Cancers (Basel). 2021 Feb 25;13(5):966. doi: 10.3390/cancers13050966.

ABSTRACT

Cytarabine is a pyrimidine nucleoside analog, commonly used in multiagent chemotherapy regimens for the treatment of leukemia and lymphoma, as well as for neoplastic meningitis. Ara-C-based chemotherapy regimens can induce a suboptimal clinical outcome in a fraction of patients. Several studies suggest that the individual variability in clinical response to Leukemia & Lymphoma treatments among patients, underlying either Ara-C mechanism resistance or toxicity, appears to be associated with the intracellular accumulation and retention of Ara-CTP due to genetic variants related to metabolic enzymes. Herein, we reported (a) the latest Pharmacogenomics biomarkers associated with the response to cytarabine and (b) the new drug formulations with optimized pharmacokinetics. The purpose of this review is to provide readers with detailed and comprehensive information on the effects of Ara-C-based therapies, from biological to clinical practice, maintaining high the interest of both researcher and clinical hematologist. This review could help clinicians in predicting the response to cytarabine-based treatments.

PMID:33669053 | DOI:10.3390/cancers13050966

Molecules. 2021 Feb 13;26(4):993. doi: 10.3390/molecules26040993.

ABSTRACT

In this study, a complex consisting of 2-hydroxypropyl-β-cyclodextrin and 5,10,15,20-tetrakis (4-hydroxyphenyl) porphyrin, (named dual chiral-achiral selector complex) was used for the determination of two novel potential anticancer agents of (I) and (II) aminoalkanol derivatives. This work aimed at developing an effective method that can be utilized for the determination of I (S), I (R), and II (S) and II (R) enantiomers of (I) and (II) compounds through the use of a dual chiral-achiral selector complex consisting of hydroxypropyl-β-cyclodextrin and 5,10,15,20-tetrakis (4-hydroxyphenyl) porphyrin system by applying capillary electrophoresis. This combination proved to be beneficial in achieving high separation selectivity due to the combined effects of different modes of chiral discrimination. The enantiomers of (I) and (II) compounds were separated within a very short time of 3.6-7.2 min, in pH 2.5 phosphate buffer containing 2-hydroxypropyl-β-cyclodextrin and 5,10,15,20-tetrakis (4-hydroxyphenyl) porphyrin system at a concentration of 5 and 10 mM, respectively, at 25 °C and +10 kV. The detection wavelength of the detector was set at 200 nm. The LOD for I (S), I (R), II (S), and II (R) was 65.2, 65.6, 65.1, and 65.7 ng/mL, respectively. LOQ for I (S), I (R), II (S), and II (R) was 216.5, 217.8, 217.1, and 218.1 ng/mL, respectively. Recovery was 94.9-99.9%. The repeatability and reproducibility of the method based on the values of the migration time, and the area under the peak was 0.3-2.9% RSD. The stability of the method was determined at 0.1-4.9% RSD. The developed method was used in the pilot studies for determining the enantiomers I (S), I (R), II (S), and II (R) in the blood serum.

PMID:33668491 | DOI:10.3390/molecules26040993

Am J Cardiol. 2021 Mar 2:S0002-9149(21)00202-2. doi: 10.1016/j.amjcard.2021.02.027. Online ahead of print.

ABSTRACT

Major adverse cardiac event (MACE) and bleeding risks following percutaneous coronary intervention (PCI) for acute coronary syndromes (ACS) are not well defined in individuals with heart failure (HF). We followed 1,145 individuals in the Pharmacogenomic Resource to improve Medication Effectiveness Genotype Guided Antiplatelet Therapy cohort for MACE and bleeding events following PCI for ACS. We constructed Cox proportional hazards models to compare MACE and bleeding in those with vs. without HF, adjusting for sociodemographics, comorbidities, and medications. We also determined predictors of MACE and bleeding events in both groups. 370 (32%) individuals did and 775 (68%) did not have HF prior to PCI. Mean age was 61.7 ± 12.2 years, 31% were female, and 24% were African American. After a median follow-up of 0.78 years, individuals with HF had higher rates of MACE compared to those without HF (48 vs. 24 events per 100 person years) which remained significant after multivariable adjustment (hazard ratio [HR] 1.31, 95% confidence interval [CI] 1.00-1.72). Similarly, bleeding was higher in those with vs. without HF (22 vs. 11 events per 100 person years), although this was no longer statistically significant after multivariable adjustment (HR 1.29, 95% CI 0.86-1.93). Diabetes and peripheral vascular disease were predictors of MACE, and ESRD was a predictor of bleeding among participants with HF. MACE risk is higher in individuals with vs. without HF following PCI for ACS. However, the risk of bleeding, especially among those with ESRD, must be considered when determining post-PCI anticoagulant strategies.

PMID:33667441 | DOI:10.1016/j.amjcard.2021.02.027

Clin Pharmacol Ther. 2021 Mar 5. doi: 10.1002/cpt.2193. Online ahead of print.

NO ABSTRACT

PMID:33667324 | DOI:10.1002/cpt.2193

Curr Hypertens Rep. 2021 Mar 5;23(3):14. doi: 10.1007/s11906-021-01131-y.

ABSTRACT

PURPOSE OF REVIEW: Hypertension is remarkably prevalent, affecting an estimated 1.13 billion people worldwide. It often requires the use of multi-drug regimens and is commonly associated with a myriad of other comorbidities which increase medication use. The pervasive use of antihypertensive medications combined with the presence of polypharmacy in many hypertensive patients results in significant risk of drug interactions. This review will summarize the relevant literature to assist clinicians in mitigating drug interaction risks when prescribing antihypertensives.

RECENT FINDINGS: Pharmacokinetic interactions affect drug disposition in the body and can occur at the steps of absorption, distribution, metabolism, or elimination of involved medications. Data has established the calcium channel blockers, namely, diltiazem and verapamil, as potent inhibitors of CYP3A4, and the majority of significant drug interactions involving antihypertensives are attributable to these two agents. Although less common, pharmacokinetic drug interactions with other antihypertensive classes have also been identified. Pharmacodynamic drug interactions with antihypertensives lead to synergy or antagonism of blood pressure lowering effects and can increase or mitigate adverse effects depending on the agents involved. Knowledge is emerging about drug-induced phenoconversion, a phenomenon whereby a drug interaction results in a drug metabolizing phenotype that is different than that predicted by an individual's genotype. Antihypertensive use in patients with comorbidities and polypharmacy increases the likelihood of encountering important drug-drug interactions. Dedicated efforts to better understand the relationship between pharmacokinetic drug interactions and pharmacogenomic information is important to advance efforts related to personalized medicine.

PMID:33666764 | DOI:10.1007/s11906-021-01131-y

Pharmacogenomics. 2021 Mar 5. doi: 10.2217/pgs-2020-0145. Online ahead of print.

ABSTRACT

Evaluating genes involved in the pharmacodynamics and pharmacokinetics of epilepsy drugs is critical to better understand pharmacoresistant epilepsy. We reviewed the pharmacogenetics literature on six antiseizure medicines (carbamazepine, perampanel, lamotrigine, levetiracetam, sodium valproate and zonisamide) and compared the genes found with those present on epilepsy gene panels using a functional annotation pathway analysis. Little overlap was found between the two gene lists; pharmacogenetic genes are mainly involved in detoxification processes, while epilepsy panel genes are involved in cell signaling and gene expression. Our work provides support for a specific pharmacoresistant epilepsy gene panel to assist antiseizure medicine selection, enabling personalized approaches to treatment. Future efforts will seek to include this panel in genomic analyses of pharmacoresistant patients, to determine clinical utility and patient treatment responses.

PMID:33666520 | DOI:10.2217/pgs-2020-0145

Basic Clin Pharmacol Toxicol. 2021 Mar 4. doi: 10.1111/bcpt.13578. Online ahead of print.

ABSTRACT

Predictive biomarkers play an important role in our efforts to individualize pharmacotherapy and within recent years, a number of different types of assays have been introduced. These biomarkers may potentially support the selection and dosage of specific drugs in order to maximize efficacy and minimize adverse reactions in the individual patient. However, in many instances, the scientific and clinical evidence is insufficient to support the prescribing decision. When predictive biomarkers are used to guide pharmacotherapy, it is important to secure that decisions are based on solid clinical evidence. Here, the regulatory authorities, especially the FDA have been at the forefront in relation to regulate this type of biomarker assay in order to secure patient safety. The approval process for companion diagnostics is an example of this effort, where the scientific validity of the biomarker and assay is in focus. With the approaching implementation of the new IVD Regulation, greater attention will also be paid to analytical and clinical validity of biomarker assays in the EU. For any type of predictive biomarker assay, including pharmacogenetic and tumour profiling tests, the clinical evidence needs to be in place before they are used routinely in the clinic.

PMID:33665955 | DOI:10.1111/bcpt.13578

Ann Oncol. 2021 Mar 1:S0923-7534(21)00160-5. doi: 10.1016/j.annonc.2021.02.020. Online ahead of print.

NO ABSTRACT

PMID:33662499 | DOI:10.1016/j.annonc.2021.02.020

Fac Rev. 2020 Dec 23;9:30. doi: 10.12703/r/9-30. eCollection 2020.

ABSTRACT

This article reviews recent advances in the genetics of obsessive-compulsive disorder (OCD). We cover work on the following: genome-wide association studies, whole-exome sequencing studies, copy number variation studies, gene expression, polygenic risk scores, gene-environment interaction, experimental animal systems, human cell models, imaging genetics, pharmacogenetics, and studies of endophenotypes. Findings from this work underscore the notion that the genetic architecture of OCD is highly complex and shared with other neuropsychiatric disorders. Also, the latest evidence points to the participation of gene networks involved in synaptic transmission, neurodevelopment, and the immune and inflammatory systems in this disorder. We conclude by highlighting that further study of the genetic architecture of OCD, a great part of which remains to be elucidated, could benefit the development of diagnostic and therapeutic approaches based on the biological basis of the disorder. Studies to date revealed that OCD is not a simple homogeneous entity, but rather that the underlying biological pathways are variable and heterogenous. We can expect that translation from bench to bedside, through continuous effort and collaborative work, will ultimately transform our understanding of what causes OCD and thus how best to treat it.

PMID:33659962 | PMC:PMC7886082 | DOI:10.12703/r/9-30

Bio Protoc. 2020 Sep 20;10(18):e3755. doi: 10.21769/BioProtoc.3755. eCollection 2020 Sep 20.

ABSTRACT

Induced pluripotent stem cell derived cardiovascular progenitor cells (iPSC-CVPCs) provide an unprecedented platform for examining the molecular underpinnings of cardiac development and disease etiology, but also have great potential to play pivotal roles in the future of regenerative medicine and pharmacogenomic studies. Biobanks like iPSCORE ( Stacey et al., 2013 ; Panopoulos et al., 2017 ), which contain iPSCs generated from hundreds of genetically and ethnically diverse individuals, are an invaluable resource for conducting these studies. Here, we present an optimized, cost-effective and highly standardized protocol for large-scale derivation of human iPSC-CVPCs using small molecules and purification using metabolic selection. We have successfully applied this protocol to derive iPSC-CVPCs from 154 different iPSCORE iPSC lines obtaining large quantities of highly pure cardiac cells. An important component of our protocol is Cell confluency estimates (ccEstimate), an automated methodology for estimating the time when an iPSC monolayer will reach 80% confluency, which is optimal for initiating iPSC-CVPC derivation, and enables the protocol to be readily used across iPSC lines with different growth rates. Moreover, we showed that cellular heterogeneity across iPSC-CVPCs is due to varying proportions of two distinct cardiac cell types: cardiomyocytes (CMs) and epicardium-derived cells (EPDCs), both of which have been shown to have a critical function in heart regeneration. This protocol eliminates the need of iPSC line-to-line optimization and can be easily adapted and scaled to high-throughput studies or to generate large quantities of cells suitable for regenerative medicine applications.

PMID:33659414 | PMC:PMC7853936 | DOI:10.21769/BioProtoc.3755

Front Pharmacol. 2021 Feb 15;12:631793. doi: 10.3389/fphar.2021.631793. eCollection 2021.

ABSTRACT

The role of organic cation transporter 1 (OCT1) in humans is gaining attention as data emerges regarding its role in physiology, drug exposure, and drug response. OCT1 variants with decreased in vitro function correlate well with altered exposure of multiple OCT1 substrates in variant carriers. In the current research, we investigate mechanisms behind activity of OCT1 variants in vitro by generating cell lines expressing known OCT1 variants and quantifying membrane OCT1 protein expression with corresponding OCT1 activity and kinetics. Oct knockout mice have provided additional insight into the role of Oct1 in the liver and have reproduced effects of altered OCT1 activity observed in the clinic. To assess the complex effect of Oct1 depletion on pharmacokinetics of prodrug proguanil and its active moiety cycloguanil, both of which are OCT1 substrates, Oct1/2-/- mice were used. Decreased membrane expression of OCT1 was demonstrated for all variant cell lines, although activity was substrate-dependent, as reported previously. Lack of change in activity for OCT1*2 resulted in increased intrinsic activity per pmol of OCT1 protein, particularly for sumatriptan but also for proguanil and cycloguanil. Similar to that reported in humans with decreased OCT1 function, systemic exposure of proguanil was minimally affected in Oct1/2-/- mice. However, proguanil liver partitioning and exposure decreased. Cycloguanil exposure decreased following proguanil administration in Oct1/2-/- mice, as did the systemic metabolite:parent ratio. When administered directly, systemic exposure of cycloguanil decreased slightly; however liver partitioning and exposure were decreased in Oct1/2-/- mice. Unexpectedly, following proguanil administration, the metabolite ratio in the liver changed only minimally, and liver partitioning of cycloguanil was affected in Oct1/2-/- mice to a lesser extent following proguanil administration than direct administration of cycloguanil. In conclusion, these in vitro and in vivo data offer additional complexity in understanding mechanisms of OCT1 variant activity as well as the effects of these variants in vivo. From cell lines, it is apparent that intrinsic activity is not directly related to OCT1 membrane expression. Additionally, in situations with a more complicated role of OCT1 in drug pharmacokinetics there is difficulty translating in vivo impact simply from intrinsic activity from cellular data.

PMID:33658943 | PMC:PMC7917185 | DOI:10.3389/fphar.2021.631793

Front Pharmacol. 2021 Feb 9;11:587590. doi: 10.3389/fphar.2020.587590. eCollection 2020.

ABSTRACT

Metformin used as a first-line drug to treat Type 2 Diabetes Mellitus is transported via organic cation channels to soft tissues. Mutations in the SLC22A1 gene, such as Gly401Ser, Ser189Leu, and Arg206Cys, may affect the drug's therapeutic effect on these patients. This study aims at proposing a potential structural model for drug interactions with the hOCT1 transporter, as well as the impact of these mutations at both topological and electronic structure levels on the channel's surface, from a chemical point of view with, in addition to exploring the frequency distribution. To chemically understand metformin diffusion, we used an open model from the protein model database, with ID PM0080367, viewed through UCSF Chimera. The effect of the mutations was assessed using computational hybrid Quantum Mechanics/Molecular Mechanics, based on the Austin Model 1 semi-empirical method using Spartan 18' software. The results demonstrate coupling energy for metformin with amino acids F, W, H and Y, because of the interaction between the metformin dication and the electron cloud of π orbitals. The mutations analyzed showed changes in the chemical polarity and topology of the structure. The proposed diffusion model is a possible approach to the interaction mechanism between metformin and its transporter, as well as the impacts of variants, suggesting structural changes in the action of the drug. Metformin efficacy considerably varies from one patient to another; this may be largely attributed to the presence of mutations on the SLC22A1 gene. This study aims at proposing a potential structural model for metformin-hOCT1 (SLC22A1) transporter interaction, as well as the identification of the effect of mutations G401S (rs34130495), S189L (rs34104736), and R206C (616C > T) of the SLC22A1 gene at the topological and electronic structure levels on the channel surfaces, from a chemical viewpoint. Our results demonstrated that the coupling energies for metformin with aromatic amino acids F, W, H and Y, because of the interaction between the metformin dication and the electron cloud of π orbitals. Changes in the chemical environment's polarity and the structure's topology were reported in the mutations assessed. The diffusion model proposed is a potential approach for the mechanism of interaction of metformin with its transporter and the effects of variants on the efficacy of the drug in the treatment of type 2 diabetes. The assessment of the frequency of these mutations in a sample of Colombian type 2 diabetes patients suggests that different SLC22A1 gene variants might be involved in reduced OCT1 activity in the Colombian population since none of these mutations were detected.

PMID:33658930 | PMC:PMC7917475 | DOI:10.3389/fphar.2020.587590

Sci Rep. 2021 Mar 3;11(1):5038. doi: 10.1038/s41598-021-83996-2.

ABSTRACT

GSTA1 encodes a member of a family of enzymes that function to add glutathione to target electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins, and products of oxidative stress. GSTA1 has several functional SNPs within its promoter region that are responsible for a change in its expression by altering promoter function. This study aims to investigate distributions of GSTA1 promoter haplotypes across different human populations and to assess their impact on the expression of GSTA1. PHASE 2.1.1 was used to infer haplotypes and diplotypes of six GSTA1 promoter SNPs on 2501 individuals from 26 populations classified by the 1000 Genomes Project into five super-populations that included Africa (N = 660), America (N = 347), East Asia (N = 504), Europe (N = 502), and South Asia (N = 488). We used pairwise FST analysis to compare sub-populations and luciferase reporter assay (LRA) to evaluate the impact of each SNP on activation of transcription and interaction with other SNPs. The distributions of GSTA1 promoter haplotypes and diplotypes were significantly different among the different human populations. Three new promoter haplotypes were found in the African super-population. LRA demonstrated that SNPs at -52 and -69 has the most impact on GSTA1 expression, however other SNPs have a significant impact on transcriptional activity. Based on LRA, a new model of cis-elements interaction is presented. Due to the significant differences in GSTA1 diplotype population frequencies, future pharmacogenomics or disease-related studies would benefit from the inclusion of the complete GSTA1 promoter haplotype based on the newly proposed metabolic grouping derived from the LRA results.

PMID:33658540 | DOI:10.1038/s41598-021-83996-2

Lupus Sci Med. 2021 Mar;8(1):e000428. doi: 10.1136/lupus-2020-000428.

ABSTRACT

OBJECTIVE: Punch biopsy, a standard diagnostic procedure for patients with cutaneous lupus erythematosus (CLE) carries an infection risk, is invasive, uncomfortable and potentially scarring, and impedes patient recruitment in clinical trials. Non-invasive tape sampling is an alternative that could enable serial evaluation of specific lesions. This cross-sectional pilot research study evaluated the use of a non-invasive adhesive tape device to collect messenger RNA (mRNA) from the skin surface of participants with CLE and healthy volunteers (HVs) and investigated its feasibility to detect biologically meaningful differences between samples collected from participants with CLE and samples from HVs.

METHODS: Affected and unaffected skin tape samples and simultaneous punch biopsies were collected from 10 participants with CLE. Unaffected skin tape and punch biopsies were collected from 10 HVs. Paired samples were tested using quantitative PCR for a candidate immune gene panel and semi-quantitative immunohistochemistry for hallmark CLE proteins.

RESULTS: mRNA collected using the tape device was of sufficient quality for amplification of 94 candidate immune genes. Among these, we found an interferon (IFN)-dominant gene cluster that differentiated CLE-affected from HV (23-fold change; p<0.001) and CLE-unaffected skin (sevenfold change; p=0.002), respectively. We found a CLE-associated gene cluster that differentiated CLE-affected from HV (fourfold change; p=0.005) and CLE-unaffected skin (fourfold change; p=0.012), respectively. Spearman's correlation between per cent area myxovirus 1 protein immunoreactivity and IFN-dominant mRNA gene cluster expression was highly significant (dermis, rho=0.86, p<0.001). In total, skin tape-derived RNA expression comprising both IFN-dominant and CLE-associated gene clusters correlated with per cent area immunoreactivity of some hallmark CLE-associated proteins in punch biopsies from the same lesions.

CONCLUSIONS: A non-invasive tape RNA collection technique is a potential tool for repeated skin biomarker measures throughout a clinical trial.

PMID:33658303 | DOI:10.1136/lupus-2020-000428

Drug Metab Dispos. 2021 Mar 3:DMD-AR-2020-000264. doi: 10.1124/dmd.120.000264. Online ahead of print.

ABSTRACT

SLCO1B1 is an important transmembrane hepatic uptake transporter. Genetic variants in the SLCO1B1 gene have been associated with altered protein folding, resulting in protein degradation and decreased transporter activity. Next-Generation Sequencing (NGS) of pharmacogenes is being applied increasingly to associate variation in drug response with genetic sequence variants. However, it is difficult to link variants of unknown significance with functional phenotypes using "one-at-a-time" functional systems. Deep mutational scanning (DMS) using a "landing pad cell-based system" is a high-throughput technique designed to analyze hundreds of gene open reading frame (ORF) missense variants in a parallel and scalable fashion. We have applied DMS to analyze 137 missense variants in the SLCO1B1 ORF obtained from the ExAC Project. ORFs containing these variants were fused to green fluorescent protein and were integrated into "landing pad" cells. Florescence-activated cell sorting was performed to separate the cells into four groups based on fluorescence readout indicating protein expression at the single cell level. NGS was then performed and SLCO1B1 variant frequencies were used to determine protein abundance. We found that six variants not previously characterized functionally displayed less than 25% and another twelve displayed approximately 50% of wild-type protein expression. These results were then functionally validated by transporter studies. Severely damaging variants identified by DMS may have clinical relevance for SLCO1B1-dependent drug transport but we need to exercise caution since the relatively small number of severely damaging variants identified raise questions with regard to the application of DMS to intrinsic membrane proteins such as OATP1B1 Significance Statement The functional implications of a large numbers of ORF "variants of unknown significance" (VUS) in transporter genes have not been characterized. This study applied deep mutational scanning to determine the functional effects of VUS that have been observed in the ORF of SLCO1B1 Several severely damaging variants were identified, studied and validated. These observations have implications for both the application of DMS to intrinsic membrane proteins and for the clinical effect of drugs and endogenous compounds transported by SLCO1B1.

PMID:33658230 | DOI:10.1124/dmd.120.000264

Pharmacogenomics. 2021 Mar 4. doi: 10.2217/pgs-2020-0112. Online ahead of print.

ABSTRACT

Aim: To assess providers' knowledge, attitudes, perceptions, and experiences related to pharmacogenomic (PGx) testing in pediatric patients. Materials & methods: An electronic survey was sent to multidisciplinary healthcare providers at a pediatric hospital. Results: Of 261 respondents, 71.3% were slightly or not at all familiar with PGx, despite 50.2% reporting prior PGx education or training. Most providers, apart from psychiatry, perceived PGx to be at least moderately useful to inform clinical decisions. However, only 26.4% of providers had recent PGx testing experience. Unfamiliarity with PGx and uncertainty about the clinical value of testing were common perceived challenges. Conclusion: Low PGx familiarity among pediatric providers suggests additional education and electronic resources are needed for PGx examples in which data support testing in children.

PMID:33657875 | DOI:10.2217/pgs-2020-0112

J Dermatolog Treat. 2021 Mar 3:1-23. doi: 10.1080/09546634.2021.1898526. Online ahead of print.

ABSTRACT

Psoriasis is a chronic disorder with increasing new treatments targeting the T-helper cell (Th)-1/Th17 axis. There remains a subset of patients who experience a primary or secondary failure to biologic treatments. We present ten patients with psoriasis who failed biologic therapy with measurement of serum drug levels and anti-drug antibody levels (ADAs) with review of the current literature. Our objective was to identify demographic factors, disease status, drug level and ADAs which might correlate with primary and secondary failure. There are a number of factors affecting drug levels in patients with psoriasis on biologics including the presence of ADAs, patient adherence to treatment regimes, pharmacogenetics and the pharmacokinetic properties of the drug following subcutaneous injection. Our results demonstrate that biologic failure is related to low serum drug levels subtherapeutic in 80% of our cohort. Primary failure may correlate with the presence of ADAs but not with serum drug levels. All patients were ANA negative and there remains considerable debate on the utility of routine ANA testing. The role of therapeutic drug monitoring in dermatology remains uncertain and requires further study. We aim to promote debate in the dermatology community as to the utility of therapeutic drug monitoring in routine practice.

PMID:33656955 | DOI:10.1080/09546634.2021.1898526

Sci Rep. 2021 Mar 2;11(1):4977. doi: 10.1038/s41598-021-83696-x.

ABSTRACT

Cytochrome P450 1A2 (CYP1A2) is one of the main hepatic CYPs involved in metabolism of carcinogens and clinically used drugs. Nonsynonymous single nucleotide polymorphisms (nsSNPs) of this enzyme could affect cancer susceptibility and drug efficiency. Hence, identification of human CYP1A2 pathogenic nsSNPs could be of great importance in personalized medicine and pharmacogenetics. Here, 176 nsSNPs of human CYP1A2 were evaluated using a variety of computational tools, of which 18 nsSNPs were found to be associated with pathogenicity. Further analysis suggested possible association of 9 nsSNPs (G73R, G73W, R108Q, R108W, E168K, E346K, R431W, F432S and R456H) with the risk of hepatocellular carcinoma. Molecular dynamics simulations revealed higher overall flexibility, decreased intramolecular hydrogen bonds and lower content of regular secondary structures for both cancer driver variants G73W and F432S when compared to the wild-type structure. In case of F432S, loss of the conserved hydrogen bond between Arg137 and heme propionate oxygen may affect heme stability and the observed significant rise in fluctuation of the CD loop could modify CYP1A2 interactions with its redox partners. Together, these findings propose CYP1A2 as a possible candidate for hepatocellular carcinoma and provide structural insights into how cancer driver nsSNPs could affect protein structure, heme stability and interaction network.

PMID:33654112 | DOI:10.1038/s41598-021-83696-x

Transl Psychiatry. 2021 Mar 2;11(1):153. doi: 10.1038/s41398-020-01097-6.

ABSTRACT

Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depressive disorder (MDD), yet their mechanisms of action are not fully understood and their therapeutic benefit varies among individuals. We used a targeted metabolomics approach utilizing a panel of 180 metabolites to gain insights into mechanisms of action and response to citalopram/escitalopram. Plasma samples from 136 participants with MDD enrolled into the Mayo Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) were profiled at baseline and after 8 weeks of treatment. After treatment, we saw increased levels of short-chain acylcarnitines and decreased levels of medium-chain and long-chain acylcarnitines, suggesting an SSRI effect on β-oxidation and mitochondrial function. Amines-including arginine, proline, and methionine sulfoxide-were upregulated while serotonin and sarcosine were downregulated, suggesting an SSRI effect on urea cycle, one-carbon metabolism, and serotonin uptake. Eighteen lipids within the phosphatidylcholine (PC aa and ae) classes were upregulated. Changes in several lipid and amine levels correlated with changes in 17-item Hamilton Rating Scale for Depression scores (HRSD17). Differences in metabolic profiles at baseline and post-treatment were noted between participants who remitted (HRSD17 ≤ 7) and those who gained no meaningful benefits (<30% reduction in HRSD17). Remitters exhibited (a) higher baseline levels of C3, C5, alpha-aminoadipic acid, sarcosine, and serotonin; and (b) higher week-8 levels of PC aa C34:1, PC aa C34:2, PC aa C36:2, and PC aa C36:4. These findings suggest that mitochondrial energetics-including acylcarnitine metabolism, transport, and its link to β-oxidation-and lipid membrane remodeling may play roles in SSRI treatment response.

PMID:33654056 | DOI:10.1038/s41398-020-01097-6

BMC Med Ethics. 2021 Mar 2;22(1):21. doi: 10.1186/s12910-021-00592-9.

ABSTRACT

BACKGROUND: In the context of translational research, researchers have increasingly been using biological samples and data in fundamental research phases. To explore informed consent practices, we conducted a retrospective study on informed consent documents that were used for CARPEM's translational research programs. This review focused on detailing their form, their informational content, and the adequacy of these documents with the international ethical principles and participants' rights.

METHODS: Informed consent forms (ICFs) were collected from CARPEM investigators. A content analysis focused on information related to biological samples and data treatment (context of sampling and collect, aims, reuse, consent renewal), including the type of consent. An automatic assessment of the readability of the ICFs were performed with the IT program "Flesch Score".

RESULTS: 29 ICFs from 25 of 49 studies were analyzed after selection criteria were applied. Three types of consent were identified: 11 broad consents, six specific consents, and two opt-out consents. The Flesch Scores showed that most of the documents were too complex to be fully understood by most of the potential research participants. Most of the biological samples were collected during the healthcare routine, but the information content about secondary use of biological samples varied between ICFs. All documents mentioned personal data treatment but information about their reuse was not standardized in the ICFs.

CONCLUSIONS: Our review of current IC procedures of CARPEM showed that practices could be improved considering new translational research methods. "Old fashion written ICFs" should be adapted to the translational research approach, to better respect individual rights and international research ethics principles. In this context, theoretically, a digital tool allowing dynamic information and consent of participants, through an electronic interactive platform may be a good way to promote more active participation in research. Nevertheless, its feasibility in the complex environment of biological samples and data research remains to prove. The way of a combination of a broad consent followed by dynamic information may be alternatively tested.

PMID:33653311 | DOI:10.1186/s12910-021-00592-9