Incorporating pharmacokinetic data into personalised prescribing for older people: challenges and opportunities.

Eur Geriatr Med. 2021 Jan 08;:

Authors: Mangoni AA, Jarmuzewska EA

Abstract
PURPOSE: We discuss the known age-associated changes in drug metabolism and elimination, the potential use of this information when selecting specific therapeutic strategies in older patients, and the steps required to fill the knowledge gap in this field.
METHODS: We conducted a narrative review that encapsulates the current knowledge regarding the main age-associated changes in drug metabolism and elimination and discusses their possible inclusion in current and future personalised prescribing tools for the older patient population.
RESULTS: Despite some progress in this field, the lack of specific information regarding the impact of frailty, pharmacogenomics, and drug-drug, drug-disease, and organ-organ interactions, particularly in subjects > 80 years, currently prevents the routine incorporation of pharmacokinetic data, barring measures of renal function, into personalised prescribing tools.
CONCLUSIONS: The incorporation of pharmacokinetic data into personalised prescribing, an approach based on the consideration of a number of patient's characteristics when selecting the right drug(s) and dose regimen(s) to maximize effectiveness and limit toxicity, remains a hypothetical construct in geriatric care. Pending the inclusion of frail and complex older patients in pre- and post-marketing studies, a better understanding of the key pharmacokinetic alterations of common medications in "real-life" patients, together with the implementation of effective strategies tackling inappropriate prescribing, is likely to improve clinical outcomes and reduce healthcare utilization in the older population.

PMID: 33417165 [PubMed - as supplied by publisher]

A Bayesian analysis of the association between Leukotriene A4 Hydrolase genotype and survival in tuberculous meningitis.

Elife. 2021 Jan 08;10:

Authors: Whitworth L, Coxon J, van Laarhoven A, Thuong NTT, Dian S, Alisjahbana B, Ganiem AR, van Crevel R, Thwaites GE, Troll M, Edelstein PH, Sewell R, Ramakrishnan L

Abstract
Tuberculous meningitis has high mortality, linked to excessive inflammation. However, adjunctive anti-inflammatory corticosteroids reduce mortality by only 30%, suggesting that inflammatory pathophysiology causes only a subset of deaths. In Vietnam, the survival benefit of anti-inflammatory corticosteroids was most pronounced in patients with a C/T promoter variant in the leukotriene A4 hydrolase (LTA4H) gene encoding an enzyme that regulates inflammatory eicosanoids. LTA4H TT patients with increased expression had increased survival, consistent with corticosteroids benefiting individuals with hyper-inflammatory responses. However, an Indonesia study did not find an LTA4H TT genotype survival benefit. Here using Bayesian methods to analyse both studies, we find that LTA4H TT genotype confers survival benefit that begins early and continues long-term in both populations. This benefit is nullified in the most severe cases with high early mortality. LTA4H genotyping together with disease severity assessment may target glucocorticoid therapy to patients most likely to benefit from it.

PMID: 33416499 [PubMed - as supplied by publisher]

Unraveling the roles of vitamin D status and melanin during Covid‑19 (Review).

Int J Mol Med. 2020 Nov 30;:

Authors: Sidiropoulou P, Docea AO, Nikolaou V, Katsarou MS, Spandidos DA, Tsatsakis A, Calina D, Drakoulis N

Abstract
As the coronavirus disease 2019 (COVID‑19) continues to spread worldwide, it has become evident that the morbidity and mortality rates clearly vary across nations. Although several factors may account for this disparity, striking differences within and between populations indicate that ethnicity might impact COVID‑19 clinical outcomes, reflecting the 'color of disease'. Therefore, the role of key biological variables that could interplay with viral spreading and severity indices has attracted increasing attention, particularly among non‑Caucasian populations. Although the links between vitamin D status and the incidence and severity of COVID-19 remain elusive, several lines of emerging evidence suggest that vitamin D signaling, targeting several immune‑mediated pathways, may offer potential benefits at different stages of SARS-CoV-2 infection. Given that the vitamin D status is modulated by several intrinsic and extrinsic factors, including skin type (pigmentation), melanin polymers may also play a role in variable COVID‑19 outcomes among diverse population settings. Moreover, apart from the well‑known limiting effects of melanin on the endogenous production of vitamin D, the potential crosstalk between the pigmentary and immune system may also require special attention concerning the current pandemic. The present review article aimed to shed light on a range of mostly overlooked host factors, such as vitamin D status and melanin pigments, that may influence the course and outcome of COVID‑19.

PMID: 33416113 [PubMed - as supplied by publisher]

Implementation of pharmacogenomic testing in oncology care (PhOCus): study protocol of a pragmatic, randomized clinical trial.

Ther Adv Med Oncol. 2020;12:1758835920974118

Authors: Reizine N, Vokes EE, Liu P, Truong TM, Nanda R, Fleming GF, Catenacci DVT, Pearson AT, Parsad S, Danahey K, van Wijk XMR, Yeo KJ, Ratain MJ, O'Donnell PH

Abstract
Background: Many cancer patients who receive chemotherapy experience adverse drug effects. Pharmacogenomics (PGx) has promise to personalize chemotherapy drug dosing to maximize efficacy and safety. Fluoropyrimidines and irinotecan have well-known germline PGx associations. At our institution, we have delivered PGx clinical decision support (CDS) based on preemptively obtained genotyping results for a large number of non-oncology medications since 2012, but have not previously evaluated the utility of this strategy for patients initiating anti-cancer regimens. We hypothesize that providing oncologists with preemptive germline PGx information along with CDS will enable individualized dosing decisions and result in improved patient outcomes.
Methods: Patients with oncologic malignancies for whom fluoropyrimidine and/or irinotecan-inclusive therapy is being planned will be enrolled and randomly assigned to PGx and control arms. Patients will be genotyped in a clinical laboratory across panels that include actionable variants in UGT1A1 and DPYD. For PGx arm patients, treating providers will be given access to the patient-specific PGx results with CDS prior to treatment initiation. In the control arm, genotyping will be deferred, and dosing will occur as per usual care. Co-primary endpoints are dose intensity deviation rate (the proportion of patients receiving dose modifications during the first treatment cycle), and grade ⩾3 treatment-related toxicities throughout the treatment course. Additional study endpoints will include cumulative drug dose intensity, progression-free survival, dosing of additional PGx supportive medications, and patient-reported quality of life and understanding of PGx.
Discussion: Providing a platform of integrated germline PGx information may promote personalized chemotherapy dosing decisions and establish a new model of care to optimize oncology treatment planning.

PMID: 33414846 [PubMed]

Dihydropyrimidine dehydrogenase deficiency in patients with severe toxicity after 5-fluorouracil: a retrospective single-center study.

Ann Gastroenterol. 2021;34(1):68-72

Authors: Detailleur S, Segelov E, Re MD, Prenen H

Abstract
Background: 5-Fluorouracil (5-FU) is an agent frequently used in the treatment of solid cancers. A deficiency in the enzyme that catabolizes 5-FU leads to severe toxicity. The gene responsible for this enzyme is DPYD, located on chromosome 1q22. The most prevalent alteration described is DPYD*2A, which leads to a splicing defect and thus skipping of the translation of an entire exon. The objectives of this retrospective study were to describe the frequencies of DPYD gene mutations in a Belgian population and to correlate them with the grade of toxicity.
Methods: This was a retrospective, single-center study conducted at the University Hospitals Leuven, by reviewing a database of patients screened for DPYD gene mutations between May 2009 and June 2015 after prolonged grade 3-4 toxicity. Polymerase chain reaction sequencing of exons 2, 6, 10, 11, 13, 18, 19 and 22, and pyrosequencing of exon 14 were performed by an in-house laboratory.
Results: Of the 80 patients screened, 65 were heterozygous or compound heterozygous for DPYD and 3 had a homozygous mutation. The most prevalent mutation in our population was DPYD*9A.
Conclusions: Despite previous reports, in our small retrospective study the most prevalent variation in patients with severe adverse events was DPYD*9A. As this variant has previously been reported to be benign, we suggest that screening for dihydropyrimidine dehydrogenase deficiency should be extended across multiple exons of the DPYD gene.

PMID: 33414624 [PubMed]

A genome-wide methylation study reveals X chromosome and childhood trauma methylation alterations associated with borderline personality disorder.

Transl Psychiatry. 2021 Jan 05;11(1):5

Authors: Arranz MJ, Gallego-Fabrega C, Martín-Blanco A, Soler J, Elices M, Dominguez-Clavé E, Salazar J, Vega D, Briones-Buixassa L, Pascual JC

Abstract
Borderline personality disorder (BPD) is a severe and highly prevalent psychiatric disorder, more common in females than in males and with notable differences in presentation between genders. Recent studies have shown that epigenetic modifications such as DNA methylation may modulate gene × environment interactions and impact on neurodevelopment. We conducted an epigenome wide study (Illumina Infinium HumanMethylation450k beadchip) in a group of BPD patients with (N = 49) and without (N = 47) childhood traumas and in a control group (N = 44). Results were confirmed in a replication cohort (N = 293 BPD patients and N = 114 controls) using EpiTYPER assays. Differentially methylated CpG sites were observed in several genes and intragenic regions in the X chromosome (PQBP1, ZNF41, RPL10, cg07810091 and cg24395855) and in chromosome 6 (TAP2). BPD patients showed significantly lower methylation levels in these CpG sites than healthy controls. These differences seemed to be increased by the existence of childhood trauma. Comparisons between BPD patients with childhood trauma and patients and controls without revealed significant differences in four genes (POU5F1, GGT6, TNFRSF13C and FAM113B), none of them in the X chromosome. Gene set enrichment analyses revealed that epigenetic alterations were more frequently found in genes controlling oestrogen regulation, neurogenesis and cell differentiation. These results suggest that epigenetic alterations in the X chromosome and oestrogen-regulation genes may contribute to the development of BPD and explain the differences in presentation between genders. Furthermore, childhood trauma events may modulate the magnitude of the epigenetic alterations contributing to BPD.

PMID: 33414392 [PubMed - in process]

PGx in psychiatry: Patients' knowledge, interest, and uncertainty management preferences in the context of pharmacogenomic testing.

Patient Educ Couns. 2020 Dec 25;:

Authors: Kastrinos A, Campbell-Salome G, Shelton S, Peterson EB, Bylund CL

Abstract
OBJECTIVE: Pharmacogenomic testing (PGx) is expanding into psychiatric care. PGx could potentially offer a unique benefit to psychiatric patients, providing information about patients' reaction to medications that could reduce the time and financial burdens of drug optimization. The aims of this study were to: (1) examine psychiatry patients' familiarity and interest in PGx, and (2) explore how Uncertainty Management Theory relates to PGx testing in psychiatry.
METHOD: We surveyed psychiatric patients, measuring their PGx familiarity and interest, attitudes toward PGx testing, and preference for managing illness uncertainty.
RESULTS: We analyzed data from 598 patients. Patients' familiarity of PGx was low, but interest was high. Thirty percent of patients were familiar with the test from communication with their healthcare provider or their own online health information seeking. A preference for seeking information was a significant positive predictor of testing interest (p < .001).
CONCLUSION: Psychiatric patients were interested in PGx testing, regardless of their uncertainty management preferences.
PRACTICE IMPLICATIONS: This study is one of the first to examine psychiatric patients' perspectives on PGx testing in mental health care. Our findings show that psychiatric patients are interested in the test and are familiar enough with PGx to be included in future research on the topic.

PMID: 33414028 [PubMed - as supplied by publisher]

Putative molecular determinants mediating sensitivity or resistance towards carnosic acid tumor cell responses.

Phytomedicine. 2020 Oct;77:153271

Authors: Mahmoud N, Saeed MEM, Sugimoto Y, Klinger A, Fleischer E, Efferth T

Abstract
BACKGROUND: Carnosic acid (CA) is one of the main constituents in rosemary extract. It possesses valuable pharmacological properties, including anti-oxidant, anti-inflammatory, anti-microbial and anti-cancer activities. Numerous in vitro and in vivo studies investigated the anticancer profile of CA and emphasized its potentiality for cancer treatment. Nevertheless, the role of multidrug-resistance (MDR) related mechanisms for CA's anticancer effect is not yet known.
PURPOSE: We investigated the cytotoxicity of CA against known mechanisms of anticancer drug resistance (P-gp, ABCB5, BCRP, EGFR and p53) and determined novel putative molecular factors associated with cellular response towards CA.
STUDY DESIGN: Cytotoxicity assays, bioinformatic analysis, flow cytometry and western blotting were performed to identify the mode of action of CA towards cancer cells.
METHODS: The cytotoxicity to CA was assessed using the resazurin assays in cell lines expressing the mentioned resistance mechanisms. A pharmacogenomic characterization of the NCI 60 cell line panel was applied via COMPARE, hierarchical cluster and network analyses. Flow cytometry was used to detect cellular mode of death and ROS generation. Changes in proteins-related to apoptosis were determined by Western blotting.
RESULTS: Cell lines expressing ABC transporters (P-gp, BCRP or ABCB5), mutant EGFR or p53 were not cross-resistant to CA compared to their parental counterparts. By pharmacogenomic approaches, we identified genes that belong to different functional groups (e.g. signal transduction, regulation of cytoskeleton and developmental regulatory system). These genes were predicted as molecular determinants that mediate CA tumor cellular responses. The top affected biofunctions included cellular development, cellular proliferation and cellular death and survival. The effect of CA-mediated apoptosis in leukemia cells, which were recognized as the most sensitive tumor type, was confirmed via flow cytometry and western blot analysis.
CONCLUSION: CA may provide a novel treatment option to target refractory tumors and to effectively cooperate with established chemotherapy. Using pharmacogenomic approaches and network pharmacology, the relationship between cancer complexity and multi-target potentials of CA was analyzed and many putative molecular determinants were identified. They could serve as novel targets for CA and further studies are needed to translate the possible implications to clinical cancer treatment.

PMID: 32659679 [PubMed - indexed for MEDLINE]

ABCB1, CYP2B6, and CYP3A4 genetic polymorphisms do not affect methadone maintenance treatment in HCV-positive patients.

Arh Hig Rada Toksikol. 2020 Dec 31;71(4):353-358

Authors: Sutlović D, Ključević Ž, Kuret S

Abstract
The aim of this study was to determine the influence of ABCB1, CYP2B6, and CYP3A4 genetic polymorphisms on methadone metabolism in patients with hepatitis C virus (HCV) undergoing methadone maintenance treatment (MMT). The study included 35 participants undergoing MMT, who were divided in three groups: HCV-positive (N=12), HCV-negative (N=16), and HCV clinical remission (CR) (N=7). The concentrations of methadone and its main metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) were determined with gas chromatography-mass spectrometry. The patients were genotyped for ABCB1 rs1045642, CYP2B6 rs3745274, CYP3A4 rs2242480, and CYP3A4 rs2740574 polymorphisms. Differences between single nucleotide polymorphism (SNP) genotypes and methadone-to-EDDP ratio were analysed with one-way ANOVA, which showed no significant difference between the genes (p=0.3772 for ABCB1 rs1045642, p=0.6909 for CYP2B6 rs3745274, and p=0.6533 for CYP3A4 rs2242480). None of the four analysed SNP genotypes correlated with methadone-to-EDDP concentration ratio. A major influence on it in hepatitis C-positive patients turned out to be the stage of liver damage.

PMID: 33410778 [PubMed - as supplied by publisher]

Patients carrying DPYD variant alleles have increased risk of severe toxicity and related treatment modifications during fluoropyrimidine chemotherapy.

Pharmacogenomics. 2021 Jan 07;:

Authors: Shakeel F, Fang F, Kwon JW, Koo K, Pasternak AL, Henry NL, Sahai V, Kidwell KM, Hertz DL

Abstract
Aim: To evaluate toxicity risk in carriers of four DPYD variants using an institutional genetic repository. Materials & methods: Of over 65,000 patients in the repository, 582 were evaluated for the primary composite end point of grade 3 or higher toxicity or treatment modification due to toxicity. Results: The primary end point was more common in DPYD variant carriers (36.5 vs 18.1%, adjusted odds ratio 2.42, 95% CI: 1.05-5.55, p = 0.04), and in patients with decreased DPD activity (≤1 vs 2) (75.6 vs 17.0%, adjusted odds ratio 16.31, 95% CI: 2.64-100.68, p = 0.003). Conclusion: Patients carrying any of the four DPYD variants are at increased risk of severe toxicity or subsequent treatment modifications, suggesting such patients may benefit from genotype-informed treatment.

PMID: 33410339 [PubMed - as supplied by publisher]

Pharmacogenetics of advanced lung cancer: Predictive value of functional genetic polymorphism AGXT Pro11Leu in clinical outcome?

Pulmonology. 2021 Jan 03;:

Authors: Catarata MJ, Lourenço M, Martins MF, Frade J, Pêgo A, Cordeiro CR, Medeiros R, Ribeiro R

Abstract
INTRODUCTION: AGXT gene codes for the enzyme alanine glyoxylate aminotransferase, which is involved in hepatic peroxisomal metabolism of platinum-based chemotherapeutic agents. The association of genetic variant AGXT rs34116584 on the clinical outcome and response to chemotherapy of patients with non-small cell lung cancer (NSCLC) remains to be established. Our aim was to evaluate the association of functional AGXT gene polymorphism in NSCLC progression, considering as primary and secondary endpoint, progression free survival (PFS) and overall survival (OS), respectively.
METHODS: Genotyping of theAGXT rs34116584 genetic polymorphism was performed by mass spectrometry on 168 DNA samples from patients with NSCLC (stages IIIA-IVB). Univariate survival analysis included the study of Kaplan-Meier curves with the Log-Rank test, while Cox regression was used as a multivariate analysis.
RESULTS: Multivariate analysis showed shorter PFS for T carriers [HR=2.0, 95% CI, 1.4-3.0, p<0.0001] and shorter OS [HR=1.8, 95% CI, 1.1-3.0, p=0.017] globally, as well as in a subgroup of patients (n=144) treated with first line platinum-based chemotherapy [HR=2.0, 95% CI, 1.3-3.1, p=0.001] and [HR=1.8, 95% CI, 1.1-3.1, p=0.026], respectively.
CONCLUSION: This polymorphism seems to have an impact on NSCLC progression, opening new perspectives for its inclusion as a pharmacogenetic predictor of response to platinum-based chemotherapy.

PMID: 33408043 [PubMed - as supplied by publisher]

RNA-Based Assay for Next-Generation Sequencing of Clinically Relevant Gene Fusions in Non-Small Cell Lung Cancer.

Cancers (Basel). 2021 Jan 04;13(1):

Authors: De Luca C, Pepe F, Iaccarino A, Pisapia P, Righi L, Listì A, Greco L, Gragnano G, Campione S, De Dominicis G, Pagni F, Sgariglia R, Nacchio M, Tufano R, Conticelli F, Vigliar E, Bellevicine C, Cortinovis DL, Novello S, Molina-Vila MA, Rosell R, Troncone G, Malapelle U

Abstract
Gene fusions represent novel predictive biomarkers for advanced non-small cell lung cancer (NSCLC). In this study, we validated a narrow NGS gene panel able to cover therapeutically-relevant gene fusions and splicing events in advanced-stage NSCLC patients. To this aim, we first assessed minimal complementary DNA (cDNA) input and the limit of detection (LoD) in different cell lines. Then, to evaluate the feasibility of applying our panel to routine clinical samples, we retrospectively selected archived lung adenocarcinoma histological and cytological (cell blocks) samples. Overall, our SiRe RNA fusion panel was able to detect all fusions and a splicing event harbored in a RNA pool diluted up to 2 ng/µL. It also successfully analyzed 46 (95.8%) out of 48 samples. Among these, 43 (93.5%) out of 46 samples reproduced the same results as those obtained with conventional techniques. Intriguingly, the three discordant results were confirmed by a CE-IVD automated real-time polymerase chain reaction (RT-PCR) analysis (Easy PGX platform, Diatech Pharmacogenetics, Jesi, Italy). Based on these findings, we conclude that our new SiRe RNA fusion panel is a valid and robust tool for the detection of clinically relevant gene fusions and splicing events in advanced NSCLC.

PMID: 33406752 [PubMed]

Definition of Personalized Medicine and Targeted Therapies: Does Medical Familiarity Matter?

J Pers Med. 2021 Jan 04;11(1):

Authors: Fournier V, Prebet T, Dormal A, Brunel M, Cremer R, Schiaratura L

Abstract
Personalized medicine (PM) is increasingly becoming a topic of discussion in public health policies and media. However, there is no consensus among definitions of PM in the scientific literature and the terms used to designate it, with some definitions emphasizing patient-centered aspects and others emphasizing biomedical aspects. Furthermore, terms used to refer to PM (e.g., "pharmacogenomics" or, more often, "targeted therapies") are diverse and differently used. To our knowledge, no study has apprehended the differences of definition and attitudes toward personalized medicine and targeted therapies according to level of familiarity with the medical field. Our cohort included 349 French students from three different academic fields, which modulated their familiarity level with the medical field. They were asked to associate words either to "personalized medicine" or "target therapies". Then, they were asked to give an emotional valence to their associations. Results showed that nonfamiliar students perceived PM as more positive than targeted therapies (TT), whereas familiar students showed no difference. Only familiar students defined PM and TT with technical aspects such as genetics or immunology. Further studies are needed in the field in order to determine which other factors could influence the definitions of PM and TT and determine how these definitions could have an impact in a clinical setting.

PMID: 33406631 [PubMed]

COVID-19 and Renin Angiotensin Aldosterone System: A Pharmacogenomic View.

Am J Ther. 2021 Jan-Feb 01;28(1):e136-e139

Authors: El Desoky ES

PMID: 33369911 [PubMed - indexed for MEDLINE]

Therapeutic drug monitoring of antiepileptic drugs: current status and future prospects.

Expert Opin Drug Metab Toxicol. 2020 Mar;16(3):227-238

Authors: Johannessen Landmark C, Johannessen SI, Patsalos PN

Abstract
Introduction: Antiepileptic drugs (AEDs) are the cornerstone of treatment of patients with epilepsy, and there are presently 27 licensed AEDs making AEDs among the most common medications for which therapeutic drug monitoring (TDM) is performed. The aim of this review is to provide an overview of the current evidence of the use and implementation of AED TDM in patients with epilepsy and other non-epilepsy conditions.Areas covered: The pharmacokinetic variability of AEDs is extensive, resulting in pronounced variability in serum concentrations between patients. TDM may thus be useful to individualize the treatment of patients with epilepsy and also in non-epilepsy conditions. Indications for TDM include settings where pharmacokinetic variability is anticipated (e.g. in children, the elderly, during pregnancy, and patients prescribed polytherapy resulting in drug interactions) and drug adherence. TDM contributes to provide a quality assurance of the treatment. Patient management is, therefore, best guided by the determination of individual therapeutic concentrations.Expert opinion: Because of pharmacokinetic variability is prevalent among AEDs, TDM allows a bespoke approach to epilepsy care allowing dose adjustments based on measured drug concentrations so as to optimize clinical outcome. Future advances include the use of additional markers of toxicity and genetic variability so as to further aid individualization and optimize AED treatment.

PMID: 32054370 [PubMed - indexed for MEDLINE]

Veterans Affairs Pharmacogenomic Testing for Veterans (PHASER) clinical program.

Pharmacogenomics. 2021 Jan 06;:

Authors: Dong OM, Bates J, Chanfreau-Coffinier C, Naglich M, Kelley MJ, Meyer LJ, Icardi M, Vassy JL, Sriram P, Heise CW, Rivas S, Ribeiro M, Jacobitz R, Rozelle S, Chapman JG, Voora D

Abstract
In 2019, the Veterans Affairs (VA), the largest integrated US healthcare system, started the Pharmacogenomic Testing for Veterans (PHASER) clinical program that provides multi-gene pharmacogenomic (PGx) testing for up to 250,000 veterans at approximately 50 sites. PHASER is staggering program initiation at sites over a 5-year period from 2019 to 2023, as opposed to simultaneous initiation at all sites, to facilitate iterative program quality improvements through Plan-Do-Study-Act cycles. Current resources in the PGx field have not focused on multisite, remote implementation of panel-based PGx testing. In addition to bringing large scale PGx testing to veterans, the PHASER program is developing a roadmap to maximize uptake and optimize the use of PGx to improve drug response outcomes.

PMID: 33403869 [PubMed - as supplied by publisher]

Usefulness of Plasma SARS-CoV-2 RNA Quantification by Droplet-based Digital PCR to Monitor Treatment Against COVID-19 in a B-cell Lymphoma Patient.

Stem Cell Rev Rep. 2021 Jan 05;:

Authors: Szwebel TA, Veyer D, Robillard N, Eshagh D, Canoui E, Bruneau T, Contejean A, Azoulay C, Serrano T, Hueso T, Izquierdo L, Rozenberg F, Terrier B, Vignon M, Laurent-Puig P, Taly V, Bélec L, Kernéis S, Lacombe K, Péré H

Abstract
We report the case of an HIV-1-infected patient, treated with anti-CD20 monoclonal antibody for a B-cell lymphoma previously treated by autologous stem cell transplant. He suffered from chronic COVID19 and we monitored by plasma SARS-CoV-2 RNA by highly sensitive droplet-based digital PCR technology (ddPCR). Under tocilizumab therapy and despite a first clinical improvement biologically associated with decreasing inflammatory markers, a slight increase of SARS-CoV-2 RNAaemia quantified by ddPCR was highlighted, confirming the absence of viral efficacy of this treatment and predicting the subsequent observed deterioration. As expected, his complete recovery, finally achieved after COVID-19 convalescent plasmatherapy, strictly paralleled plasma SARS-CoV-2 RNA clearance. With these results, we confirmed the interest of SARS-CoV-2 RNAaemia monitoring by ddPCR in COVID-19 patients, particularly during treatment, and firstly showed that this new and specific biomarker could be helpful to select eligible patient for anti-IL6 receptors therapy considering the variable levels of efficacy recently observed with such therapy.

PMID: 33403488 [PubMed - as supplied by publisher]

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Nat Commun. 2021 01 05;12(1):24

Authors: Lagou V, Mägi R, Hottenga JJ, Grallert H, Perry JRB, Bouatia-Naji N, Marullo L, Rybin D, Jansen R, Min JL, Dimas AS, Ulrich A, Zudina L, Gådin JR, Jiang L, Faggian A, Bonnefond A, Fadista J, Stathopoulou MG, Isaacs A, Willems SM, Navarro P, Tanaka T, Jackson AU, Montasser ME, O'Connell JR, Bielak LF, Webster RJ, Saxena R, Stafford JM, Pourcain BS, Timpson NJ, Salo P, Shin SY, Amin N, Smith AV, Li G, Verweij N, Goel A, Ford I, Johnson PCD, Johnson T, Kapur K, Thorleifsson G, Strawbridge RJ, Rasmussen-Torvik LJ, Esko T, Mihailov E, Fall T, Fraser RM, Mahajan A, Kanoni S, Giedraitis V, Kleber ME, Silbernagel G, Meyer J, Müller-Nurasyid M, Ganna A, Sarin AP, Yengo L, Shungin D, Luan J, Horikoshi M, An P, Sanna S, Boettcher Y, Rayner NW, Nolte IM, Zemunik T, Iperen EV, Kovacs P, Hastie ND, Wild SH, McLachlan S, Campbell S, Polasek O, Carlson O, Egan J, Kiess W, Willemsen G, Kuusisto J, Laakso M, Dimitriou M, Hicks AA, Rauramaa R, Bandinelli S, Thorand B, Liu Y, Miljkovic I, Lind L, Doney A, Perola M, Hingorani A, Kivimaki M, Kumari M, Bennett AJ, Groves CJ, Herder C, Koistinen HA, Kinnunen L, Faire U, Bakker SJL, Uusitupa M, Palmer CNA, Jukema JW, Sattar N, Pouta A, Snieder H, Boerwinkle E, Pankow JS, Magnusson PK, Krus U, Scapoli C, de Geus EJCN, Blüher M, Wolffenbuttel BHR, Province MA, Abecasis GR, Meigs JB, Hovingh GK, Lindström J, Wilson JF, Wright AF, Dedoussis GV, Bornstein SR, Schwarz PEH, Tönjes A, Winkelmann BR, Boehm BO, März W, Metspalu A, Price JF, Deloukas P, Körner A, Lakka TA, Keinanen-Kiukaanniemi SM, Saaristo TE, Bergman RN, Tuomilehto J, Wareham NJ, Langenberg C, Männistö S, Franks PW, Hayward C, Vitart V, Kaprio J, Visvikis-Siest S, Balkau B, Altshuler D, Rudan I, Stumvoll M, Campbell H, van Duijn CM, Gieger C, Illig T, Ferrucci L, Pedersen NL, Pramstaller PP, Boehnke M, Frayling TM, Shuldiner AR, Peyser PA, Kardia SLR, Palmer LJ, Penninx BW, Meneton P, Harris TB, Navis G, Harst PV, Smith GD, Forouhi NG, Loos RJF, Salomaa V, Soranzo N, Boomsma DI, Groop L, Tuomi T, Hofman A, Munroe PB, Gudnason V, Siscovick DS, Watkins H, Lecoeur C, Vollenweider P, Franco-Cereceda A, Eriksson P, Jarvelin MR, Stefansson K, Hamsten A, Nicholson G, Karpe F, Dermitzakis ET, Lindgren CM, McCarthy MI, Froguel P, Kaakinen MA, Lyssenko V, Watanabe RM, Ingelsson E, Florez JC, Dupuis J, Barroso I, Morris AP, Prokopenko I, Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC)

Abstract
Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.

PMID: 33402679 [PubMed - in process]

Corrigendum to "Role of senescence marker p16INK4A measured in peripheral blood T-lymphocytes in predicting length of hospital stay after coronary artery bypass surgery in older adults" [Exp. Gerontol. 74 (2016) 29-36].

Exp Gerontol. 2021 Jan 02;:111217

Authors: Pustavoitau A, Barodka V, Sharpless NE, Torrice C, Nyhan D, Berkowitz DE, Shah AS, Bandeen Roche KJ, Walston J

PMID: 33402297 [PubMed - as supplied by publisher]

Exploring pharmacogenetics of paclitaxel- and docetaxel-induced peripheral neuropathy by evaluating the direct pharmacogenetic-pharmacokinetic and pharmacokinetic-neuropathy relationships.

Expert Opin Drug Metab Toxicol. 2021 Jan 06;:1-13

Authors: Hertz DL

Abstract
Introduction: Peripheral neuropathy (PN) is an adverse effect of several classes of chemotherapy including the taxanes. Predictive PN biomarkers could inform individualized taxane treatment to reduce PN and enhance therapeutic outcomes. Pharmacogenetics studies of taxane-induced PN have focused on genes involved in pharmacokinetics, including enzymes and transporters. Contradictory findings from these studies prevent translation of genetic biomarkers into clinical practice. Areas covered: This review discusses the progress toward identifying pharmacogenetic predictors of PN by assessing the evidence for two independent associations; the effect of pharmacogenetics on taxane pharmacokinetics and the evidence that taxane pharmacokinetics affects PN. Assessing these direct relationships allows the reader to understand the progress toward individualized taxane treatment and future research opportunities. Expert opinion: Paclitaxel pharmacokinetics is a major determinant of PN. Additional clinical trials are needed to confirm the clinical benefit of individualized dosing to achieve target paclitaxel exposure. Genetics does not meaningfully contribute to paclitaxel pharmacokinetics and may not be useful to inform dosing. However, genetics may contribute to PN sensitivity and could be useful for estimating patients' optimal paclitaxel exposure. For docetaxel, genetics has not been demonstrated to have a meaningful effect on pharmacokinetics and there is no evidence that pharmacokinetics determines PN.

PMID: 33401943 [PubMed - as supplied by publisher]