Pharmacogenomics. 2021 Sep 16. doi: 10.2217/pgs-2021-0048. Online ahead of print.

ABSTRACT

Although gene fusions occur rarely in non-small-cell lung cancer (NSCLC) patients, they represent a relevant target in treatment decision algorithms. To date, immunohistochemistry and fluorescence in situ hybridization are the two principal methods used in clinical trials. However, using these methods in routine clinical practice is often impractical and time consuming because they can only analyze single genes and the quantity of tissue material is often insufficient. Thus, novel technologies, able to test multiple genes in a single run with minimal sample input, are being under investigation. Here, we discuss the utility of next-generation sequencing and nCounter technologies in detecting simultaneous gene fusions in NSCLC patients.

PMID:34525844 | DOI:10.2217/pgs-2021-0048

Cell Stem Cell. 2021 Sep 14:S1934-5909(21)00343-X. doi: 10.1016/j.stem.2021.08.006. Online ahead of print.

ABSTRACT

Doxorubicin is an anthracycline chemotherapy agent effective in treating a wide range of malignancies, but its use is limited by dose-dependent cardiotoxicity. A recent genome-wide association study identified a SNP (rs2229774) in retinoic acid receptor-γ (RARG) as statistically associated with increased risk of anthracycline-induced cardiotoxicity. Here, we show that human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with rs2229774 and who suffered doxorubicin-induced cardiotoxicity (DIC) are more sensitive to doxorubicin. We determine that the mechanism of this RARG variant effect is mediated via suppression of topoisomerase 2β (TOP2B) expression and activation of the cardioprotective extracellular regulated kinase (ERK) pathway. We use patient-specific hiPSC-CMs as a drug discovery platform, determining that the RARG agonist CD1530 attenuates DIC, and we confirm this cardioprotective effect in an established in vivo mouse model of DIC. This study provides a rationale for clinical prechemotherapy genetic screening for rs2229774 and a foundation for the clinical use of RARG agonist treatment to protect cancer patients from DIC.

PMID:34525346 | DOI:10.1016/j.stem.2021.08.006

Biomed Pharmacother. 2021 Sep 12;142:112060. doi: 10.1016/j.biopha.2021.112060. Online ahead of print.

ABSTRACT

BACKGROUND: Adequate opioid prescribing is critical for therapeutic success of pain management. Despite the widespread use of opioids, optimized opioid therapy remains unresolved with risk of accidental lethal overdosing. With the emergence of accumulating evidence linking genetic variation to opioid response, pharmacogenetic based treatment recommendations have been proposed.

OBJECTIVE: The aim of this review is to evaluate pharmacogenetic evidence and provide an overview on genes involved in the pharmacokinetics and pharmacodynamics of opioids.

METHODS: For this review, a systematic literature search of published articles was used in PubMed®, with no language restriction and between the time period of January 2000 to December 2020. We reviewed randomized clinical studies, study cohorts and case reports that investigated the influence of genetic variants on selected opioid pharmacokinetics and pharmacodynamics. In addition, we reviewed current CPIC clinical recommendations for pharmacogenetic testing.

RESULTS: Results of this review indicate consistent evidence supporting the association between selected genetic variants of CYP2D6 for opioid metabolism. CPIC guidelines include recommendations that indicate the avoidance of tramadol use, in addition to codeine, in CYP2D6 poor metabolizers and ultrarapid metabolizers, and to monitor intermediate metabolizers for less-than-optimal response. While there is consistent evidence for OPRM1 suggesting increased postoperative morphine dosing requirements in A118G G-allele carriers, the clinical relevance remains limited.

CONCLUSION: There is emerging evidence of clinical relevance of CYP2D6 and, to a lesser extent, OPRM1 polymorphism in personalized opioid drug dosing. As a result, first clinics have started to implement pharmacogenetic guidelines for CYP2D6 and codeine.

PMID:34523422 | DOI:10.1016/j.biopha.2021.112060

Pharmacogenomics. 2021 Sep 15. doi: 10.2217/pgs-2021-0083. Online ahead of print.

ABSTRACT

Aim: Sirolimus (SIR) is an immunosuppressant with limitations, including a narrow treatment window, multiple adverse reactions and large differences within and among individuals. Objective: We analyzed the correlation between numerous SNPs and SIR in terms of trough concentration in the early stage after kidney transplantation. Materials & method: A retrospective cohort study involving 69 kidney transplantation recipients was designed. Blood samples were collected to extract total DNAs, and trough SIR concentrations were measured. Logistic regression was used to analyze the association between SNPs and SIR trough concentrations. Result: At 7 days, 1 month and 3 months, the mean SIR trough concentration of patients in the CYP3A5 rs4646453-CC group was significantly higher than that in the CYP3A5 rs4646453-AA and CYP3A5 rs4646453-CA groups (p < 0.001) and CYP3A5 rs15524-AA group was significantly higher than that in the CYP3A5 rs15524-AG and CYP3A5 rs15524-GG groups (p < 0.001). Conclusion: Our study indicated that both CYP3A5 rs4646453 and CYP3A5 rs15524 had a certain influence on SIR trough concentration at 7 days, 1 month and 3 months.

PMID:34523354 | DOI:10.2217/pgs-2021-0083

Curr Pharm Teach Learn. 2021 Oct;13(10):1370-1375. doi: 10.1016/j.cptl.2021.07.017. Epub 2021 Jul 24.

ABSTRACT

BACKGROUND: An interprofessional (IP) experience was created that demonstrated the roles and responsibilities of pharmacists and physicians in clinical implementation of pharmacogenomics (PGx). The IP experience focused on PGx-themed patient cases and application of genotyping results to drug therapy management.

INTERPROFESSIONAL EDUCATION ACTIVITY: In 2016 and 2017, third-year pharmacy students and first-year medical students were placed on interprofessional teams with two to three students each. The teams resolved PGx patient cases, medical students wrote prescriptions for altered drug therapy based on the PGx profiles of the patients, and pharmacy students assessed and provided feedback to medical students about the prescriptions. Student could also volunteer to be genotyped for CYP2C19*2, and the results were compared.

DISCUSSION: The IP experience significantly enhanced PGx knowledge and increased the confidence of using PGx in patient cases for the majority of participants. The experience did not increase the recognition of each discipline's role in precision medicine in a statistically significant manner. Accurate prescription writing was challenging for the first-year medical students (44.3% prescriptions written correctly). The genotyping results did not deviate from a Hardy Weinberg equilibrium for this population.

IMPLICATIONS: IP experiences focused on PGx present an ideal opportunity to educate and initiate collaborations between pharmacists and physicians and to promote utilization of PGx in precision medicine. The roles and responsibilities for each discipline can be easily recreated in an IP experience to provide robust training to the students.

PMID:34521534 | DOI:10.1016/j.cptl.2021.07.017

Trials. 2021 Sep 14;22(1):616. doi: 10.1186/s13063-021-05456-6.

ABSTRACT

BACKGROUND: Internationally, older patients (≥65 years) account for more than 40% of acute admissions. Older patients admitted to the emergency department (ED) are frequently malnourished and exposed to inappropriate medication prescribing, due in part to the inaccuracy of creatinine-based equations for estimated glomerular filtration rate (eGFR). The overall aims of this trial are to investigate: (1) the efficacy of a medication review (MED intervention) independent of nutritional status, (2) the accuracy of eGFR equations based on various biomarkers compared to measured GFR (mGFR) based on 99mTechnetium-diethylenetriaminepentaacetic acid plasma clearance, and (3) the efficacy of an individualized multimodal and transitional nutritional intervention (MULTI-NUT-MED intervention) in older patients with or at risk of malnutrition in the ED.

METHODS: The trial is a single-center block randomized, controlled, observer-blinded, superiority and explorative trial with two parallel groups. The population consists of 200 older patients admitted to the ED: 70 patients without malnutrition or risk of malnutrition and 130 patients with or at risk of malnutrition defined as a Mini Nutritional Assessment-Short Form score ≤11. All patients without the risk of malnutrition receive the MED intervention, which consists of a medication review by a pharmacist and geriatrician in the ED. Patients with or at risk of malnutrition receive the MULTI-NUT-MED intervention, which consists of the MED intervention in addition to, dietary counseling and individualized interventions based on the results of screening tests for dysphagia, problems with activities of daily living, low muscle strength in the lower extremities, depression, and problems with oral health. Baseline data are collected upon study inclusion, and follow-up data are collected at 8 and 16 weeks after discharge. The primary outcomes are (1) change in medication appropriateness index (MAI) score from baseline to 8 weeks after discharge, (2) accuracy of different eGFR equations compared to mGFR, and (3) change in health-related quality of life (measured with EuroQol-5D-5L) from baseline to 16 weeks after discharge.

DISCUSSION: The trial will provide new information on strategies to optimize the treatment of malnutrition and inappropriate medication prescribing among older patients admitted to the ED.

TRAIL REGISTRATION: ClinicalTrials.gov NTC03741283 . Retrospectively registered on 14 November 2018.

PMID:34521465 | DOI:10.1186/s13063-021-05456-6

Pharmacogenomics. 2021 Sep 15. doi: 10.2217/pgs-2021-0064. Online ahead of print.

ABSTRACT

Aim: To identify novel genetic variants predisposing to elevation of Alanine aminotransferase (ALT) in rheumatoid arthritis (RA) patients after initiation of methotrexate (MTX) treatment. Patients & methods: We performed genome-wide association studies in 198 RA patients starting MTX. Outcomes were maximum level of ALT and ALT >1.5-times the upper level of normal within the first 6 months of treatment. Results: RAVER2 (rs72675408) was significantly associated with maximum level of ALT (p = 4.36 × 10-8). This variant is in linkage disequilibrium with rs72675451, which is associated with differential expression of JAK1 and RAVER2. Conclusion: We found an association between ALT elevation and genetic variants that may regulate the expression of JAK1 and RAVER2. JAK1 encodes a janus kinase involved in the pathogenesis of RA.

PMID:34521259 | DOI:10.2217/pgs-2021-0064

Pharmacogenomics. 2021 Sep 15. doi: 10.2217/pgs-2021-0044. Online ahead of print.

ABSTRACT

Opioid misuse and mismanagement has been a public health crisis for several years. Pharmacogenomics (PGx) has been proposed as another tool to enhance opioid selection and optimization, with recent studies demonstrating successful implementation and outcomes. However, broad engagement with PGx for opioid management is presently limited. The purpose of this Perspective is to highlight a series of barriers to PGx implementation within the specific context of opioid management. Areas of advancement needed for more robust pharmacogenomic engagement with opioids will be discussed, including clinical and economic research needs, education and training needs, policy and public health considerations, as well as legal and ethical issues. Continuing efforts to address these issues may help to further operationalize PGx toward improving opioid use.

PMID:34521258 | DOI:10.2217/pgs-2021-0044

J Mol Neurosci. 2021 Sep 14. doi: 10.1007/s12031-021-01892-w. Online ahead of print.

ABSTRACT

Cluster headache (CH) is a severe primary headache disorder with a genetic component, as indicated by family and twin studies. Diurnal and seasonal rhythmicity are key features of the disease and might be related to vitamin D, as low vitamin D levels have been observed in patients with cluster headache. In addition, the vitamin D receptor (VDR) occurs in brain areas and particularly in the hypothalamus. The aim of the present case-control study was to investigate the association of cluster headache susceptibility and clinical phenotypes with the VDR gene polymorphisms FokI, BsmI and TaqI in a Southeastern European Caucasian population. DNA was extracted from 131 unrelated CH patients and 282 non-headache controls and genotyped using real-time PCR (melting curve analysis). Linkage disequilibrium (LD) analysis confirmed that BsmI and TaqI, both located in the 3'UTR of the VDR gene, are in strong LD. Genotype and allele frequency distribution analysis of the VDR FokI, BsmI, and TaqI polymorphisms showed no statistically significant difference between cases and controls, whereas haplotype analysis indicated that the TAC haplotype might be associated with decreased cluster headache susceptibility. Intra-patient analysis according to diverse clinical phenotypes showed an association of the BsmI GG and TaqI TT genotypes with more frequent occurrence of CH attacks in this cohort. Therefore, a possible association was observed between VDR gene polymorphisms BsmI and TaqI or a linked locus and susceptibility for cluster headache development and altered clinical phenotypes in the Southeastern European Caucasian study population. Further large-scale replication studies are needed to validate these findings.

PMID:34519950 | DOI:10.1007/s12031-021-01892-w

Pharmacogenomics. 2021 Sep 14. doi: 10.2217/pgs-2021-0061. Online ahead of print.

ABSTRACT

Aim: To compare the cost-effectiveness of olaparib versus control treatment in metastatic castration-resistant prostate cancer patients with at least one gene mutation in BRCA1, BRCA2 or ATM from the US payer perspective. Methods: A Markov model was constructed to assess the quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios. Sensitivity analyses and scenario analyses were conducted to explore the impact of uncertainties. Results: The base-case result indicated that, for patients with specific gene mutations, olaparib gained 1.26 QALYs and USD$ 157,732 total cost. Compared with control treatment, the incremental cost-effectiveness ratio of olaparib was USD$ 248,248/QALY. The price of olaparib was the most influential parameter. Conclusion: Olaparib is not cost-effective in comparison with control treatment in metastatic castration-resistant prostate cancer patients with specific gene mutations.

PMID:34517749 | DOI:10.2217/pgs-2021-0061

Sci Adv. 2021 Sep 3;7(36):eabg9241. doi: 10.1126/sciadv.abg9241. Epub 2021 Sep 1.

ABSTRACT

[Figure: see text].

PMID:34516906 | DOI:10.1126/sciadv.abg9241

JMIR Mhealth Uhealth. 2021 Sep 13;9(9):e33223. doi: 10.2196/33223.

ABSTRACT

[This corrects the article DOI: 10.2196/24555.].

PMID:34516388 | DOI:10.2196/33223

Annu Rev Pharmacol Toxicol. 2021 Sep 13. doi: 10.1146/annurev-pharmtox-052120-014115. Online ahead of print.

ABSTRACT

Human leukocyte antigen (HLA) is a hallmark genetic marker for the prediction of certain immune-mediated adverse drug reactions (ADRs). Numerous basic and clinical research studies have provided the evidence base to push forward the clinical implementation of HLA testing for the prevention of such ADRs in susceptible patients. This review explores current translational progress in using HLA as a key susceptibility factor for immune ADRs and highlights gaps in our knowledge. Furthermore, relevant findings of HLA-mediated drug-specific T cell activation are covered, focusing on cellular approaches to link genetic associations to drug-HLA binding as a complementary approach to understand disease pathogenesis. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PMID:34516290 | DOI:10.1146/annurev-pharmtox-052120-014115

Annu Rev Pharmacol Toxicol. 2021 Sep 13. doi: 10.1146/annurev-pharmtox-032221-085807. Online ahead of print.

ABSTRACT

As costs of next-generation sequencing decrease, identification of genetic variants has far outpaced our ability to understand their functional consequences. This lack of understanding is a central challenge to a key promise of pharmacogenomics: using genetic information to guide drug selection and dosing. Recently developed multiplexed assays of variant effect enable experimental measurement of the function of thousands of variants simultaneously. Here, we describe multiplexed assays that have been performed on nearly 25,000 variants in eight key pharmacogenes (ADRB2, CYP2C9, CYP2C19, NUDT15, SLCO1B1, TMPT, VKORC1, and the LDLR promoter), discuss advances in experimental design, and explore key challenges that must be overcome to maximize the utility of multiplexed functional data. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PMID:34516287 | DOI:10.1146/annurev-pharmtox-032221-085807

Cancer Chemother Pharmacol. 2021 Sep 13. doi: 10.1007/s00280-021-04354-7. Online ahead of print.

ABSTRACT

BACKGROUND: Pretherapeutic screening for dihydropyrimidine dehydrogenase (DPD) deficiency is recommended prior to the administration of fluoropyrimidine-based chemotherapy. However, the best strategy to identify DPD deficiency in End Stage Renal Disease (ESRD) patients is unknown.

METHODS: We assessed the characteristics of both DPD phenotypes and DPYD genotypes in 20 dialyzed patients before and after dialysis session. The extent to which the concentrations of uracil [U] and dihydrouracil [UH2] were affected by dialysis was evaluated.

RESULTS: Mean [U] was 14 ± 3.3 ng/ml before the dialysis session, and 7.9 ± 2.7 ng/ml after. Notably, mean [U] in 119 non-ESRD patients during the same timeline was 8.7 ± 3.9 ng/ml, which is similar to [U] values after dialysis session (p = 0.38). [U] values > 16 ng/ml were measured in 4 ESRD patients (20%), whereas the rate was 3.3% in the non-ESRD cohort. Whole gene sequencing did not reveal DPYD deleterious allelic variants in the 4 ESRD patients with [U] values > 16 ng/ml. The profile of [UH2] values during dialysis was similar to that of [U]: 385 ± 86 ng/ml before, and 185 ± 62 ng/ml after (mean reduction rate 42.5%). Thus, [UH2]:[U] ratio remained unaffected by dialysis, and was similar to the values in non-ESRD patients (22.4 ± 7.1).

CONCLUSION: Phenotyping based on measuring plasma [U] before a dialysis sessions in ESRD patients is associated with an unacceptable high rate of false positives. The optimal strategy for the identification of patients with DPD deficiency in this population would be the monitor the [UH2]:[U] ratio, which remains unaffected.

PMID:34515833 | DOI:10.1007/s00280-021-04354-7

Int J Mol Med. 2021 Nov;48(5):200. doi: 10.3892/ijmm.2021.5033. Epub 2021 Sep 13.

ABSTRACT

Soon after the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) pandemic in December, 2019, numerous research teams, assisted by vast capital investments, achieved vaccine development in a fraction of time. However, almost 8 months following the initiation of the European vaccination programme, the need for prospective monitoring of the vaccine‑induced immune response, its determinants and related side‑effects remains a priority. The present study aimed to quantify the immune response following full vaccination with the BNT162b2 coronavirus disease 2019 (COVID‑19) mRNA vaccine by measuring the levels of immunoglobulin G (IgG) titers in healthcare professionals. Moreover, common side‑effects and factors associated with IgG titers were identified. For this purpose, blood samples from 517 individuals were obtained and analysed. Blood sampling was performed at a mean period of 69.0±23.5 days following the second dose of the vaccine. SARS‑CoV‑2 IgG titers had an overall mean value of 4.23±2.76. Females had higher titers than males (4.44±2.70 and 3.89 ±2.84, respectively; P=0.007), while non‑smokers had higher titers than smokers (4.48±2.79 and 3.80±2.64, respectively; P=0.003). An older age was also associated with lower antibody titers (P<0.001). Moreover, the six most prevalent adverse effects were pain at the injection site (72.1%), generalized fatigue (40.5%), malaise (36.3%), myalgia (31,0%), headache (25.8%) and dizziness/weakness (21.6%). The present study demonstrated that the immune response after receiving the BNT162b2 COVID‑19 mRNA vaccine is dependent on various modifiable and non‑modifiable factors. Overall, the findings of the present study highlight two key aspects of the vaccination programs: First, the need for prospective immunosurveillance studies in order to estimate the duration of immunity, and second, the need to identify those individuals who are at a greater risk of developing low IgG titers in order to evaluate the need for a third dose of the vaccine.

PMID:34515322 | DOI:10.3892/ijmm.2021.5033

Acta Diabetol. 2021 Sep 12. doi: 10.1007/s00592-021-01795-7. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Education might be causal to type 2 diabetes mellitus (T2DM). We triangulated cohort and genetic evidence to consolidate the causality between education and T2DM.

METHODS: We obtained observational evidence from the English Longitudinal Study of Ageing (ELSA). Self-reporting educational attainment was categorised as high (post-secondary and higher), middle (secondary), and low (below secondary or no academic qualifications) in 6,786 community-dwelling individuals aged ≥ 50 years without diabetes at ELSA wave 2, who were followed until wave 8 for the first diabetes diagnosis. Additionally, we performed two-sample Mendelian randomisation (MR) using an inverse-variance weighted (IVW), MR-Egger, weighted median (WM), and weighted mode-based estimate (WMBE) method. Steiger filtering was further applied to exclude single-nucleotide polymorphisms (SNPs) that were correlated with an outcome (T2DM) stronger than exposure (education attainment).

RESULTS: We observed 598 new diabetes cases after 10.4 years of follow-up. The adjusted hazard ratios (95% CI) of T2DM were 1.20 (0.97-1.49) and 1.58 (1.28-1.96) in the middle- and low-education groups, respectively, compared to the high-education group. Low education was also associated with increased glycated haemoglobin levels. Psychosocial resources, occupation, and health behaviours fully explained these inverse associations. In the MR analysis of 210 SNPs (R2 = 0.0161), the odds ratio of having T2DM per standard deviation-decreasing years (4.2 years) of schooling was 1.33 (1.01-1.75; IVW), 1.23 (0.37-4.17; MR-Egger), 1.56 (1.09-2.27; WM), and 2.94 (0.98-9.09; WMBE). However, applying Steiger filtering attenuated most MR results towards the null.

CONCLUSIONS: Our inconsistent findings between cohort and genetic evidence did not support the causality between education and T2DM.

PMID:34514530 | DOI:10.1007/s00592-021-01795-7

Front Pharmacol. 2021 Aug 27;12:730461. doi: 10.3389/fphar.2021.730461. eCollection 2021.

ABSTRACT

Depression disorder is one of the most serious mental illnesses in the world. Escitalopram is the essential first-line medication for depression disorder. It is the substrate of hepatic cytochrome P450 (CYP) enzyme CYP2C19 with high polymorphism. The effect of CYP2C19 on pharmacokinetics and pharmacodynamics on Caucasian population has been studied. The Clinical Pharmacogenetics Implementation Consortium Guideline provides dosing recommendations for escitalopram on CYP2C19 genotypes on the basis of the studies on Caucasian population. However, the gene frequency of the alleles of CYP2C19 showed racial differences between Chinese and Caucasian populations. Representatively, the frequency of the *2 and *3 allele, which were considered as poor metabolizer, has been shown to be three times higher in Chinese than in Caucasians. In addition, the environments might also lead to different degrees of impacts on genotypes. Therefore, the guidelines based on the Caucasians may not be applicable to the Chinese, which induced the establishment of a guideline in China. It is necessary to provide the evidence of individual treatment of escitalopram in Chinese by studying the effect of CYP2C19 genotypes on the pharmacokinetics parameters and steady-state concentration on Chinese. In this study, single-center, randomized, open-label, two-period, two-treatment crossover studies were performed. Ninety healthy Chinese subjects finished the trials, and they were included in the statistical analysis. The pharmacokinetics characteristics of different genotypes in Chinese were obtained. The results indicate that the poor metabolizer had higher exposure, and increased half-life than the extensive metabolizer and intermediate metabolite. The prediction of steady-state concentration based on the single dose trial on escitalopram shows that the poor metabolizer might have a higher steady-state concentration than the extensive metabolizer and intermediate metabolite in Chinese. The results indicate that the genetic testing before medication and the adjustment of escitalopram in the poor metabolizer should be considered in the clinical treatments in Chinese. The results provide the evidence of individual treatment of escitalopram in Chinese, which will be beneficial for the safer and more effective application of escitalopram in the Chinese population. Clinical Trial Registration: identifier ChiCTR1900027226.

PMID:34512354 | PMC:PMC8429954 | DOI:10.3389/fphar.2021.730461

Front Pharmacol. 2021 Aug 27;12:720619. doi: 10.3389/fphar.2021.720619. eCollection 2021.

ABSTRACT

Vemurafenib, a BRAF V600E inhibitor, provides therapeutic benefits for patients with melanoma, but the frequent emergence of drug resistance remains a challenge. An understanding of the mechanisms underlying vemurafenib resistance may generate novel therapeutic strategies for patients with melanoma. Here, we showed that eIF3a, a translational regulatory protein, was an important mediator involved in vemurafenib resistance. eIF3a was expressed at significantly lower levels in vemurafenib-resistant A375 melanoma cells (A375R) than in parental A375 cells. Overexpression of eIF3a enhanced the sensitivity to BRAF inhibitors by reducing p-ERK levels. Furthermore, eIF3a controlled ERK activity by regulating the expression of the phosphatase PPP2R1B via a translation mechanism, thus determining the sensitivity of melanoma cells to vemurafenib. In addition, a positive correlation between eIF3a and PPP2R1B expression was also observed in tumor samples from the Human Protein Atlas and TCGA databases. In conclusion, our studies reveal a previously unknown molecular mechanism of BRAF inhibitor resistance, which may provide a new strategy for predicting vemurafenib responses in clinical treatment.

PMID:34512348 | PMC:PMC8430041 | DOI:10.3389/fphar.2021.720619

Front Pharmacol. 2021 Aug 25;12:693453. doi: 10.3389/fphar.2021.693453. eCollection 2021.

ABSTRACT

Pharmacogenomics (PGx) studies the use of genetic data to optimize drug therapy. Numerous clinical centers have commenced implementing pharmacogenetic tests in clinical routines. Next-generation sequencing (NGS) technologies are emerging as a more comprehensive and time- and cost-effective approach in PGx. This review presents the main considerations for applying NGS in guiding drug treatment in clinical practice. It discusses both the advantages and the challenges of implementing NGS-based tests in PGx. Moreover, the limitations of each NGS platform are revealed, and the solutions for setting up and management of these technologies in clinical practice are addressed.

PMID:34512329 | PMC:PMC8424415 | DOI:10.3389/fphar.2021.693453