J Am Coll Cardiol. 2022 Nov 8;80(19):1815-1817. doi: 10.1016/j.jacc.2022.08.796.

NO ABSTRACT

PMID:36328692 | DOI:10.1016/j.jacc.2022.08.796

Lupus Sci Med. 2022 Nov;9(1):e000811. doi: 10.1136/lupus-2022-000811.

ABSTRACT

OBJECTIVE: Determine the pharmacokinetics (PK) and exposure-response of hydroxychloroquine (HCQ) and desethylhydroxychloroquine (DHCQ) in paediatric SLE (pSLE).

METHODS: We conducted an exploratory phase 2, direct-to-family trial. Children enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry with a diagnosis of pSLE were eligible if they were receiving HCQ as standard of care for ≥3 months. Biological samples were collected at up to four visits over a 6-month period. At each visit, plasma was obtained to measure the concentrations of HCQ and DHCQ, as well as cytokines. HCQ and DHCQ plasma PK data were analysed using a population PK modelling approach.

RESULTS: Twenty-five subjects provided a total of 88 plasma concentrations for PK analysis. There was a poor linear fit between HCQ concentrations and total body weight (R2=0.03). There was a decline in both interferon (IFN)-alpha and IFN-gamma with higher concentrations of HCQ and DHCQ. Volume of distribution for HCQ in plasma was higher in children compared with published values in adults (73 000 L vs 44 000 L), but clearance values in children were similar to adults.

CONCLUSIONS: We report the first population PK model for HCQ and DHCQ in children using data from a novel direct-to-family clinical trial. We observed high interindividual variability in HCQ PK and found that weight-based dosing for HCQ is poorly correlated with drug concentrations, suggesting the need to use therapeutic drug monitoring to individualise dosing. Furthermore, our results suggest that the current weight-based dosing paradigm for HCQ may result in suboptimal drug exposures, particularly for children with obesity. Accordingly, additional studies of HCQ are needed in pSLE to determine the optimal drug concentration and dosing to reduce disease activity and improve outcomes.

TRIAL REGISTRATION NUMBER: NCT04358302.

PMID:36328395 | DOI:10.1136/lupus-2022-000811

PLoS Genet. 2022 Nov 3;18(11):e1010367. doi: 10.1371/journal.pgen.1010367. eCollection 2022 Nov.

ABSTRACT

Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.

PMID:36327219 | DOI:10.1371/journal.pgen.1010367

J Genet Eng Biotechnol. 2022 Nov 3;20(1):153. doi: 10.1186/s43141-022-00437-x.

ABSTRACT

BACKGROUND: This research work included bioinformatics modeling of the dipotassium-trioxohydroxytetrafluorotriborate-halogenated boroxine molecule, as well as simulation and prediction of structural interactions between the halogenated boroxine molecule, human carbonic anhydrase, and human catalase structures. Using computational methods, we tried to confirm the inhibitory effect of halogenated boroxine on the active sites of these previously mentioned enzymes. The three-dimensional crystal structures of human catalase (PDB ID: 1DGB) and human carbonic anhydrase (PDB ID: 6FE2) were retrieved from RCSB Protein Data Bank and the protein preparation was performed using AutoDock Tools. ACD/ChemSketch and ChemDoodle were used for creating the three-dimensional structure of halogenated boroxine. Molecular docking was performed using AutoDock Vina, while the results were visualized using PyMOL.

RESULTS: Results obtained in this research are showing evidence that there are interactions between the halogenated boroxine molecule and both previously mentioned proteins (human carbonic anhydrase and human catalase) in their active sites, which led us to the conclusion that the inhibitory function of halogenated boroxine has been confirmed.

CONCLUSION: These findings could be an important step in determining the exact mechanisms of inhibitory activity and will hopefully serve in further research purposes of complex pharmacogenomics studies.

PMID:36326969 | DOI:10.1186/s43141-022-00437-x

J Neurol. 2022 Nov 3. doi: 10.1007/s00415-022-11457-5. Online ahead of print.

ABSTRACT

INTRODUCTION: Although migraine prevalence decreases with aging, some older patients still suffer from chronic migraine (CM). This study aimed to investigate the outcome of OnabotulinumtoxinA (OBT-A) as preventative therapy in elderly CM patients.

METHODS: This is a post hoc analysis of real-life prospectively collected data at 16 European headache centers on CM patients treated with OBT-A over the first three treatment cycles (i.e., Cy1-3). We defined: OLD patients aged ≥ 65 years and nonOLD those < 65-year-old. The primary endpoint was the changes in monthly headache days (MHDs) from baseline to Cy 1-3 in OLD compared with nonOLD participants. The secondary endpoints were the responder rate (RR) ≥ 50%, conversion to episodic migraine (EM) and the changes in days with acute medication use (DAMs).

RESULTS: In a cohort of 2831 CM patients, 235 were OLD (8.3%, 73.2% females, 69.6 years SD 4.7). MHDs decreased from baseline (24.8 SD 6.2) to Cy-1 (17.5 SD 9.1, p < 0.000001), from Cy-1 to Cy-2 (14.8 SD 9.2, p < 0.0001), and from Cy-2 to Cy-3 (11.9 SD 7.9, p = 0.001). DAMs progressively reduced from baseline (19.2 SD 9.8) to Cy-1 (11.9 SD 8.8, p < 0.00001), to Cy-2 (10.9 SD 8.6, p = 0.012), to Cy-3 (9.6 SD 7.4, p = 0.049). The 50%RR increased from 30.7% (Cy-1) to 34.5% (Cy-2), to 38.7% (Cy-3). The above outcome measures did not differ in OLD compared with nonOLD patients.

CONCLUSION: In a population of elderly CM patients with a long history of migraine OBT-A provided a significant benefit, over the first three treatment cycles, as good as in non-old patients.

PMID:36326890 | DOI:10.1007/s00415-022-11457-5

Pharmacogenomics. 2022 Nov 3. doi: 10.2217/pgs-2022-0093. Online ahead of print.

ABSTRACT

Pharmacogenomics (PGx) implementation has become increasingly widespread. One of the most important aspects of this implementation process is the development of appropriate clinical decision support (CDS). Major PGx resources, such as the Clinical Pharmacogenetics Implementation Consortium, provide valuable recommendations for the development of CDS for specific gene-drug pairs but do not specify whether the administration route of a drug is clinically relevant. It is also unknown if PGx alerts for nonorally and non-intravenously administered PGx-relevant medications should be suppressed to reduce alert fatigue. The purpose of this scoping review was to identify studies and their clinical, pharmacokinetic and pharmacodynamic outcomes to better determine if CDS alerts are relevant for nonorally and non-intravenously administered PGx-relevant medications. Although this scoping review identified multiple PGx studies, the results of these studies were inconsistent, and more evidence is needed regarding different routes of medication administration and PGx.

PMID:36326000 | DOI:10.2217/pgs-2022-0093

Clin Pharmacol Ther. 2022 Nov 3. doi: 10.1002/cpt.2786. Online ahead of print.

ABSTRACT

The relationship between race and biology is complex. In contemporary medical science, race is a social construct that is measured via self-identification of study participants. But even though race has no biological essence, it is often used as variable in medical guidelines (e.g. treatment recommendations specific for Black people with hypertension). Such recommendations are based on clinical trials in which there was a significant correlation between self-identified race and actual, but often unmeasured, health-related factors such as (pharmaco)genetics, diet, sun-exposure etc.. Many teachers are insufficiently aware of this complexity. In their classes, they (unintentionally) portray self-reported race as having a biological essence. This may cause students to see people of shared race as biologically or genetically homogeneous, and believe that race-based recommendations are true for all individuals (rather than reflecting the average of a heterogeneous group). This medicalizes race and reinforces already existing healthcare disparities. Moreover, students may fail to learn that the relation between race and health is easily biased by factors such as socio-economic status, racism, ancestry, and environment and that this limits the generalizability of race-based recommendations. We observed that the clinical case vignettes that we use in our teaching contain many stereotypes and biases, and do not generally reflect the diversity of actual patients. This guide, written by clinical pharmacology and therapeutics teachers, aims to help our colleagues and other health professions teachers to reflect on and improve our teaching on race-based medical guidelines and to make our clinical case vignettes more inclusive and diverse.

PMID:36325997 | DOI:10.1002/cpt.2786

Stroke. 2022 Nov 3. doi: 10.1161/STROKEAHA.122.037717. Online ahead of print.

ABSTRACT

There is considerable interindividual variability in the response to antiplatelet and anticoagulant therapies, and this variation may be attributable to genetic variants. There has been an increased understanding of the genetic architecture of stroke and cardiovascular disease, which has been driven by advancements in genomic technologies and this has raised the possibility of more targeted pharmaceutical treatments. Pharmacogenetics promises to use a patient's genetic profile to treat those who are more likely to benefit from a particular intervention by selecting the best possible therapy. Although there are numerous studies indicating strong evidence for the effect of specific genotypes on the outcomes of vascular drugs, the adoption of pharmacogenetic testing in clinical practice has been slow. This resistance may stem from sometimes conflicting findings among pharmacogenetic studies, a lack of stroke-specific randomized controlled trials to test the effectiveness of genetically-guided therapies, and the practical and cost-effective implementation of genetic testing within the clinic. Thus, this review provides an overview of the genetic variants that influence the individual responses to aspirin, clopidogrel, warfarin and statins and the different methods for pharmacogenetic testing and guidelines for clinical implementation for stroke patients.

PMID:36325912 | DOI:10.1161/STROKEAHA.122.037717

J Tradit Complement Med. 2022 Aug 3;12(6):556-566. doi: 10.1016/j.jtcme.2022.07.002. eCollection 2022 Nov.

ABSTRACT

BACKGROUND AND AIM: The present study investigates Plectranthus scutellarioides (L.) R.Br. as potential antibacterial oral rinse against bacteria associated with peri-implantitis to prevent the initial infection as well as disease progression.

EXPERIMENTAL PROCEDURE: Phytochemical screening was done on P. scutellarioides lyophilized extract to identify the presence of chemical constituent by using mass-based identification. The extract was screened for its antibacterial activity against 4 Gram-positive aerobes (early colonizer) and 5 Gram-negative facultative anaerobes as well as obligate anaerobes (late colonizer) using disc diffusion method. The extract was tested for minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), its cytotoxicity effects on human gingival fibroblast cell (HnGF) as well as bacteria morphological changes by scanning electron microscopy (SEM).

RESULTS AND CONCLUSION: Four flavonoid compounds were identified namely quercetin-3-glucoside, quercitrin, quercetin 3-(6″-acetylglucoside) and quercetin 3-O-acetyl-rhamnoside. The sensitivity test revealed that P. scutellarioides extract was effective against all the bacteria tested. MIC concentrations for the Gram-positive aerobes were in the range of 1.56-12.50 mg/mL, and the MBC concentrations were within 3.13-12.50 mg/mL. For Gram-negative obligate anaerobes, the MIC concentration were within 3.13-12.50 mg/mL and MBC within 6.25-200.00 mg/mL. The ethanolic extract did not have any cytotoxic effect on HnGF cells at the tested concentrations. SEM images showed bacterial cell wall disruption for all the bacteria tested. The results showed that P. scutellarioides extract exerts its antibacterial property by disrupting the cell wall of all the bacteria tested. Hence, P. scutellarioides may benefit from further investigations on its safety for oral use as an adjunctive treatment for peri-implantitis.

PMID:36325238 | PMC:PMC9618393 | DOI:10.1016/j.jtcme.2022.07.002

Cell Rep. 2022 Nov 1;41(5):111582. doi: 10.1016/j.celrep.2022.111582.

ABSTRACT

In "healthy" tumor cells, phosphatidylserine (PS) is predominately localized in the inner plasma membrane leaflet. During apoptosis, PS relocates to the outer leaflet. Herein, we established PSout tumor models with tumor cells lacking PS flippase component CDC50A, constantly exposing PS but alive. PSout tumors developed bigger than wild-type (WT) tumors, featuring M2 polarized tumor-associated macrophages (TAMs) and fewer tumor-antigen-specific T cells. The PS receptor TIM-3 is responsible for PS recognition. Employing an opposite tumor model, PSin, with tumor cells lacking the PS scramblase Xkr8 and unable to expose PS during otherwise normal apoptosis, we find that the accumulated apoptotic tumor cells produce and release cyclic GAMP (cGAMP) to immune cells to activate the STING pathway, leading to TAM M1 polarization, suppressed interleukin (IL)-10 secretion, and natural killer (NK) cell cytotoxicity. Silencing Xkr8 in vivo by either short hairpin RNA (shRNA) or small interfering RNA (siRNA) to achieve a PS externalization blockade provides robust therapeutic anti-tumor efficiency.

PMID:36323258 | DOI:10.1016/j.celrep.2022.111582

OMICS. 2022 Nov 2. doi: 10.1089/omi.2022.0108. Online ahead of print.

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19, emanated from the Wuhan Province in China and rapidly spread across the globe causing extensive morbidity and mortality rate, and affecting the global economy and livelihoods. Contrary to early predictions of "body bags" across Africa, the African COVID-19 pandemic was marked by apparent low case numbers and an overall mortality rate when compared with the other geographical regions. Factors used to describe this unexpected pattern included a younger population, a swifter and more effective national health policy, limited testing capacities, and the possibility of inadequate reporting of the cases, among others. However, despite genomics contributing to interindividual variations in many diseases across the world, there are inadequate genomic and multiomics data on COVID-19 in Africa that prevent richer transdisciplinary discussions on the contribution of genomics to the spread of COVID-19 pandemic. To invite future debates on comparative studies of COVID-19 genomics and the pandemic spread around the world regions, this expert review evaluates the reported frequency distribution of genetic variants in candidate genes that are likely to affect COVID-19 infection dynamics/disease outcomes. We propose here that genomic variation should be considered among the many factors determining the COVID-19 infection and its outcomes in African populations and across the world.

PMID:36322905 | DOI:10.1089/omi.2022.0108

J Clin Gastroenterol. 2022 Nov 3. doi: 10.1097/MCG.0000000000001791. Online ahead of print.

ABSTRACT

BACKGROUND: Thiopurines' toxicity often leads to dose reduction or discontinuation. This systematic review aims to synthesize the evidence on the effect of genotype-based dosing of thiopurines on treatment efficacy and safety in inflammatory bowel disease (objective #1), and the association between genotype status and the efficacy and safety profile (objective #2).

METHODS: The Cochrane Library, MEDLINE, and EMBASE were searched in August 2021. A total of 80 studies (19,859 individuals) were included. Meta-analyses for mortality, different types of adverse events (AEs), withdrawal due to AE, change in disease activity and clinical remission were performed following mainly a fixed-effects model. PROSPERO registration: CRD42020148130.

RESULTS: Genotype-based dosing was associated to a significantly lower incidence of hematologic AEs (risk ratio=0.71; 95% CI: 0.56-0.90; I2: 47%; 4 randomized controlled trials; moderate quality), which may be attributable to nudix hydrolase 15 (NUDT15) testing more than to thiopurine methyltransferase (TPMT) genotyping. No differences were found in other outcomes. Mutations in TPMT and NUDT15 genes were associated to a higher probability of serious AEs [odds ratio (OR) TPMT=4.98; OR NUDT15=11.44], hematologic AEs (OR TPMT=3.18), and serious hematologic AEs (OR TPMT=7.88; OR NUDT15=12.83). TPMT was also associated with a higher risk of withdrawals due to AEs (OR=3.38), and NUDT15 with gastrointestinal AEs (OR=2.04). Mutations in the ITPA gene did not lead to significant differences. Evidence of an association between other genes and clinical outcomes is still scarce.

CONCLUSIONS: Mutations in TPMT and NUDT15 genes predispose patients to suffer thiopurine-induced toxicity, and genotype-guided treatment has been shown to contribute to the prevention of thiopurine-induced toxicity, especially in the case of NUDT15 in Asians.

PMID:36322453 | DOI:10.1097/MCG.0000000000001791

Clin Pharmacol Ther. 2022 Nov 2. doi: 10.1002/cpt.2787. Online ahead of print.

ABSTRACT

Accuracy of warfarin dose prediction algorithms may be improved by including data from diverse populations in genetic studies of dose variability. Here, we surveyed single nucleotide polymorphisms in vitamin K-related genes for association with warfarin dose requirements in two admixed Latino populations in standard-principal component adjusted and contemporary-local ancestry adjusted regression models. A total of 5 variants from vitamin K-related genes/pathways were associated with warfarin dose in both cohorts (p<0.0125) in standard models. Local ancestry-adjusted analysis unveiled 35 associated variants with absolute effects ranging from β = 9.04 (±2.23) to 39.18 (±10.89) per ancestral allele in the discovery cohort and β = 6.47 (±2.02) to 17.82 (±6.83) in the replication cohort. Importantly, we demonstrate the technical validity of the Tractor model in cohorts with admixed ancestry from three founder populations and bring attention to the technical hurdles obstructing the inclusion of diverse, especially admixed, populations in pharmacogenomic research.

PMID:36321873 | DOI:10.1002/cpt.2787

Pharmacogenomics. 2022 Nov 2. doi: 10.2217/pgs-2022-0115. Online ahead of print.

ABSTRACT

Background: Patients with sickle cell disease (SCD) are exposed to numerous drugs over their lifespan, and many of these drugs have Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for personalized dosing. The authors' aim was to ascertain the number of drugs with CPIC guidelines prescribed to SCD patients. Materials & methods: A search of Indiana University Health affiliated hospitals' electronic medical record identified 957 patients with a diagnosis of SCD. Drugs or drug classes with CPIC actionable guidelines ordered as inpatient and outpatient prescriptions were collected from SCD patients. Results: During the 16-year period, 892 (93%) patients received at least one drug that could have been dosed according to CPIC guidelines. Conclusion: Preemptive pharmacogenetics testing should be considered in SCD patients in order to utilize these data throughout the patient's life.

PMID:36321553 | DOI:10.2217/pgs-2022-0115

J Geriatr Oncol. 2022 Oct 29:S1879-4068(22)00497-0. doi: 10.1016/j.jgo.2022.10.013. Online ahead of print.

NO ABSTRACT

PMID:36319551 | DOI:10.1016/j.jgo.2022.10.013

Per Med. 2022 Nov 1. doi: 10.2217/pme-2022-0056. Online ahead of print.

ABSTRACT

Aim: To elicit preferences for pharmacogenomic (PGx) testing in polypharmacy patients. Materials & methods: A face-to-face discrete choice experiment survey was designed and administered to adult polypharmacy patients recruited at a local retail pharmacy in Albuquerque (NM, USA). Results: A total of 128 eligible polypharmacy patients completed the discrete choice experiment survey and significantly preferred a PGx test with lower cost, better confidentiality and higher certainty of identifying best medication/dose and side effects and one that can be used to advocate for their treatment needs (all p < 0.01). Conclusion: This is the first study eliciting preferences for PGx testing among polypharmacy patients. The study found most polypharmacy patients were willing to take a PGx test and their preferences were mostly influenced by test cost.

PMID:36317592 | DOI:10.2217/pme-2022-0056

Medicine (Baltimore). 2022 Oct 28;101(43):e31380. doi: 10.1097/MD.0000000000031380.

ABSTRACT

BACKGROUND: Advances in next-generation sequencing technologies are changing the ways cancer diagnosis and treatment, which leads to a new branch of precision medicine: "Precision Oncology". This study aims to deliver a structured overview to carry out a bibliometric analysis of precision oncology research over the past 10 years retrospectively.

METHODS: Bibliometric methods including clustering analysis and co-occurrence visualized study were conducted based on publications of academic databases Web of Science Main Collection from 1st January 2012, to 31st December 2021. This study analyzed the information about related research outputs, countries, institutions, authors, cited papers, and hot topics.

RESULTS: 7163 papers related to precision oncology were identified. Since 2014, the number of articles has proliferated, and oncology precision has attracted significant attention from scholars worldwide in recent years. The USA leads the research in this field, and the League of European Research Universities is the primary research institution. Research institutions from Asia paid more attention to this field through high-level international cooperation. Besides, there are still many issues expected to be explored and evaluated correctly. Such as the considerable uncertainty that pharmacogenomic methods have no significant influence on patient outcomes.

CONCLUSIONS: Precision oncology serves as an essential method in clinical treatment, and is closely related to biological study, including biochemistry, molecular and genetics, advanced technology, and pharmacology discovery. The future research prospect would be the broad involvement of social participation and global cooperation in oncology precision research to acquire better results via the balance of technology and public health policy.

PMID:36316889 | DOI:10.1097/MD.0000000000031380

Cancer Rep (Hoboken). 2022 Oct 31:e1744. doi: 10.1002/cnr2.1744. Online ahead of print.

ABSTRACT

BACKGROUND AND AIM: Different studies have shown pharmacogenetic variants related to drug toxicity in acute myeloid leukemia (AML) patients. Our aim was to identify the association between ABCB1, CDA, DCK, GSTT1, and GSTM1 variants with clinical outcomes and toxicity in pediatric patients with AML.

METHODS: Fifty-one confirmed de novo AML pediatric patients were included. A SNaPshot™ assay and conventional PCR were used to evaluate ABCB1, CDA, DCK, GSTT1, and GSTM1 variants. Clinical outcomes and toxicity associations were evaluated using odds ratios and Chi-square analysis.

RESULTS: Patients carrying ABCB1 (1236C > T, rs1128503) GG genotype in had a 6.8 OR (CI 95% 1.08-42.73, p = .044) for cardiotoxicity as compared to patients carrying either AA or GA genotypes 0.14 OR (CI 95% 0.023-0.92, p = .044). For ABCB1 (1236G > A rs1128503/2677C > A/T rs2032582/3435G > A rs1045642) AA/AA/AA combined genotypes had a strong association with death after HSTC OR 13.73 (CI 95% 1.94-97.17, p = .009). Combined genotypes GG/CC/GG with CDA (79A > C, rs2072671) CA genotype or CDA (-451G > A, rs532545) CT genotype, had a 4.11 OR (CI 95% 2.32-725, p = .007) and 3.8 OR (CI 95% 2.23-6.47, p = .027) with MRD >0.1% after first chemotherapy cycle, respectively.

CONCLUSION: Our results highlight the importance of pharmacogenetic analysis in pediatric AML, particularly in populations with a high degree of admixture, and might be useful as a future tool for patient stratification for treatment.

PMID:36316809 | DOI:10.1002/cnr2.1744

J Int Assoc Provid AIDS Care. 2022 Jan-Dec;21:23259582221134751. doi: 10.1177/23259582221134751.

ABSTRACT

Tenofovir disoproxil fumarate (TDF) associates with renal tubular dysfunction (RTD) in some people living with HIV (PLWH). We studied clinical and genetic factors associated with RTD in Thai PLWH receiving TDF. RTD was diagnosed in 13 of 65 (20%) patients. The median (interquartile range) age and CD4 cell counts were 43.8 (40.4-50.9) years and 554 (437-716) cells/mm3, respectively. The median duration of TDF use was 46.9 (31.5-54.1) months. Univariate logistic regression demonstrated body mass index (BMI), concomitant use of protease inhibitor (PI), hyperlipidemia, and homozygous C/C SNP rs1059751 of ABCC4 gene as predisposing factors of RTD. In multivariate model, concomitant use of PI [adjusted odds ratio (aOR) 11.39; 95% confidence interval (CI), 1.59- 81.56; P = 0.015], hyperlipidemia (aOR 8.59; 95% CI, 1.46-50.40; P = 0.017), and BMI (aOR 0.76; 95% CI, 0.59-0.98; P = 0.037) remained associated with RTD in patients receiving TDF. PLWH receiving TDF with the presence of these factors should be closely monitored for RTD.

PMID:36314476 | DOI:10.1177/23259582221134751

Eur Rev Med Pharmacol Sci. 2022 Oct;26(20):7580-7593. doi: 10.26355/eurrev_202210_30033.

ABSTRACT

OBJECTIVE: Polymerase ε exonuclease (POLE) is an enzyme involved in DNA replication and may be an attractive therapeutic target in various cancers. Here we sought to model the impact of specific POLE mutations on protein function. Due to the lack of a crystal structure, the tertiary structures of the wild type and four common mutants were modeled using I-Tasser server.

MATERIALS AND METHODS: Molecular docking and dynamic simulation studies were performed, and the structure and function of the mutants analyzed through residue conservation analysis and protein folding energy changes.

RESULTS: All mutants of POLE gene had favorable binding affinities compared with their wild type of counterpart. The P286R variant, but not the other variants, disrupted cladribine binding to the protein. Similarly, dynamics studies revealed instability of the P286R mutant, while V411L, L424V, and L424F appeared to favor cladribine binding.

CONCLUSIONS: Since P286R is a hotspot mutation in endometrioid carcinomas, patients with this variant may not respond to cladribine. Population-based pharmacogenomics studies will be required to validate our results.

PMID:36314330 | DOI:10.26355/eurrev_202210_30033