Metabolism. 2021 Dec 4:154954. doi: 10.1016/j.metabol.2021.154954. Online ahead of print.

ABSTRACT

INTRODUCTION: Atherosclerotic Coronary Artery Disease (ASCAD) is the leading cause of mortality worldwide. Novel therapeutic approaches aiming to improve the atheroprotective functions of High Density Lipoprotein (HDL) include the use of reconstituted HDL forms containing human apolipoprotein A-I (rHDL-apoA-I). Given the strong atheroprotective properties of apolipoprotein E3 (apoE3), rHDL-apoE3 may represent an attractive yet largely unexplored therapeutic agent.

OBJECTIVE: To evaluate the atheroprotective potential of rHDL-apoE3 starting with the unbiased assessment of global transcriptome effects and focusing on endothelial cell (EC) migration as a critical process in re-endothelialization and atherosclerosis prevention. The cellular, molecular and functional effects of rHDL-apoE3 on EC migration-associated pathways were assessed, as well as the potential translatability of these findings in vivo.

METHODS: Human Aortic ECs (HAEC) were treated with rHDL-apoE3 and total RNA was analyzed by whole genome microarrays. Expression and phosphorylation changes of key EC migration-associated molecules were validated by qRT-PCR and Western blot analysis in primary HAEC, Human Coronary Artery ECs (HCAEC) and the human EA.hy926 EC line. The capacity of rHDL-apoE3 to stimulate EC migration was assessed by wound healing and transwell migration assays. The contribution of MEK1/2, PI3K and the transcription factor ID1 in rHDL-apoE3-induced EC migration and activation of EC migration-related effectors was assessed using specific inhibitors (PD98059: MEK1/2, LY294002: PI3K) and siRNA-mediated gene silencing, respectively. The capacity of rHDL-apoE3 to improve vascular permeability and hypercholesterolemia in vivo was tested in a mouse model of hypercholesterolemia (apoE KO mice) using Evans Blue assays and lipid/lipoprotein analysis in the serum, respectively.

RESULTS: rHDL-apoE3 induced significant expression changes in 198 genes of HAECs mainly involved in re-endothelialization and atherosclerosis-associated functions. The most pronounced effect was observed for EC migration, with 42/198 genes being involved in the following EC migration-related pathways: 1) MEK/ERK, 2) PI3K/AKT/eNOS-MMP2/9, 3) RHO-GTPases, 4) integrin. rHDL-apoE3 induced changes in 24 representative transcripts of these pathways in HAECs, increasing the expression of their key proteins PIK3CG, EFNB2, ID1 and FLT1 in HCAEC and EA.hy926 cells. In addition, rHDL-apoE3 stimulated migration of HCAEC and EA.hy926 cells, and the migration was markedly attenuated in the presence of PD98059 or LY294002. rHDL-apoE3 also increased the phosphorylation of ERK1/2, AKT, eNOS and p38 MAPK in these cells, while PD98059 and LY294002 inhibited rHDL-apoE3-induced phosphorylation of ERK1/2, AKT and p38 MAPK, respectively. LY had no effect on rHDL-apoE3-mediated eNOS phosphorylation. ID1 siRNA markedly decreased EA.hy926 cell migration by inhibiting rHDL-apoE3-triggered ERK1/2 and AKT phosphorylation. Finally, administration of a single dose of rHDL-apoE3 in apoE KO mice markedly improved vascular permeability as demonstrated by the reduced concentration of Evans Blue dye in tissues such as the stomach, the tongue and the urinary bladder and ameliorated hypercholesterolemia.

CONCLUSIONS: rHDL-apoE3 significantly enhanced EC migration in vitro, predominantly via overexpression of ID1 and subsequent activation of MEK1/2 and PI3K, and their downstream targets ERK1/2, AKT and p38 MAPK, respectively and improved vascular permeability in vivo. These novel insights into the rHDL-apoE3 functions suggest a potential clinical use to promote re-endothelialization and retard development of atherosclerosis.

PMID:34875308 | DOI:10.1016/j.metabol.2021.154954

Circulation. 2021 Dec 7. doi: 10.1161/CIRCULATIONAHA.121.055801. Online ahead of print.

ABSTRACT

Background: Multiple pharmacogenomic studies have identified the synonymous genomic variant rs7853758 (G>A, L461L) and the intronic variant rs885004 in SLC28A3 as statistically associated with a lower incidence of anthracycline-induced cardiotoxicity (AIC). However, the true causal variant(s), the cardioprotective mechanism of this locus, the role of SLC28A3 and other solute carrier (SLC) transporters in AIC, and the suitability of SLC transporters as targets for cardioprotective drugs has not been investigated. Methods: Six well-phenotyped, doxorubicin-treated pediatric patients from the original association study cohort were re-recruited and human induced pluripotent stem cell-derived cardiomyocytes were generated. Patient-specific doxorubicin-induced cardiotoxicity (DIC) was then characterized using assays of cell viability, activated caspase 3/7, and doxorubicin uptake. The role of SLC28A3 in DIC was then queried using overexpression and knockout of SLC28A3 in isogenic hiPSCs using a CRISPR/Cas9. Fine-mapping of the SLC28A3 locus was then completed after SLC28A3 resequencing and an extended in silico haplotype and functional analysis. Genome editing of potential causal variant was done using cytosine base editor. SLC28A3-AS1 overexpression was done using a lentiviral plasmid-based transduction and was validated using stranded RNA-Seq after ribosomal RNA depletion. Drug screening was done using the Prestwick drug library (n = 1200) followed by in vivo validation in mice. The effect of desipramine on DOX cytotoxicity was also investigated in eight cancer cell lines. Results: Here, using the most commonly used anthracycline, doxorubicin, we demonstrate that patient-derived cardiomyocytes recapitulate the cardioprotective effect of the SLC28A3 locus and that SLC28A3 expression influences the severity of DIC. Using Nanopore¬-based fine-mapping and base editing we identify a novel cardioprotective SNP rs11140490 in the SLC28A3 locus which exerts its effect by regulating an antisense long noncoding-RNA (SLC28A3-AS1) that overlaps with SLC28A3. Using high-throughput drug screening in patient-derived cardiomyocytes and whole organism validation in mice, we identify the SLC competitive inhibitor desipramine as protective against DIC. Conclusions: This work demonstrates the power of the human induced pluripotent stem cell model to take a SNP from a statistical association through to drug discovery, providing human cell-tested data for clinical trials to attenuate DIC.

PMID:34874743 | DOI:10.1161/CIRCULATIONAHA.121.055801

J Med Genet. 2021 Dec 6:jmedgenet-2021-108112. doi: 10.1136/jmedgenet-2021-108112. Online ahead of print.

ABSTRACT

Population databases could help patients with cancer and providers better understand current pharmacogenomic prescribing and testing practices. This retrospective observational study analysed patients with cancer, drugs with pharmacogenomic evidence and related genetic testing in the National Institutes of Health All of Us database. Most patients with cancer (19 633 (88.3%) vs 2590 (11.7%)) received ≥1 drug and 36 (0.2%) received genetic testing, with a significant association between receiving ≥1 drug and age group (p<0.001), but not sex (p=0.612), race (p=0.232) or ethnicity (p=0.971). Drugs with pharmacogenomic evidence-but not genetic testing-were common for patients with cancer, reflecting key gaps preventing precision medicine from becoming standard of care.

PMID:34872990 | DOI:10.1136/jmedgenet-2021-108112

Front Genet. 2021 Nov 17;12:727475. doi: 10.3389/fgene.2021.727475. eCollection 2021.

ABSTRACT

Background: The causal relationship between childhood obesity and stroke remains unclear. Our objective was to elucidate the causal relationship between childhood obesity and the risk of stroke and its subtypes by performing Mendelian randomisation (MR) analyses. Methods: Genetic instruments for childhood obesity were obtained from a genome-wide association study (GWAS) of 13,848 European participants. Summary level data for stroke, intracerebral haemorrhage, ischaemic stroke (IS), and its subtypes were evaluated using the MEGASTROKE GWAS dataset, which included 446,696 European adults. Inverse-variance weighting, weighted-median analysis, MR-Egger regression, MR Pleiotropy RESidual Sum and Outlier test (MR-PRESSO), and MR-Robust Adjusted Profile Score were applied in this MR analysis. The leave-one-out sensitivity test, MR-PRESSO Global test, and Cochran's Q test were conducted to confirm the accuracy and robustness of our results. Results: Genetic evaluations revealed that childhood obesity was associated with a higher risk of stroke (OR = 1.04, 95%CI: 1.01-1.07, p = 0.005) and IS (OR = 1.05, 95%CI: 1.02-1.08, p = 0.003), but not with intracerebral haemorrhage (ICH, OR = 0.93, 95%CI: 0.80-1.09, p = 0.39). In the subtype analysis, childhood obesity was also associated with large artery stroke (LAS, OR = 1.12, 95%CI: 1.02-1.22, p = 0.016) but not with cardioembolic stroke (OR = 1.06, 95%CI: 0.96-1.18, p = 0.21) and small vessel stroke (OR = 1.06, 95%CI: 0.98-1.15, p = 0.17). These results were stable in the sensitivity analysis and remained significant after Bonferroni correction. Conclusion: Our study provides evidence that childhood obesity is associated with a higher risk of stroke, IS, and LAS. The prevention of stroke, especially IS and LAS, should be promoted in populations with childhood obesity.

PMID:34868204 | PMC:PMC8638161 | DOI:10.3389/fgene.2021.727475

Front Pharmacol. 2021 Nov 19;12:798447. doi: 10.3389/fphar.2021.798447. eCollection 2021.

NO ABSTRACT

PMID:34867430 | PMC:PMC8640121 | DOI:10.3389/fphar.2021.798447

Pharmacogenomics. 2021 Dec 5. doi: 10.2217/pgs-2021-0092. Online ahead of print.

ABSTRACT

Clopidogrel is an antiplatelet drug commonly used to prevent coagulation. This review aimed to investigate the effect of polymorphisms of G6PD, GCLC, GCLM, GSS, GST, GSR, HK and GLRX genes on clopidogrel during phase II metabolism through exploring previous studies. The results revealed that low glutathione plasma levels caused by several alleles related to these genes could affect the bioactivation process of the clopidogrel prodrug, making it unable to inhibit platelet aggregation perfectly and thus leading to severe consequences in patients with a high risk of blood coagulation. However, the study recommends platelet reactivity tests to predict clopidogrel efficacy rather than studying gene mutations, as most of these mutations are rare and other nongenetic factors could affect the drug's efficacy.

PMID:34866404 | DOI:10.2217/pgs-2021-0092

Biol Psychiatry. 2021 Sep 28:S0006-3223(21)01632-2. doi: 10.1016/j.biopsych.2021.09.020. Online ahead of print.

ABSTRACT

BACKGROUND: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs).

METHODS: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms.

RESULTS: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program.

CONCLUSIONS: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.

PMID:34865855 | DOI:10.1016/j.biopsych.2021.09.020

EBioMedicine. 2021 Dec 2;74:103728. doi: 10.1016/j.ebiom.2021.103728. Online ahead of print.

ABSTRACT

BACKGROUND: Low-dose aspirin can cause gastric and duodenal ulceration, hereafter called peptic ulcer disease (PUD). Predisposition is thought to be related to clinical and genetic factors; our aim was to identify genetic risk factors associated with aspirin-induced PUD.

METHODS: Patients (n=1478) were recruited from 15 UK hospitals. Cases (n=505) were defined as patients with endoscopically confirmed PUD within 2 weeks of using aspirin and non-aspirin Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). They were compared to two control groups: patients with endoscopically confirmed PUD without any history of NSAID use within 3 months of diagnosis (n=495), and patients with no PUD on endoscopy (n=478). A genome-wide association study (GWAS) of aspirin-induced cases (n=247) was compared to 476 controls. The results were validated by replication in another 84 cases and 162 controls.

FINDINGS: The GWAS identified one variant, rs12678747 (p=1·65×10-7) located in the last intron of EYA1 on chromosome 8. The association was replicated in another sample of 84 PUD patients receiving aspirin (p=0·002). Meta-analysis of discovery and replication cohort data for rs12678747, yielded a genome-wide significant association (p=3·12×10-11; OR=2·03; 95% CI 1·65-2·50). Expression of EYA1 was lower at the gastric ulcer edge when compared with the antrum.

INTERPRETATION: Genetic variation in an intron of the EYA1 gene increases the risk of endoscopically confirmed aspirin-induced PUD. Reduced EYA1 expression in the upper gastrointestinal epithelium may modulate risk, but the functional basis of this association will need mechanistic evaluation.

FUNDING: Department of Health Chair in Pharmacogenetics, MRC Centre for Drug Safety Science and the Barts Cardiovascular NIHR Biomedical Research Centre, British Heart Foundation (BHF).

PMID:34864618 | DOI:10.1016/j.ebiom.2021.103728

Clin Microbiol Infect. 2021 Dec 1:S1198-743X(21)00669-8. doi: 10.1016/j.cmi.2021.11.021. Online ahead of print.

ABSTRACT

OBJECTIVES: Benznidazole is the first line treatment for Chagas disease. Adverse events appear in more than 50% of patients, leading to discontinuation in approximately 15%. Cutaneous reactions are one of the most frequent adverse events. HLA-genotyping previous studies identified an association between cutaneous reactions to benznidazole and carrying the specific allele HLA-B*35:05. We designed the present study to prospectively confirm this association.

METHODS: This is a prospective observational study including Chagas disease patients aged 18 years or more who accepted to receive benznidazole treatment following current guidelines. Allele genotyping of HLA-B was determined in all patients. Clinical and analytical follow-up was performed at days 0, 7, 14, 30 and 60 of treatment.

RESULTS: Two-hundred and seven patients were included. Seventy percent were female with a mean age of 45.1 (SD ±9.86) years mainly from Bolivia (92.8%). In 102 (49.3%) cases a cutaneous reaction was diagnosed. Forty-eight (46.6%) were classified as mild, 37 (35.9%) as moderate and 18 (17.5%) as severe. Thirty-two (15.4%) patients had to definitively interrupt the treatment due to a cutaneous reaction. Female sex (OR 4.49; 95%CI 1.62-12.47), new-onset eosinophilia prior to cutaneous symptoms (OR 2.55; 95%CI 1.2-5.43) and carrying the HLA-B*35 allelic group (OR 2.58; 95%CI 1.2-5.51) were all predictors of moderate to severe cutaneous reactions. No statistical significance was found when the specific allele HLA-B*35:05 was analyzed.

CONCLUSIONS: Patients carrying the HLA-B*35 allelic group are at higher risk of moderate to severe reactions when taking benznidazole treatment.

PMID:34863919 | DOI:10.1016/j.cmi.2021.11.021

Eur J Cancer. 2021 Nov 30:S0959-8049(21)01182-5. doi: 10.1016/j.ejca.2021.10.024. Online ahead of print.

ABSTRACT

PURPOSE: An increasing number of advanced non-small cell lung cancer (NSCLC) cases are being reported in the ageing population. However, studies on the use of afatinib in elderly patients are scarce. We conducted a prospective multicentre, single-arm, and open-label phase II trial for low-dose afatinib (30 mg/day) use in elderly patients with NSCLC with EGFR mutation to assess quality-of-life (QOL) and pharmacokinetic (PK)/pharmacogenomic (PGx) parameters.

PATIENTS AND METHODS: The primary end-point was the objective response rate (ORR), and the planned number of registered cases was 35, with a threshold ORR of 50%, an expected ORR of 75%, α of 0.05, and β of 0.1. Secondary end-points were progression-free survival (PFS), overall survival (OS), the incidence rate of adverse events (AEs), QOL survey (FACT-L), and trough plasma concentration of afatinib at steady state (Css) and at the occurrence of clinically significant AEs.

RESULTS: The median age of the patients was 79 years. The ORR was 80.0% and the disease control rate was 91.4%. The median PFS and OS were 15.6 and 29.5 months, respectively. Four patients discontinued because of AEs. Treatment-related death was not observed. No significant change in QOL was observed at baseline and after 4, 8, and 12 weeks. Css was comparable with those in previous reports and was significantly higher in patients with grade 3 AEs. Direct correlations between afatinib treatment and PGx profiles were not observed.

CONCLUSIONS: An afatinib starting dose of 30 mg/day could be an effective and safe treatment option for elderly patients.

PMID:34862083 | DOI:10.1016/j.ejca.2021.10.024

Sr Care Pharm. 2021 Dec 1;36(12):674-680. doi: 10.4140/TCP.n.2021.674.

ABSTRACT

This is a patient case exploring the importance of evaluating herbal and dietary supplements and how they may impact drug-drug and drug-gene implications based on pharmacogenomics test results. Even though herbal supplements are considered natural by many patients, which is often the reason for starting them, herbal supplements may still be metabolized by the same pathways as other medications, potentially contributing to drug-drug, drug-herb, and drug-gene interactions, and therefore, potentially impacting a patient's response to medications.

PMID:34861907 | DOI:10.4140/TCP.n.2021.674

Lancet Psychiatry. 2021 Nov 30:S2215-0366(21)00386-2. doi: 10.1016/S2215-0366(21)00386-2. Online ahead of print.

ABSTRACT

BACKGROUND: Negative symptoms of schizophrenia are associated with adverse clinical outcomes, but there are few effective treatments. We aimed to assess the effects of pimavanserin, a selective 5-HT2A inverse agonist and antagonist, on negative symptoms of schizophrenia.

METHODS: The ADVANCE study was a phase 2, 26-week, randomised, double-blind, placebo-controlled study of pimavanserin in stable outpatients with schizophrenia aged 18-55 years with predominant negative symptoms. Patients were randomly assigned (1:1) across 83 sites (18 in North America and 65 in Europe) to receive pimavanserin or placebo daily, added to an ongoing antipsychotic medication, per a computer-generated schedule (stratification by geographical region). Eligible patients had a score of at least 20 on the sum of seven Positive and Negative Syndrome Scale (PANSS) Marder negative factor items (and scores of ≥4 on at least three or ≥5 on at least two of negative symptom items). The starting dosage of 20 mg of pimavanserin or placebo could be adjusted to 34 mg or 10 mg within the first 8 weeks of the study, after which dosage remained stable until the end of the study. Both pimavanserin and placebo were administered orally once daily as two individual tablets (pimavanserin tablets were either 10 mg or 17 mg). The primary endpoint was change in total score using the 16-item Negative Symptom Assessment (NSA-16) from baseline to week 26. Primary outcomes were analysed in patients who received at least one dose of the study drug and had NSA-16 assessments at baseline and at least once post-baseline (full analysis set). Safety outcomes were analysed in patients who had received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, NCT02970305, and is complete.

FINDINGS: Between Nov 4, 2016, and April 16, 2019, we randomly assigned 403 patients to pimavanserin (n=201; 131 [65%] male; 187 [93%] White) or placebo (n=202; 137 [68%] male, 186 (92%) White), of whom 400 were included in the efficacy analysis (199 in the pimavanserin group, 201 in the placebo group). Mean age was 37·7 years (SD 9·4) in the pimavanserin group and 36·7 (9·2) years in the placebo group. The change in total NSA-16 score from baseline to week 26 was significantly improved with pimavanserin (least squares mean -10·4 [SE 0·67]) versus placebo (least squares mean -8·5 [0·67]; p=0·043; effect size: 0·211). The number of patients with treatment-emergent adverse events (TEAEs) was similar between groups: 80 (40%) patients experienced TEAEs in the pimavanserin group and 71 (35%) in the placebo group. Most TEAEs were headache (6% [n=13] vs 5% [n=10]) and somnolence (5% [n=11] vs 5% [n=10]). One patient from the placebo group reported severe headache (0·5%), rhinorrhoea (0·5%), cough (0·5%), and influenza (0·5%). In the pimavanserin group, one patient reported severe toothache (0·5%), and two patients had worsening of schizophrenia (1%). Mean change in QTcF interval was higher with pimavanerin (4·5 ms [SD 18·0]) than with placebo (0·0 ms [16·0]).

INTERPRETATION: Stable patients with predominant negative symptoms of schizophrenia showed a reduction in negative symptoms after treatment with pimavanserin. However, given the small effect size, further investigation with optimised dosing is warranted to determine the clinical significance of this effect.

FUNDING: Acadia Pharmaceuticals.

PMID:34861170 | DOI:10.1016/S2215-0366(21)00386-2

Cell Stem Cell. 2021 Dec 2;28(12):2039-2040. doi: 10.1016/j.stem.2021.11.006.

ABSTRACT

Doxorubicin chemotherapy causes cardiotoxicity in some patients and spares others. In this issue of Cell Stem Cell, Magdy et al. (2021) use genome-edited iPSCs to establish a common RARG coding variant as a causal risk factor, pointing to a pharmacogenomic application and to RARG-targeting treatments to protect patients from cardiotoxicity.

PMID:34861143 | DOI:10.1016/j.stem.2021.11.006

J Int Med Res. 2021 Dec;49(12):3000605211060144. doi: 10.1177/03000605211060144.

ABSTRACT

OBJECTIVE: Oxidative stress caused by the pro-inflammatory cytokine interleukin (IL)-1β has been widely investigated for cancer risk. In this study, we focused on the role of IL-1β rs1143634 polymorphism to reveal its impact on cancer development.

METHODS: Related studies with fixed inclusion criteria were selected from electronic databases to May 2021. This meta-analysis was performed with odds ratios and 95% confidence intervals. Heterogeneity, publication bias and sensitivity analyses were also conducted. Trial sequential analysis (TSA) and in-silico gene expression analysis were performed.

RESULTS: Forty-four case-control studies involving 18,645 patients with cancer and 22,882 controls were included. We observed a significant association of this single nucleotide polymorphism with overall cancer risk in the codominant model 3 (1.13-fold), recessive model (1.14-fold) and allelic model (1.08-fold). Subgroup analysis revealed that rs1143634 elevated the risk of gastric cancer, breast cancer and multiple myeloma. In addition, Asian and mixed populations and hospital-based controls had a significantly higher risk of cancer development. TSA confirmed our findings.

CONCLUSION: Our meta-analysis revealed that the presence of IL-1β rs1143634 polymorphism increases the risk of cancer development. Among polymorphism carriers, the Asian population has a higher risk than other ethnic populations.This meta-analysis was registered retrospectively at INPLASY (https://inplasy.com/, INPLASY2021100044).

PMID:34861128 | DOI:10.1177/03000605211060144

Drug Metab Pers Ther. 2021 Dec 6. doi: 10.1515/dmpt-2020-0156. Online ahead of print.

ABSTRACT

OBJECTIVES: ABCB1 gene polymorphisms can modify P-glycoprotein function with clinical consequences.

METHODS: The 3435C>T polymorphism prevalence was analyzed using oligonucleotide probes and next-generation sequencing in 421 unrelated healthy individuals living in Cuba. Data were stratified by gender, ethnic background and residence. The genotype and allelic frequencies were determined.

RESULTS: The genotype distribution met the Hardy-Weinberg equilibrium assumption. The allelic frequency was 63.5% for the 3435C variant. The genotype frequencies were 41.1% for CC, 44.9% for CT and 14.0% for TT. The allele and genotype distributions differed between individuals living in La Habana and Santiago de Cuba (p<0.05) when ethnic background was analyzed. The allelic distribution was similar among Admixed and Black subjects, and they differed from Caucasians. The CC genotype was equally distributed among Admixed and Black subjects, and they differed from Caucasians. The TT genotype frequency differed between Caucasians and Admixed. The CT genotype was distributed differently among the three groups. Similar distribution was obtained in Brazilians, whereas some similarities were observed in African, Spanish and Chinese populations, consistent with the mixed Cuban ethnic origin.

CONCLUSIONS: This is the first report on allele and genotype frequencies of the 3435C>T polymorphism in Cuba, which may support personalized medicine programs.

PMID:34860473 | DOI:10.1515/dmpt-2020-0156

Front Mol Biosci. 2021 Nov 11;8:785370. doi: 10.3389/fmolb.2021.785370. eCollection 2021.

ABSTRACT

PDZ-binding kinase (PBK) is known to regulate tumor progression in some cancer types. However, its relationship to immune cell infiltration and prognosis in different cancers is unclear. This was investigated in the present study by analyzing data from TCGA, GEO, GETx, TIMER, CPTAC, GEPIA2, cBioPortal, GSCALite, PROGNOSCAN, PharmacoDB, STRING, and ENCORI databases. PBK was overexpressed in most tumors including adenocortical carcinoma (hazard ratio [HR] = 2.178, p < 0.001), kidney renal clear cell carcinoma (KIRC; HR = 1.907, p < 0.001), kidney renal papillary cell carcinoma (HR = 3.024, p < 0.001), and lung adenocarcinoma (HR = 1.255, p < 0.001), in which it was associated with poor overall survival and advanced pathologic stage. PBK methylation level was a prognostic marker in thyroid carcinoma (THCA). PBK expression was positively correlated with the levels of BIRC5, CCNB1, CDC20, CDK1, DLGAP5, MAD2L1, MELK, PLK1, TOP2A, and TTK in 32 tumor types; and with the levels of the transcription factors E2F1 and MYC, which regulate apoptosis, the cell cycle, cell proliferation and invasion, tumorigenesis, and metastasis. It was also negatively regulated by the microRNAs hsa-miR-101-5p, hsa-miR-145-5p, and hsa-miR-5694. PBK expression in KIRC, liver hepatocellular carcinoma, THCA, and thymoma was positively correlated with the infiltration of immune cells including B cells, CD4+T cells, CD8+ T cells, macrophages, monocytes, and neutrophils. The results of the functional enrichment analysis suggested that PBK and related genes contribute to tumor development via cell cycle regulation. We also identified 20 drugs that potentially inhibit PBK expression. Thus, PBK is associated with survival outcome in a variety of cancers and may promote tumor development and progression by increasing immune cell infiltration into the tumor microenvironment. These findings indicate that PBK is a potential therapeutic target and has prognostic value in cancer treatment.

PMID:34859058 | PMC:PMC8632063 | DOI:10.3389/fmolb.2021.785370

Oncol Lett. 2022 Jan;23(1):19. doi: 10.3892/ol.2021.13137. Epub 2021 Nov 16.

ABSTRACT

Cancer growth in host tissues features glutamine (gln) depletion over time, decreasing epithelial cells' optimal functioning. In addition, radiotherapy (RT) and/or chemotherapy (CT) cause damage to normal tissues, probably enhanced by this depletion. The present study prospectively examined the effect of gln supplementation on 72 patients with thoracic and upper aerodigestive malignancies (T&UAM) treated with sequential or concurrent RT-CT or RT alone. All patients received prophylactic gln powder 15 g bid for the full duration of treatment. The severity of acute radiation toxicities was graded according to the RT Oncology Group/European Organization for Research and Treatment of Cancer criteria. Primary endpoints were the incidence of grade >2 toxicities, weight loss and requirement for analgesics, and the secondary endpoint was the association of the length of irradiated esophagus from treatment planning with the use of opioids. The incidence of adverse effects was as follows: Grade >2 stomatitis, 25.0%; esophagitis, 60.5%; dysphagia, 54.2%; pain, 25.4%; mycosis, 40.8%. Stomatitis grade >2 was more frequent in patients with head and neck tumors (P<0.001) and in those with prior surgery (P<0.001). Esophagitis (P=0.020) and dysphagia (P=0.008) grade >2 were more frequent in patients with concurrent RT-CT. Regarding analgesics, 9.9% of patients received no pain treatment, 56.3% received simple analgesic therapy and 33.8% opioids. Patients on opioid therapy had a greater mean length of irradiated esophagus (P=0.024) or length >12 cm (P=0.018). In 54.2% of patients, weight loss was observed, particularly with concurrent RT-CT (P=0.007). Thus, the use of oral gln may have an important role in reducing acute radiation toxicities and weight loss, and in lowering the requirement for analgesics in patients with T&UAM. Further randomized trials are required to identify the appropriate gln dose, duration of treatment and precise radiation dosimetric parameters in this group of patients. The present clinical trial was retrospectively registered in the ClinicalTrials.gov Protocol Registration and Results System (registration no. NCT05054517/22-09-2021).

PMID:34858523 | PMC:PMC8617560 | DOI:10.3892/ol.2021.13137

Sci Rep. 2021 Dec 2;11(1):23301. doi: 10.1038/s41598-021-02767-1.

ABSTRACT

Acute myeloid leukaemia (AML) is a neoplasm of immature myeloid cells characterized by various cytogenetic alterations. The present study showed that in addition to the FLT3-ITD and NPM1 mutation status, telomere length (TL) and telomerase reverse transcriptase (TERT) gene polymorphisms may affect risk and overall survival (OS) in AML. TL was longer in healthy controls than in AML patients and positively correlated with age in the patients, but not in healthy subjects. TL was found to be independently affected by the presence of the FLT3-ITD mutation. As for the TERT gene polymorphism, AML patients with the TERT rs2853669 CC genotype were characterized by significantly shorter OS than patients carrying the T allele. Another observation in our study is the difference in TL and OS in patients belonging to various risk stratification groups related to the FLT3-ITD and NPM1 mutation status. Patients with adverse risk classification (mutation in FLT3-ITD and lack of mutation in NPM1) presented with the shortest telomeres and significantly worse OS. In conclusion, OS of AML patients appears to be affected by TERT gene variability and TL in addition to other well-established factors such as age, WBC count, or FLT3-ITD and NPM1 mutation status.

PMID:34857839 | DOI:10.1038/s41598-021-02767-1

Curr Opin Psychiatry. 2022 Jan 1;35(1):22-29. doi: 10.1097/YCO.0000000000000759.

ABSTRACT

PURPOSE OF REVIEW: Despite advances in treatment modalities for mood disorders over recent decades, further therapeutic options are still required. Increased research is occurring, with the pursuit of psychedelic-based pharmacotherapies for a range of mood disorders and other conditions.

RECENT FINDINGS: Serotonergic psychedelics have been found to modulate brain networks underlying various psychiatric disorders, as well promoting neurogenesis and neuroplasticity. Randomized placebo-controlled trials have found psilocybin with psychological support effective at treating depression, including treatment-resistant depression; with emergent research also signalling N,N-dimethyltryptamine/ayahuasca also as a potential option for the treatment of depression. Lysergic acid diethylamide has been found to have anxiolytic effects, whereas 3,4-methylenedioxymethamphetamine (MDMA) has been used effectively to treat post-traumatic stress disorder (PTSD), with Phase III clinical trial evidence. Microdosing of psychedelics is a growing phenomenon that has shown benefits in some preclinical data; however, a recent self-directed controlled trial reported no evidence of improved mood.

SUMMARY: Current research with medicinal psychedelics, usually as an adjunct to psychotherapy, has shown encouraging results in treating mood disorders. However, there are challenges regarding blinding and sample sizes remain small, and there have been no definitive Phase III studies (aside from MDMA for PTSD). Further work exploring novel formulations, interface with pharmacogenomics and the microbiome, and inflammatory pathways can be advised.

PMID:34855694 | DOI:10.1097/YCO.0000000000000759

World J Biol Psychiatry. 2021 Dec 2:1-19. doi: 10.1080/15622975.2021.2012397. Online ahead of print.

ABSTRACT

Pharmacogenetic investigations into the opioid crisis suggest genetic variation could be a significant cause of opioid- related morbidity and mortality. Variability in opioid system genes, including single nucleotide polymorphisms, manifest after pharmacogenetic testing, as previously invisible risk factors for addiction and overdose. Pharmacodynamic genes regulate opioid-sensitive brain networks and neural reward circuitry. Pharmacokinetic genes expressed in drug metabolic pathways regulate blood levels of active versus inactive opioid metabolites. Elucidating the complex interplay of genetic variations in pharmacokinetic and pharmacodynamic pathways will shed new light on the addictive and toxic properties of opioids. This narrative review serves to promote understanding of key genetic mechanisms affecting the metabolism and actions of opioids, and to explore causes of the recent surge in opioid-related mortality associated with COVID-19. Personalized treatment plans centred around an individual's genetic makeup could make opioid-based pain management and opioid use disorder (OUD) treatments safer and more effective at both the individual and system levels.

PMID:34854362 | DOI:10.1080/15622975.2021.2012397