first trial of a genetic POCT aimed at altering management in the acute setting. This round table discussion outlines the novel ethical issues faced in the development of this trial and the legal barriers to implementation. We ask five stakeholders to provide their opinions on this trial and their perspectives on the concept of genetic testing in the acute setting.Trial registration numberISRCTN-13704894.

PMID: 32651253 [PubMed - as supplied by publisher]

As3MT and GST Polymorphisms Influencing Arsenic Metabolism in Human Exposure to Drinking Groundwater.

Int J Mol Sci. 2020 Jul 08;21(14):

Authors: González-Martínez F, Sánchez-Rodas D, Varela NM, Sandoval CA, Quiñones LA, Johnson-Restrepo B

Abstract
The urinary arsenic metabolites may vary among individuals and the genetic factors have been reported to explain part of the variation. We assessed the influence of polymorphic variants of Arsenic-3-methyl-transferase and Glutathione-S-transferase on urinary arsenic metabolites. Twenty-two groundwater wells for human consumption from municipalities of Colombia were analyzed for assessed the exposure by lifetime average daily dose (LADD) (µg/kg bw/day). Surveys on 151 participants aged between 18 and 81 years old were applied to collect demographic information and other factors. In addition, genetic polymorphisms (GSTO2-rs156697, GSTP1-rs1695, As3MT-rs3740400, GSTT1 and GSTM1) were evaluated by real time and/or conventional PCR. Arsenic metabolites: AsIII, AsV, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) were measured using HPLC-HG-AFS. The influence of polymorphic variants, LADD and other factors were tested using multivariate analyses. The median of total arsenic concentration in groundwater was of 33.3 μg/L and the median of LADD for the high exposure dose was 0.33 µg/kg bw/day. Univariate analyses among arsenic metabolites and genetic polymorphisms showed MMA concentrations higher in heterozygous and/or homozygous genotypes of As3MT compared to the wild-type genotype. Besides, DMA concentrations were lower in heterozygous and/or homozygous genotypes of GSTP1 compared to the wild-type genotype. Both DMA and MMA concentrations were higher in GSTM1-null genotypes compared to the active genotype. Multivariate analyses showed statistically significant association among interactions gene-gene and gene-covariates to modify the MMA and DMA excretion. Interactions between polymorphic variants As3MT*GSTM1 and GSTO2*GSTP1 could be potential modifiers of urinary excretion of arsenic and covariates as age, LADD, and alcohol consumption contribute to largely vary the arsenic individual metabolic capacity in exposed people.

PMID: 32650499 [PubMed - as supplied by publisher]

Proteogenomics of Non-smoking Lung Cancer in East Asia Delineates Molecular Signatures of Pathogenesis and Progression.

Cell. 2020 Jul 09;182(1):226-244.e17

Authors: Chen YJ, Roumeliotis TI, Chang YH, Chen CT, Han CL, Lin MH, Chen HW, Chang GC, Chang YL, Wu CT, Lin MW, Hsieh MS, Wang YT, Chen YR, Jonassen I, Ghavidel FZ, Lin ZS, Lin KT, Chen CW, Sheu PY, Hung CT, Huang KC, Yang HC, Lin PY, Yen TC, Lin YW, Wang JH, Raghav L, Lin CY, Chen YS, Wu PS, Lai CT, Weng SH, Su KY, Chang WH, Tsai PY, Robles AI, Rodriguez H, Hsiao YJ, Chang WH, Sung TY, Chen JS, Yu SL, Choudhary JS, Chen HY, Yang PC, Chen YJ

Abstract
Lung cancer in East Asia is characterized by a high percentage of never-smokers, early onset and predominant EGFR mutations. To illuminate the molecular phenotype of this demographically distinct disease, we performed a deep comprehensive proteogenomic study on a prospectively collected cohort in Taiwan, representing early stage, predominantly female, non-smoking lung adenocarcinoma. Integrated genomic, proteomic, and phosphoproteomic analysis delineated the demographically distinct molecular attributes and hallmarks of tumor progression. Mutational signature analysis revealed age- and gender-related mutagenesis mechanisms, characterized by high prevalence of APOBEC mutational signature in younger females and over-representation of environmental carcinogen-like mutational signatures in older females. A proteomics-informed classification distinguished the clinical characteristics of early stage patients with EGFR mutations. Furthermore, integrated protein network analysis revealed the cellular remodeling underpinning clinical trajectories and nominated candidate biomarkers for patient stratification and therapeutic intervention. This multi-omic molecular architecture may help develop strategies for management of early stage never-smoker lung adenocarcinoma.

PMID: 32649875 [PubMed - as supplied by publisher]

Evaluation of the impact of body mass index on venous thromboembolism risk factors.

PLoS One. 2020;15(7):e0235007

Authors: Tajik F, Wang M, Zhang X, Han J

Abstract
In this paper, we investigate the interaction impacts of body mass index (BMI) on the other important risk factors for venous thromboembolism (VTE), using deep venous thrombosis (DVT) patient data from the International Warfarin Pharmacogenetics Consortium (IWPC). We apply eight machine learning techniques, including naive Bayes classifier (NB), support vector machine (SVM), elastic net regression (ENET), logistic regression (LR), lasso regression (LAR), multivariate adaptive regression splines (MARS), boosted regression tree (BRT) and random forest model (RF). The RF method is selected as the best model for classification. Out of 33 features considered in this study, we identify 12 variables as relatively important risk factors for VTE. Finally, we examine the interaction impacts of BMI on these important VTE risk factors. We conclude that the impacts of risk factors on VTE incidence are varying across different BMI groups, and the variations are different for different risk factors. Therefore the interaction impacts of BMI on the other risk factors have to be taken into account in order to better understand the incidence of VTE.

PMID: 32645000 [PubMed - as supplied by publisher]

Rheostat positions: A new classification of protein positions relevant to pharmacogenomics.

Med Chem Res. 2020 Jul;29(7):1133-1146

Authors: Fenton AW, Page BM, Spellman-Kruse A, Hagenbuch B, Swint-Kruse L

Abstract
To achieve the full potential of pharmacogenomics, one must accurately predict the functional out comes that arise from amino acid substitutions in proteins. Classically, researchers have focused on understanding the consequences of individual substitutions. However, literature surveys have shown that most substitutions were created at evolutionarily conserved positions. Awareness of this bias leads to a shift in perspective, from considering the outcomes of individual substitutions to understanding the roles of individual protein positions. Conserved positions tend to act as "toggle" switches, with most substitutions abolishing function. However, nonconserved positions have been found equally capable of affecting protein function. Indeed, many nonconserved positions act like functional dimmer switches ("rheostat" positions): This is revealed when multiple substitutions are made at a single position. Each substitution has a different functional outcome; the set of substitutions spans arange of outcomes. Finally, some nonconserved positions appear neutral, capable of accommodating all amino acid types without modifying function. This manuscript reviews the currently-known properties of rheost at positions, with examples shown for pyruvate kinase, organic anion transporting polypeptide 1B1, the beta-lactamase inhibitory protein, and angiotensin-converting enzyme 2. Outcomes observed for rheostat positions have implications for the rational design of drug analogs and allosteric drugs. Furthermore, this new framework - comprising three types of protein positions - provides a new approach to interpreting disease and population-based databases of amino acid changes. In conclusion, although a full understanding of substitution out comes at rheostat positions poses a challenge, utilization of this new frame of reference will further advance the application of pharmacogenomics.

PMID: 32641900 [PubMed]

Native American gene flow into Polynesia predating Easter Island settlement.

Nature. 2020 Jul 08;:

Authors: Ioannidis AG, Blanco-Portillo J, Sandoval K, Hagelberg E, Miquel-Poblete JF, Moreno-Mayar JV, Rodríguez-Rodríguez JE, Quinto-Cortés CD, Auckland K, Parks T, Robson K, Hill AVS, Avila-Arcos MC, Sockell A, Homburger JR, Wojcik GL, Barnes KC, Herrera L, Berríos S, Acuña M, Llop E, Eng C, Huntsman S, Burchard EG, Gignoux CR, Cifuentes L, Verdugo RA, Moraga M, Mentzer AJ, Bustamante CD, Moreno-Estrada A

Abstract
The possibility of voyaging contact between prehistoric Polynesian and Native American populations has long intrigued researchers. Proponents have pointed to the existence of New World crops, such as the sweet potato and bottle gourd, in the Polynesian archaeological record, but nowhere else outside the pre-Columbian Americas1-6, while critics have argued that these botanical dispersals need not have been human mediated7. The Norwegian explorer Thor Heyerdahl controversially suggested that prehistoric South American populations had an important role in the settlement of east Polynesia and particularly of Easter Island (Rapa Nui)2. Several limited molecular genetic studies have reached opposing conclusions, and the possibility continues to be as hotly contested today as it was when first suggested8-12. Here we analyse genome-wide variation in individuals from islands across Polynesia for signs of Native American admixture, analysing 807 individuals from 17 island populations and 15 Pacific coast Native American groups. We find conclusive evidence for prehistoric contact of Polynesian individuals with Native American individuals (around AD 1200) contemporaneous with the settlement of remote Oceania13-15. Our analyses suggest strongly that a single contact event occurred in eastern Polynesia, before the settlement of Rapa Nui, between Polynesian individuals and a Native American group most closely related to the indigenous inhabitants of present-day Colombia.

PMID: 32641827 [PubMed - as supplied by publisher]

Estimation versus measurement of the glomerular filtration rate for kidney function assessment in patients with cancer undergoing cisplatin-based chemotherapy.

Sci Rep. 2020 Jul 08;10(1):11219

Authors: Klöckl MC, Kasparek AK, Riedl JM, Moik F, Mollnar S, Stotz M, Szkandera J, Terbuch A, Gerger A, Niedrist T, Pichler M, Bauernhofer T, Schilcher G, Zitta S, Rosenkranz AR, Friedl C, Stöger H, Posch F

Abstract
Glomerular filtration rate (GFR) assessment is indicated before every administration of cisplatin. The optimal modality for this purpose [GFR measurement by urinary Creatinine Clearance (uCrCl) versus GFR estimation (eGFR) by the CKD-EPI formula versus both] is unclear. We investigated whether eGFR only is safe in this setting. Paired uCrCl and eGFR determinations from 470 cisplatin cycles from 121 patients were analyzed [median age: 55 years; most frequent tumor site: genitourinary (45%); palliative treatment: n = 41 (34%)]. Primary endpoint was the proportion of cycles with uCrCl < 50 ml/min/1.73m2 and eGFR ≥ 50 ml/min/1.73m2 (i.e. a "false negative" result when only determining eGFR). The primary endpoint occurred in 8 of 470 cisplatin cycles (1.7%, 95%CI 0.5-2.9). In all 8 events, uCrCl was lower than eGFR (mean uCrCl vs. eGFR: 43 versus 112 ml/min/1.73m2). The uCrCl was re-measured in all patients, and showed normal results in all but 1 patient. None of these events precluded the administration of cisplatin at the planned date, and no subsequent cases of acute nephrotoxicity occurred. Overall agreement between uCrCl and eGFR was low, with qualitative analysis suggesting frequent incompliance with 24-h urine collection. We conclude that an eGFR is sufficient for assessing kidney function in patients with cancer undergoing cisplatin therapy.

PMID: 32641710 [PubMed - in process]

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 2020/07/09

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.

11 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 2020/07/08

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.

Mood Stabilizing Antiepileptic Treatment Response in Bipolar Disorder: A Genome-Wide Association Study.

Clin Pharmacol Ther. 2020 Jul 05;:

Authors: Man-Choi Ho A, Coombes BJ, Nguyen TTL, Liu D, McElroy SL, Singh B, Nassan M, Colby CL, Larrabee BR, Weinshilboum RM, Frye MA, Biernacka JM

Abstract
Several anti-epileptic drugs (AED) have FDA approval for use as mood stabilizers in bipolar disorder (BD), but not all BD patients respond to these AED mood stabilizers (AED-MS). To identify genetic polymorphisms that contribute to the variability in AED-MS response, we performed a discovery genome-wide association study of 199 BD patients from the Mayo Clinic Bipolar Disorder Biobank. Most of these patients had been treated with the AED-MS valproate and/or lamotrigine. AED-MS response was assessed using the Alda scale, which quantifies clinical improvement while accounting for potential confounding factors. We identified two genome-wide significant single-nucleotide polymorphism (SNP) signals that mapped to the THSD7A (rs78835388, p=7.1E-09) and SLC35F3 (rs114872993, p=3.2E-08) genes. We also identified two genes with statistically significant gene-level associations: ABCC1 (p=6.7E-07; top SNP rs875740, p=2.0E-6), and DISP1 (p=8.9E-07; top SNP rs34701716, p=8.9E-07). THSD7A SNPs were previously found to be associated with risk for several psychiatric disorders including BD. Both THSD7A and SLC35F3 are expressed in excitatory/glutamatergic and inhibitory/GABAergic neurons, which are targets of AED-MSs. ABCC1 is involved in the transport of valproate and lamotrigine metabolites, and the SNPs in ABCC1 and DISP1 with the strongest evidence of association with AED-MS in our GWAS are strong splicing quantitative trait loci in the human gut, suggesting a possible influence on drug absorption. In conclusion, our pharmacogenomic study identified novel genetic loci that appear to contribute to AED-MS treatment response, and may facilitate precision medicine in BD.

PMID: 32627186 [PubMed - as supplied by publisher]

Germline and Somatic Pharmacogenomics to Refine Rectal Cancer Patients Selection for Neo-Adjuvant Chemoradiotherapy.

Front Pharmacol. 2020;11:897

Authors: De Mattia E, Roncato R, Palazzari E, Toffoli G, Cecchin E

Abstract
Neoadjuvant chemoradiotherapy (nCRT) followed by radical surgery is the standard of care for patients with Locally Advanced Rectal Cancer (LARC). Current selection for nCRT is based on clinical criteria regardless of any molecular marker. Pharmacogenomics may be a useful strategy to personalize and optimize nCRT in LARC. This review aims to summarize the most recent and relevant findings about the role of germline and somatic pharmacogenomics in the prediction of nCRT outcome in patients with LARC, discussing the state of the art of their application in the clinical practice. A systematic literature search of the PubMed database was completed to identify relevant English-language papers published up to January 2020. The chemotherapeutic backbone of nCRT is represented by fluoropyrimidines, mainly metabolized by DPD (Dihydro-Pyrimidine Dehydrogenase, DPYD). The clinical impact of testing DPYD*2A, DPYD*13, c.2846A > T and c.1236G > A-HapB3 before a fluoropyrimidines administration to increase treatment safety is widely acknowledged. Other relevant target genes are TYMS (Thymidylate Synthase) and MTHFR (Methylene-Tetrahydro-Folate Reductase), whose polymorphisms were mainly studied as potential markers of treatment efficacy in LARC. A pivotal role of a TYMS polymorphism in the gene promoter region (rs34743033) was reported and was pioneeringly used to guide nCRT treatment in a phase II study. The pharmacogenomic analysis of other pathways mostly involved in the cellular response to radiation damage, as the DNA repair and the activation of the inflammatory cascade, provided less consistent results. A high rate of somatic mutation in genes belonging to PI3K (Phosphatidyl-Inositol 3-Kinase) and MAPK (Mitogen-Activated Protein Kinase) pathways, as BRAF (V-raf murine sarcoma viral oncogene homolog B1), KRAS (Kirsten Rat Sarcoma viral oncogene homolog), NRAS (Neuroblastoma RAS viral (v-ras) oncogene homolog), PIK3CA (Phosphatidyl-Inositol-4,5-bisphosphate 3-Kinase, Catalytic Subunit Alpha), as well as TP53 (Tumor Protein 53) was reported in LARC. Their pharmacogenomic role, already defined in colorectal cancer, is under investigation in LARC with promising results concerning specific somatic mutations in KRAS and TP53, as predictors of tumor response and prognosis. The availability of circulating tumor DNA in plasma may also represent an opportunity to monitor somatic mutations in course of therapy.

PMID: 32625092 [PubMed]

High fractional exhaled nitric oxide levels may predict short-term worsening of respiratory oscillometry in asthma.

Allergy. 2020 Jul 04;:

Authors: Endo Y, Shirai T, Hirai K, Akamatsu T, Kato E, Furui H, Hiramatsu T

Abstract
High fractional exhaled nitric oxide (FeNO) levels, reflecting uncontrolled airway inflammation, are regarded as a risk factor for an upcoming asthma exacerbation. A previous study found that persistently high FeNO (> 40 ppb) was associated with a rapid decline in FEV1, even in controlled asthma patients, in a 3-year prospective study. However, little is known about the effect of high FeNO levels on short-term course of lung function. Oscillometry, also known as the forced oscillation technique, is a non-invasive method with which to measure respiratory mechanics and is useful for the evaluation or management of asthma. The aim of this study was to assess whether high FeNO levels (> 35 ppb) would predict the short-term worsening of lung function, especially oscillometric parameters.

PMID: 32623752 [PubMed - as supplied by publisher]

Next-Generation Sequencing of CYP2C19 in Stent Thrombosis: Implications for Clopidogrel Pharmacogenomics.

Cardiovasc Drugs Ther. 2020 Jul 04;:

Authors: Morales-Rosado JA, Goel K, Zhang L, Åkerblom A, Baheti S, Black JL, Eriksson N, Wallentin L, James S, Storey RF, Goodman SG, Jenkins GD, Eckloff BW, Bielinski SJ, Sicotte H, Johnson S, Roger VL, Wang L, Weinshilboum R, Klee EW, Rihal CS, Pereira NL

Abstract
PURPOSE: Describe CYP2C19 sequencing results in the largest series of clopidogrel-treated cases with stent thrombosis (ST), the closest clinical phenotype to clopidogrel resistance. Evaluate the impact of CYP2C19 genetic variation detected by next-generation sequencing (NGS) with comprehensive annotation and functional studies.
METHODS: Seventy ST cases on clopidogrel identified from the PLATO trial (n = 58) and Mayo Clinic biorepository (n = 12) were matched 1:1 with controls for age, race, sex, diabetes mellitus, presentation, and stent type. NGS was performed to cover the entire CYP2C19 gene. Assessment of exonic variants involved measuring in vitro protein expression levels. Intronic variants were evaluated for potential splicing motif variations.
RESULTS: Poor metabolizers (n = 4) and rare CYP2C19*8, CYP2C19*15, and CYP2C19*11 alleles were identified only in ST cases. CYP2C19*17 heterozygote carriers were observed more frequently in cases (n = 29) than controls (n = 18). Functional studies of CYP2C19 exonic variants (n = 11) revealed 3 cases and only 1 control carrying a deleterious variant as determined by in vitro protein expression studies. Greater intronic variation unique to ST cases (n = 169) compared with controls (n = 84) was observed with predictions revealing 13 allele candidates that may lead to a potential disruption of splicing and a loss-of-function effect of CYP2C19 in ST cases.
CONCLUSION: NGS detected CYP2C19 poor metabolizers and paradoxically greater number of so-called rapid metabolizers in ST cases. Rare deleterious exonic variation occurs in 4%, and potentially disruptive intronic alleles occur in 16% of ST cases. Additional studies are required to evaluate the role of these variants in platelet aggregation and clopidogrel metabolism.

PMID: 32623598 [PubMed - as supplied by publisher]

Glycemic variability: adverse clinical outcomes and how to improve it?

Cardiovasc Diabetol. 2020 Jul 04;19(1):102

Authors: Zhou Z, Sun B, Huang S, Zhu C, Bian M

Abstract
Glycemic variability (GV), defined as an integral component of glucose homoeostasis, is emerging as an important metric to consider when assessing glycemic control in clinical practice. Although it remains yet no consensus, accumulating evidence has suggested that GV, representing either short-term (with-day and between-day variability) or long-term GV, was associated with an increased risk of diabetic macrovascular and microvascular complications, hypoglycemia, mortality rates and other adverse clinical outcomes. In this review, we summarize the adverse clinical outcomes of GV and discuss the beneficial measures, including continuous glucose monitoring, drugs, dietary interventions and exercise training, to improve it, aiming at better addressing the challenging aspect of blood glucose management.

PMID: 32622354 [PubMed - as supplied by publisher]

Risk and association of HLA alleles with methimazole-induced cutaneous adverse reactions in Chinese Han population.

J Invest Dermatol. 2020 Jul 01;:

Authors: Xiong H, Jiang M, Shao F, Ye H, Zhang W, Chen Z, Zeng F, Chen SA, Yuan H, Yan L, Xing Q, Luo X

PMID: 32621825 [PubMed - as supplied by publisher]

Pharmacogenomics for Immunotherapy and Immune-related Cardiotoxicity.

Hum Mol Genet. 2020 Jul 03;:

Authors: Castrillon JA, Eng C, Cheng F

Abstract
Immune checkpoint blockade (ICB) has become a standard of care in a subset of solid tumors. Although cancer survivorship has extended, rates of durable response of ICB remain poor; furthermore, cardiac adverse effects are emerging which impacts several mechanical aspects of the heart. Cardio-oncology programs implement a clinical assessment to curtail cardiovascular disease progression but are limited to the current clinical parameters used in cardiology. Pharmacogenomics provides the potential to unveil heritable and somatic genetic variations for guiding precision immunotherapy treatment to reduce risk of immune-related cardiotoxicity. A better understanding of pharmacogenomics will optimize the current treatment selection and dosing of immunotherapy. Here we summarize the recent pharmacogenomics studies in immunotherapy responsiveness and its related cardiotoxicity and highlight how patient genetics and epigenetics can facilitate researchers and clinicians in designing new approaches for precision immunotherapy. We highlight and discuss how single-cell technologies, human induced pluripotent stem cells, and systems pharmacogenomics accelerate future studies of precision cardio-oncology.

PMID: 32620943 [PubMed - as supplied by publisher]

Hepatic Adaptation to Therapeutic Doses of acetaminophen: An Exploratory Study in healthy Individuals.

Clin Ther. 2020 Jun 30;:

Authors: Maeda M, Tanaka R, Aso M, Sakamoto Y, Song I, Ochiai M, Saito Y, Maekawa K, Arakawa N, Ohno Y, Kumagai Y

Abstract
PURPOSE: Acetaminophen (APAP) has hepatotoxic potential when overdosed. Recent studies have reported serum alanine aminotransferase (ALT) elevations that resolve spontaneously with continued use of the drug, referred to as adaptation, in several individuals receiving therapeutic doses of APAP. However, the clinical significance of these ALT elevations remains unclear. This study was performed to investigate the incidence and characteristics of hepatic adaptation to therapeutic doses of APAP in healthy individuals.
METHODS: In a randomized, single-blind, placebo-controlled study, 242 healthy Japanese individuals were enrolled. Each person received 3 g/d of APAP (n = 202) or placebo (n = 40) for 28 days. All study participants underwent analysis of genetic polymorphisms of CYP2E1 and UGT1A1; measurements of plasma APAP concentration and urine metabolites (glucuronide, sulfate, cysteine, and mercapturate); liver function monitoring, including ALT, microRNA-122, and high-mobility group box 1. Individuals with ALT levels remaining below the upper limit of normal (ULN; 40 U/L) during the study period were defined as tolerant and those with ALT elevations above the ULN as susceptible. Susceptible individuals who developed ALT elevations exceeding 2 × ULN discontinued use of the study drug for tolerability consideration. Susceptible individuals who had ALT elevations that decreased toward the ULN spontaneously with continued use of the study drug were classified as adaptation.
FINDINGS: In the APAP group, 129 individuals (66%) were classified as tolerant and 65 (34%) as susceptible. Among 65 susceptible individuals, 12 (18%) discontinued use of APAP because of ALT elevations (>2 × ULN), whereas 53 (82%) completed 28-day APAP dosing. Thirty of 65 susceptible individuals (46%) had adaptation within 28 days. In the placebo group, no individuals was withdrawn from the study because of elevated ALT levels, 33 individuals (89%) were classified as tolerant, and 4 (11%) were classified as susceptible. None had clinical signs of liver injury. ALT level correlated significantly with microRNA-122 but not with high-mobility group box 1. No association was found between plasma APAP concentrations and ALT levels. Urinary excretion of APAP mercapturate was higher in susceptible than in tolerant individuals (P = 0.018, Wilcoxon or Kruskal-Wallis test). The frequency of homozygotes and compound heterozygotes for UGT1A1∗28 and UGT1A1∗6 (∗28/∗28, ∗6/∗6, and ∗6/∗28) was higher in susceptible than in tolerant individuals (13.9% vs 3.9%; P = 0.011, χ2 test).
IMPLICATIONS: These findings indicate that in healthy individuals, APAP at a therapeutic dose can cause transient and self-limiting ALT elevation, reflecting subclinical hepatocellular damage, and these ALT elevations may be associated with the disposition of APAP metabolites and genetic factors. UMIN-CTR identifier: UMIN000019607.

PMID: 32620339 [PubMed - as supplied by publisher]

11 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 2020/07/05

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.