Appl Clin Genet. 2021 Feb 9;14:27-35. doi: 10.2147/TACG.S278652. eCollection 2021.

ABSTRACT

BACKGROUND: Allopurinol, a common anti-hyperuricemia drug, is well known as an inducer of severe cutaneous adverse drug reactions (SCARs). One of the most well-defined risk factors of allopurinol-induced SCARs is the presence of polymorphic alleles of human leukocyte antigen (HLA) genes, such as HLA-B*58:01 and HLA-C*03:02 alleles. There is no commercial test or published in-house protocol for the specific detection of the HLA-C*03:02 allele. In this article, we established for the first time a simple allele-specific (AS) PCR method to identify HLA-C*03:02 allele carriers, and at the same time, determine their zygosities.

METHODS: A two-step AS-PCR protocol, using four primer sets, was designed to specifically amplify and differentiate the HLA-C*03:02 allele from 17 other HLA-C alleles found in Vietnamese people. The protocol was validated with PCR-sequencing-based typing (SBT) of 100 samples of unknown genotypes.

RESULTS: The PCR protocol can detect the HLA-C*03:02 allele and determine the zygosity. The results of this protocol were highly consistent with those of the SBT (ĸ = 0.98, p < 0.001). Regarding the specific detection of the HLA-C*03:02 allele, the PCR protocol had a sensitivity of 100% (95% CI: 91.61-100%) and specificity of 98.3% (95% CI: 90.9-99.7%). The protocol was used to determine the distribution of the HLA-C*03:02 allele in 810 unrelated Vietnamese Kinh people, 14.2% of which were HLA-C*03:02 carriers, the allele frequency was 7.5%.

CONCLUSION: A novel AS-PCR protocol with a sensitivity of 100% for the detection of the HLA-C*03:02 allele was established. The protocol can be used for personalized treatment with allopurinol in order to minimize the risk of SCARs in Vietnamese people as well as in other Asian populations with similar genetic characteristics.

PMID:33603436 | PMC:PMC7881795 | DOI:10.2147/TACG.S278652

Sci Rep. 2021 Feb 18;11(1):4158. doi: 10.1038/s41598-021-83570-w.

ABSTRACT

Recently, the Clinical Pharmacogenetics Implementation Consortium (CPIC) have revised recommendations for the translation of CYP2D6 genotype to phenotype. Changes affect phenotype grouping, as well as the value used to calculate activity score for the CYP2D6*10 allele to better reflect the substantially decreased activity of this allele which is the most frequent allele found in Asian populations. This study aimed to evaluate whether the lower value for CYP2D6*10 as recommended, and the revised phenotype groupings improve the relationship between CYP2D6 genotype and risperidone measures. One hundred and ninety-nine children and adolescents with autism treated with a risperidone-based regimen for at least four weeks were included. CYP2D6 genotype was determined using the Luminex xTAG CYP2D6 Kit assay and translated into phenotype using different translation methods. Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured using LC/MS/MS. Plasma levels of risperidone, risperidone concentration/dose ratio, and risperidone/9-hydroxyrisperidone ratio in patients with an activity score < 1 were significantly higher than those ≥ 1 (P value < 0.001 for all three parameters). Plasma risperidone levels and risperidone concentration/dose ratios were significantly higher in intermediate metabolizers (defined as AS = 0.25-0.75) than normal metabolizer (defined as AS = 1-2) patients (1.44 vs. 0.23 ng/ml, P < 0.001 and 1.63 vs. 0.29 ng/ml/ng, P < 0.001, respectively) as well as risperidone/9-hydroxyrisperidone ratio (0.20 vs. 0.04, P < 0.001). This is the first study in an Asian population utilizing the revised CPIC-recommended method for translating the CYP2D6 genotype to phenotype. In addition to validating that CYP2D6 genetic variation significantly impacts risperidone metabolism, we demonstrated that revised value for the CYP2D6*10 was superior for genotype to phenotype translation. However, at least for risperidone, subjects with an activity score of 1 presented as phenotypic normal, and not intermediate metabolizers, suggesting that phenotype classification is substrate dependent.

PMID:33603025 | PMC:PMC7892547 | DOI:10.1038/s41598-021-83570-w

BMC Gastroenterol. 2021 Feb 18;21(1):77. doi: 10.1186/s12876-021-01650-7.

ABSTRACT

BACKGROUND: The threshold concentration of infliximab during maintenance therapy has not been well-defined in relation to histologic remission. The aim of the study is to dentify the maintenance-phase infliximab concentration associated with histologic remission in inflammatory bowel disease patients (IBD).

METHODS: A prospective cohort study was carried out in 104 IBD patients seen at a tertiary care centre in London, Canada. Infliximab trough concentrations were collected during the maintenance phase of treatment and compared between participants with and without evidence of histologic remission. Participants were additionally evaluated for sustained histologic remission, and relapse to active disease.

RESULTS: Participants in histologic remission attained higher mean concentrations of infliximab during the maintenance phase (10.34 ± 0.69 μg/ml) compared to those with persistent disease activity (6.23 ± 0.67 μg/ml, p-value < 0.0001). Additionally, during the maintenance phase, sustained histologic remission was also associated with a higher mean concentration of infliximab (10.81 ± 5.46 μg/ml) compared to those who relapsed to active disease (5.68 ± 3.70, p < 0.001). Overall, participants with a mean infliximab trough concentration greater than 8ug/ml were more likely to have histologic remission (area under the receiver operating characteristic curve, AUROC = 0.72, 95%CI = 0.65-0.84, p < 0.0001) and sustained histologic remission (AUC = 0.77, 95%CI = 0.63-0.91, p = 0.002).

CONCLUSION: Maintenance-phase infliximab trough concentrations greater than 8 μg/ml, which is higher than the currently recommended target concentration, are highly associated with histologic remission and sustained histologic remission.

PMID:33602145 | PMC:PMC7890824 | DOI:10.1186/s12876-021-01650-7

Pharmacogenomics. 2021 Feb 19. doi: 10.2217/pgs-2020-0077. Online ahead of print.

ABSTRACT

Aim: To assess the impact of sociodemographic factors and beliefs about medicines on the uptake of pharmacogenomic testing in older adults in a public healthcare system. Materials & methods: Data are based on a sample of 347 primary care older adults. Results: Most respondents (90%) were willing to provide a saliva sample and 47% were willing to pay for it. Increased age (odd ratio: 0.91; p = 0.04) and negative beliefs about the harmfulness of medicines (odd ratio: 0.68; p = 0.02) were associated with a decreased willingness to provide a sample. Lower education (less than university, odd ratio: 0.54; p = 0.04) was associated with a decreased willingness to pay. Conclusion: Education and beliefs about medicines are important factors in the acceptability of pharmacogenomic testing in older adults.

PMID:33601907 | DOI:10.2217/pgs-2020-0077

J Affect Disord. 2021 Mar 1;282:1272-1277. doi: 10.1016/j.jad.2021.01.034. Epub 2021 Jan 14.

ABSTRACT

BACKGROUND: Pharmacogenetic (PGx) testing is a potentially important, but understudied approach to precision medicine that could improve prescribing practices for antidepressants (ADs) in patients with Major Depressive Disorder (MDD). Thus, it is important to understand the scope of its potential impact and to identify patients who may benefit most from PGx-guided care.

METHODS: Participants were treatment-seeking US veterans (N=1149) with MDD enrolled in the Precision Medicine in Mental Health Care study, a pragmatic multi-site, randomized, controlled trial that examines the utility of PGx testing in the context of pharmacotherapy for MDD. We report the prevalence of ADs with predicted moderate and clinically significant gene-drug interaction potential based on next-intended treatment. We also examined demographic and treatment history characteristics as predictors of the gene-drug interaction potential of participants' next-intended treatment.

RESULTS: Prevalence of the next-intended AD with moderate or clinically significant gene-drug interaction was 45.1% and19.3%. Previous treatment with an AD in the past two years was associated with a 1.59 increased likelihood of having a next-intended AD treatment with predicted clinically significant gene-drug interaction (95% CI: 1.08-2.35).

LIMITATIONS: The gene-drug interaction potential of ADs is specific to the PGx test panel used in this study and may not generalize to other PGx test panels.

CONCLUSIONS: PGx testing could benefit one in five patients prescribed ADs with clinically significant gene-drug interaction potential. Patients with prior AD treatment are more likely to have an AD with significant gene-drug interaction potential as their next-intended treatment and therefore may benefit most from PGx testing.

PMID:33601706 | DOI:10.1016/j.jad.2021.01.034

SARS-CoV-2 tropism, entry, replication, and propagation: Considerations for drug discovery and development.

PLoS Pathog. 2021 Feb;17(2):e1009225

Authors: Murgolo N, Therien AG, Howell B, Klein D, Koeplinger K, Lieberman LA, Adam GC, Flynn J, McKenna P, Swaminathan G, Hazuda DJ, Olsen DB

Abstract
Since the initial report of the novel Coronavirus Disease 2019 (COVID-19) emanating from Wuhan, China, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has spread globally. While the effects of SARS-CoV-2 infection are not completely understood, there appears to be a wide spectrum of disease ranging from mild symptoms to severe respiratory distress, hospitalization, and mortality. There are no Food and Drug Administration (FDA)-approved treatments for COVID-19 aside from remdesivir; early efforts to identify efficacious therapeutics for COVID-19 have mainly focused on drug repurposing screens to identify compounds with antiviral activity against SARS-CoV-2 in cellular infection systems. These screens have yielded intriguing hits, but the use of nonhuman immortalized cell lines derived from non-pulmonary or gastrointestinal origins poses any number of questions in predicting the physiological and pathological relevance of these potential interventions. While our knowledge of this novel virus continues to evolve, our current understanding of the key molecular and cellular interactions involved in SARS-CoV-2 infection is discussed in order to provide a framework for developing the most appropriate in vitro toolbox to support current and future drug discovery efforts.

PMID: 33596266 [PubMed - as supplied by publisher]

Pharmacogenetics of novel glucose-lowering drugs.

Diabetologia. 2021 Feb 16;:

Authors: Rathmann W, Bongaerts B

Abstract
The aim of this work was to review studies in which genetic variants were assessed with respect to metabolic response to treatment with novel glucose-lowering drugs: dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i). In total, 22 studies were retrieved from the literature (MEDLINE). Variants of the GLP-1 receptor gene (GLP1R) were associated with a smaller reduction in HbA1c in response to DPP-4i. Variants of a number of other genes (KCNQ1, KCNJ11, CTRB1/2, PRKD1, CDKAL1, IL6 promoter region, TCF7L2, DPP4, PNPLA3) have also been related to DPP-4i response, although replication studies are lacking. The GLP1R gene was also reported to play a role in the response to GLP-1 RA, with larger weight reductions being reported in carriers of GLP1R variant alleles. There were variants of a few other genes (CNR1, TCF7L2, SORCS1) described to be related to GLP-1 RA. For SGLT2i, studies have focused on genes affecting renal glucose reabsorption (e.g. SLC5A2) but no relationship between SLC5A2 variants and response to empagliflozin has been found. The relevance of the included studies is limited due to small genetic effects, low sample sizes, limited statistical power, inadequate statistics (lack of gene-drug interactions), inadequate accounting for confounders and effects modifiers, and a lack of replication studies. Most studies have been based on candidate genes. Genome-wide association studies, in that respect, may be a more promising approach to providing novel insights. However, the identification of distinct subgroups of type 2 diabetes might also be necessary before pharmacogenetic studies can be successfully used for a stratified prescription of novel glucose-lowering drugs.

PMID: 33594477 [PubMed - as supplied by publisher]

Acute respiratory distress syndrome (ARDS) caused by the novel coronavirus disease (COVID-19): a practical comprehensive literature review.

Expert Rev Respir Med. 2021 02;15(2):183-195

Authors: Montenegro F, Unigarro L, Paredes G, Moya T, Romero A, Torres L, López JC, González FEJ, Del Pozo G, López-Cortés A, Diaz AM, Vasconez E, Cevallos-Robalino D, Lister A, Ortiz-Prado E

Abstract
INTRODUCTION: The exponential growth of SARS-CoV-2 virus transmission during the first months of 2020 has placed substantial pressure on most health systems around the world. The complications derived from the novel coronavirus disease (COVID-19) vary due to comorbidities, sex and age, with more than 50% of the patients requiring some level of intensive care developing acute respiratory distress syndrome (ARDS). The authors carried out an extensive and comprehensive literature review on SARS-CoV-2 infection, the clinical, pathological, and radiological presentation as well as the current treatment strategies.
AREAS COVERED: Various complications caused by SARS-CoV-2 infection have been identified, the most lethal being the acute respiratory distress syndrome, caused most likely by the presence of severe immune cell response and the concomitant alveolus inflammation. The new treatment strategies are updated, and the analysis of the physiopathology is included in this review.
EXPERT OPINION: ARDS is one of the most frequent complications in patients with COVID-19. Information regarding the etiology and physiopathology are still unfolding and for the prevention and amelioration, good clinical management, adequate ventilatory support and the use of systemic corticoids seem to be the most efficient way to reduce mortality and to reduce hospital lengths.

PMID: 32902367 [PubMed - indexed for MEDLINE]

BoLA-DRB3 Polymorphism is Associated with Differential Susceptibility to Bovine Leukemia Virus-Induced Lymphoma and Proviral Load.

Viruses. 2020 03 22;12(3):

Authors: Lo CW, Borjigin L, Saito S, Fukunaga K, Saitou E, Okazaki K, Mizutani T, Wada S, Takeshima SN, Aida Y

Abstract
Bovine leukemia virus (BLV) is the causative agent of enzootic bovine leucosis. However, less than 5% of BLV-infected cattle will develop lymphoma, suggesting that, in addition to viral infection, host genetic polymorphisms might play a role in disease susceptibility. Bovine leukocyte antigen (BoLA)-DRB3 is a highly polymorphic gene associated with BLV proviral load (PVL) susceptibility. Due to the fact that PVL is positively associated with disease progression, it is believed that controlling PVL can prevent lymphoma development. Thus, many studies have focused on the relationship between PVL and BoLA-DRB3. Despite this, there is little information regarding the relationship between lymphoma and BoLA-DRB3. Furthermore, whether or not PVL-associated BoLA-DRB3 is linked to lymphoma-associated BoLA-DRB3 has not been clarified. Here, we investigated whether or not lymphoma-associated BoLA-DRB3 is correlated with PVL-associated BoLA-DRB3. We demonstrate that two BoLA-DRB3 alleles were specifically associated with lymphoma resistance (*010:01 and *011:01), but no lymphoma-specific susceptibility alleles were found; furthermore, two other alleles, *002:01 and *012:01, were associated with PVL resistance and susceptibility, respectively. In contrast, lymphoma and PVL shared two resistance-associated (DRB3*014:01:01 and *009:02) BoLA-DRB3 alleles. Interestingly, we found that PVL associated alleles, but not lymphoma associated alleles, are related with the anti-BLV gp51 antibody production level in cows. Overall, our study is the first to demonstrate that the BoLA-DRB3 polymorphism confers differential susceptibility to BLV-induced lymphoma and PVL.

PMID: 32235771 [PubMed - indexed for MEDLINE]

Biochim Biophys Acta Mol Basis Dis. 2021 Feb 15:166101. doi: 10.1016/j.bbadis.2021.166101. Online ahead of print.

ABSTRACT

Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are two nuclear receptors that are well-known for their roles in xenobiotic detoxification by regulating the expression of drug-metabolizing enzymes and transporters. In addition to metabolizing drugs and other xenobiotics, the same enzymes and transporters are also responsible for the production and elimination of numerous endogenous chemicals, or endobiotics. Moreover, both PXR and CAR are highly expressed in the liver. As such, it is conceivable that PXR and CAR have major potentials to affect the pathophysiology of the liver by regulating the homeostasis of endobiotics. In recent years, the physiological functions of PXR and CAR in the liver were extensively studied. Emerging evidence has suggested the roles of PXR and CAR in energy metabolism, bile acid homeostasis, cell proliferation, to name a few. This review summarizes the recent progress in our understanding of the roles of PXR and CAR in liver physiology.

PMID:33600998 | DOI:10.1016/j.bbadis.2021.166101

PLoS One. 2021 Feb 18;16(2):e0247087. doi: 10.1371/journal.pone.0247087. eCollection 2021.

ABSTRACT

BACKGROUND: G protein-coupled receptor kinase 6 (GRK6) is part of the G protein-coupled receptor kinase family, whose members act as key regulators of seven-transmembrane receptor signalling. GRK6 seems to play a role in regulation of inflammatory processes, but mechanisms of transcriptional regulation of GRK6 expression in inflammatory cell lines have not been characterized. Protein kinase C (PKC) signalling is also involved in inflammatory regulation and an impact of PKC activation on GRK6 protein expression was described previously. Thus, the aim of this study was to 1) characterize the GRK6 promoter, and 2) investigate a potential influence of PKC on GRK6 expression.

METHODS: Five deletion constructs of the GRK6 promoter were cloned. After transient transfection into a human T cell line, promoter activity was assessed using luciferase reporter gene assays. Putative transcription factor binding sites were identified, mutated, and binding was investigated using electrophoretic mobility shift assays (EMSA). Following stimulation with a PKC activator, GRK6 expression on mRNA and protein levels was assessed by reverse transcriptase qPCR and Western blots.

RESULTS: Investigation of the GRK6 promoter revealed a putative cAMP responsive element (CRE), whose mutation led to decreased promoter activity (p = 0.0006). Functionality of the CRE binding protein (CREB) binding site was verified in EMSA blots. Stimulation with a PKC activator resulted in decreased GRK6 promoter activity (p = 0.0027), mRNA (p = 0.04) and protein expression.

CONCLUSION: We characterized the human GRK6 promoter and identified promoter activity to be influenced by a CREB binding site. PKC might be one determinant contributing to altered GRK6 expression.

PMID:33600497 | DOI:10.1371/journal.pone.0247087

PLoS Genet. 2021 Feb 18;17(2):e1009323. doi: 10.1371/journal.pgen.1009323. eCollection 2021 Feb.

ABSTRACT

Preemptive pharmacogenetic testing has the potential to improve drug dosing by providing point-of-care patient genotype information. Nonetheless, its implementation in the Chinese population is limited by the lack of population-wide data. In this study, secondary analysis of exome sequencing data was conducted to study pharmacogenomics in 1116 Hong Kong Chinese. We aimed to identify the spectrum of actionable pharmacogenetic variants and rare, predicted deleterious variants that are potentially actionable in Hong Kong Chinese, and to estimate the proportion of dispensed drugs that may potentially benefit from genotype-guided prescription. The projected preemptive pharmacogenetic testing prescription impact was evaluated based on the patient prescription data of the public healthcare system in 2019, serving 7.5 million people. Twenty-nine actionable pharmacogenetic variants/ alleles were identified in our cohort. Nearly all (99.6%) subjects carried at least one actionable pharmacogenetic variant, whereas 93.5% of subjects harbored at least one rare deleterious pharmacogenetic variant. Based on the prescription data in 2019, 13.4% of the Hong Kong population was prescribed with drugs with pharmacogenetic clinical practice guideline recommendations. The total expenditure on actionable drugs was 33,520,000 USD, and it was estimated that 8,219,000 USD (24.5%) worth of drugs were prescribed to patients with an implicated actionable phenotype. Secondary use of exome sequencing data for pharmacogenetic analysis is feasible, and preemptive pharmacogenetic testing has the potential to support prescription decisions in the Hong Kong Chinese population.

PMID:33600428 | DOI:10.1371/journal.pgen.1009323

Mol Genet Genomic Med. 2021 Feb 18:e1527. doi: 10.1002/mgg3.1527. Online ahead of print.

ABSTRACT

BACKGROUND: Cytochrome P450 (CYP2B6) is an important enzyme that metabolizes about 3.0% of therapeutic drugs. Drugs metabolized mainly by CYP2B6 include artemisinin, bupropion, cyclophosphamide, efavirenz, ketamine, and methadone. The genetic polymorphisms in the CYP2B6 gene have earlier been studied in many populations, but the data are lacking for the Pakistani population. This research study aimed to determine the frequencies of the three of the most important variant alleles and genotypes of the CYP2B6 gene in the Pakistani population.

METHODS: Blood was withdrawn from healthy volunteers after taking informed consent. DNA was extracted using commercial kits, and allelic and genotype frequencies were determined after PCR amplification followed by restriction fragment length polymorphism (RFLP) and gel electrophoresis.

RESULTS: Our results show a minor allele frequency of 33.8% for CYP2B6*6, 25.8% for CYP2B6*4, 6.5% for CYP2B6*3, whereas wild-type genotype frequency was 48.57% for CYP2B6*6, 59.79% for CYP2B6*4, and 90.20% for CYP2B6*3. A significant interethnic variation was also observed.

CONCLUSIONS: Our results suggest that the frequency of poor metabolizers of CYP2B6, especially *6 variant, is significant enough in the Pakistani population to be given an important consideration when drugs metabolized by this enzyme are prescribed.

PMID:33599403 | DOI:10.1002/mgg3.1527

18 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 2021/02/17

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

18 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 2021/02/17

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

Medicine (Baltimore). 2021 Feb 5;100(5):e24194. doi: 10.1097/MD.0000000000024194.

ABSTRACT

BACKGROUND: The relationship between p53 expression and chemosensitivity of non-small cell lung cancer (NSCLC) is unclear. This study aims to explore the correlation between p53 expression and sensitivity to platinum-based chemotherapy in patients with NSCLC.

METHODS: Pubmed, Web of Science, EMBASE, CNKI, China Wanfang databases were searched for studies on the relationship between the p53 expression and the chemosensitivity to platinum drugs in patients with NSCLC. The last search time was May 2020. Stata 15.0 software was used for statistical analysis.

RESULTS: A total of 21 studies were included, covering 1387 patients in total. The results showed that the pooled OR = 1.55 (95%CI: 1.05∼2.29, P < .05), for Asian population, the pooled OR = 1.67 (95%CI: 0.95∼3.09, P > .05), for Caucasian population, the pooled OR = 1.34 (95%CI: 0.74∼2.43), there was no significant difference between Asian and Caucasian. The results of subgroup analysis of publication year showed that, the pooled OR = 2.07 (95%CI: 1.39∼3.07, P < .01), the heterogeneity among the studies decreased remarkably after 2005. The subgroup analysis of advanced patients showed that the pooled OR = 1.93 (95%CI: 1.27∼2.93), the difference was statistically significant.

CONCLUSION: Patients with p53 negative expression is more sensitive to platinum-based chemotherapy than those with p53 positive expression in NSCLC, especially in advanced NSCLC.

PMID:33592864 | PMC:PMC7870161 | DOI:10.1097/MD.0000000000024194

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

pharmacogenomics

These pubmed results were generated on 2021/02/16

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.

Nat Commun. 2021 Feb 15;12(1):1033. doi: 10.1038/s41467-021-21330-0.

ABSTRACT

Clinical trials of novel therapeutics for Alzheimer's Disease (AD) have consumed a large amount of time and resources with largely negative results. Repurposing drugs already approved by the Food and Drug Administration (FDA) for another indication is a more rapid and less expensive option. We present DRIAD (Drug Repurposing In AD), a machine learning framework that quantifies potential associations between the pathology of AD severity (the Braak stage) and molecular mechanisms as encoded in lists of gene names. DRIAD is applied to lists of genes arising from perturbations in differentiated human neural cell cultures by 80 FDA-approved and clinically tested drugs, producing a ranked list of possible repurposing candidates. Top-scoring drugs are inspected for common trends among their targets. We propose that the DRIAD method can be used to nominate drugs that, after additional validation and identification of relevant pharmacodynamic biomarker(s), could be readily evaluated in a clinical trial.

PMID:33589615 | DOI:10.1038/s41467-021-21330-0

Comput Biol Chem. 2021 Feb 8;91:107452. doi: 10.1016/j.compbiolchem.2021.107452. Online ahead of print.

ABSTRACT

Immunotherapy is a research area with great potential in drug discovery for cancer treatment. Because of the capacity of tumor antigens to activate the immune response and promote the destruction of tumor cells, they are considered excellent immunotherapeutic drugs. In this work, we evaluated fifteen machine learning algorithms for the classification of tumor antigens. For this purpose, we build robust datasets, carefully selected from the TANTIGEN and IEDB databases. The feature computation of all antigens in this study was performed by developing a script written in Python 3.8, which allowed the calculation of 544 physicochemical and biochemical properties extracted from the AAindex database. All classifiers were subjected to the training, 10-fold cross-validation, and testing on an independent dataset. The results of this study showed that the quadratic discriminant classifier presented the best performance measures over the independent dataset, accuracy = 0.7384, AUC = 0.817, recall = 0.676, precision = 0.7857, F1 = 0.713, kappa = 0.4764, and Matthews correlation coefficient = 0.4834, outperforming common machine learning classifiers used in the bioinformatics area. We believe that our prediction model could be of great importance in the field of cancer immunotherapy for the search of potential tumor antigens. Taking all aspects mentioned before, we developed an immunoinformatic tool called TAP 1.0 with a friendly interface for tumor antigens prediction, available at https://tapredictor.herokuapp.com/.

PMID:33592504 | DOI:10.1016/j.compbiolchem.2021.107452

Curr Opin Lipidol. 2021 Feb 10. doi: 10.1097/MOL.0000000000000746. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: To collect evidence on statin pharmacogenomics, and review what is known in this field for familial hypercholesterolemia (FH) patients.

RECENT FINDINGS: There are well-known associations between specific single nucleotide polymorphisms involved in statin transport and metabolism and either adverse effects or altered lipid-lowering efficacy. However, the applicability of this knowledge is uncertain, especially in high-risk populations. There are alternative approaches to study plasma concentrations of statins and new insights on why some association studies fail to be replicated.

SUMMARY: Statin therapy recommendations are not always followed in primary and secondary prevention and, even when followed, patients often fail to reach therapeutic target values. Considering the stringent 2019 European Atherosclerosis Society and European Society of Cardiology recommended target lipid levels, as well as the persistently high cost for alternative lipid-lowering therapies such as PCSK9 inhibitors, the variability in low-density lipoprotein cholesterol reductions on statin therapy is still an important factor that needs to be addressed to ensure better cardiovascular disease risk management, especially for FH patients, who have not been well studied historically in this context.

PMID:33591029 | DOI:10.1097/MOL.0000000000000746