Glob Cardiol Sci Pract. 2021 Dec 31;2021(4):e202131. doi: 10.21542/gcsp.2021.31. eCollection 2021 Dec 31.

ABSTRACT

Introduction: Familial hypercholesterolaemia (FH) is a common autosomal dominant genetic condition, characterised by elevated LDL cholesterol (LDL-C), leading to premature cardiovascular disease (CVD). Early and accurate diagnosis, with implementation of preventative therapies, has a major impact on reducing premature CVD, morbidity and mortality. Genetic testing is recommended to confirm clinical diagnosis in the proband and enable cascade testing in relatives. There is growing evidence that the risk of CVD conferred by hypercholesterolaemia depends not only on monogenic causes but also on polygenic factors. GENinCode has developed a novel genomic testing system (Lipid inCode®) which we have assessed against an accredited National Health Service (NHS UK) genetic screening service in order to validate its diagnostic and clinical utility. Methods: DNA samples from 40 index cases who had been referred for FH testing in an ISO15189-accredited NHS genetic screening service, were retrospectively tested using the Lipid inCode® assay. The results were compared with those from NHS testing. Results: There was absolute concordance in variant detection between both diagnostic tests for monogenic and polygenic FH, the only difference being in the interpretation and classification of DNA variants based on ACMG guidelines, which did not differ by more than one classification class. The Lipid inCode® test was equivalent to the NHS test in providing comprehensive genetic analysis that included the assessment of both monogenic (FH) and polygenic determinants of blood cholesterol and including a pharmacogenomic assessment of predisposition to statin-related myopathy. Conclusion: The Lipid inCode® diagnostic test can be undertaken with rapid turnaround and gave the same results as those reported by standard NHS genetic laboratory testing. In addition to assessment of monogenic FH, the Lipid inCode® assay provides additional genetic data, such as polygenic factors contributing to hypercholesterolaemia, a polygenic risk score (PRS) for coronary artery disease (CAD), pharmacogenomic testing for statin myopathy, and genetic predisposition to raised Lp(a).

PMID:36185161 | PMC:PMC9491391 | DOI:10.21542/gcsp.2021.31

Chest. 2022 Sep 29:S0012-3692(22)03896-X. doi: 10.1016/j.chest.2022.08.2240. Online ahead of print.

ABSTRACT

There is now ample evidence that differences in sex and gender contribute to the incidence, susceptibility, presentation, diagnosis, and clinical course of many lung diseases. Some conditions are more prevalent in females, such as pulmonary arterial hypertension (PAH) and sarcoidosis. Some life stages -such as pregnancy- are unique to females and can affect the onset and course of lung disease. Clinical presentation may differ as well, such as higher number of exacerbations experienced by women with cystic fibrosis (CF), more fatigue in women with sarcoidosis, and more difficulty in achieving smoking cessation. Outcomes such as mortality may be different as well, as noted by higher mortality in females with CF. In addition, response to therapy and medication safety may also differ by sex, and yet, pharmacogenomic factors are often not adequately addressed in clinical trials. Various aspects of lung/sleep biology and pathobiology are impacted by female sex and female reproductive transitions. Differential gene expression or organ development can be impacted by these biologic differences. Understanding these differences is the first step in moving towards precision medicine for all patients.. This article is the second part of a state-of-the-art review of specific effects of sex and gender focused on epidemiology, disease presentation, risk factors and management of selected lung diseases. We review the recent literature and focus on recent guidelines incorporating sex and gender differences in pulmonary hypertension, cystic fibrosis (CF) and non-CF bronchiectasis, sarcoidosis, restless legs syndrome (RLS) and insomnia, and critical illness. We also provide a brief summary on effects of pregnancy on lung diseases and discuss impact of sex and gender on tobacco use and treatment of nicotine use disorder.

PMID:36183784 | DOI:10.1016/j.chest.2022.08.2240

Lancet Oncol. 2022 Sep 29:S1470-2045(22)00555-1. doi: 10.1016/S1470-2045(22)00555-1. Online ahead of print.

ABSTRACT

BACKGROUND: In advanced oestrogen receptor-positive, HER2-negative breast cancer, acquired resistance to aromatase inhibitors frequently stems from ESR1-mutated subclones, which might be sensitive to fulvestrant. The PADA-1 trial aimed to show the efficacy of an early change in therapy on the basis of a rising ESR1 mutation in blood (bESR1mut), while assessing the global safety of combination fulvestrant and palbociclib.

METHODS: We did a randomised, open-label, phase 3 trial in 83 hospitals in France. Women aged at least 18 years with oestrogen receptor-positive, HER2-negative advanced breast cancer and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited and monitored for rising bESR1mut during first-line aromatase inhibitor (2·5 mg letrozole, 1 mg anastrozole, or 25 mg exemestane, orally once per day, taken continuously) and palbociclib (125 mg orally once per day on days 1-21 of a 28-day cycle) therapy. Patients with newly present or increased bESR1mut in circulating tumour DNA and no synchronous disease progression were randomly assigned (1:1) to continue with the same therapy or to switch to fulvestrant (500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1) and palbociclib (dosing unchanged). The randomisation sequence was generated within an interactive web response system using a minimisation method (with an 80% random factor); patients were stratified according to visceral involvement (present or absent) and the time from inclusion to bESR1mut detection (<12 months or ≥12 months). The co-primary endpoints were investigator-assessed progression-free survival from random assignment, analysed in the intention-to-treat population (ie, all randomly assigned patients), and grade 3 or worse haematological adverse events in all patients. The trial is registered with Clinicaltrials.gov (NCT03079011), and is now complete.

FINDINGS: From March 22, 2017, to Jan 31, 2019, 1017 patients were included, of whom 279 (27%) developed a rising bESR1mut and 172 (17%) were randomly assigned to treatment: 88 to switching to fulvestrant and palbociclib and 84 patients to continuing aromatase inhibitor and palbociclib. At database lock on July 31, 2021, randomly assigned patients had a median follow-up of 35·3 months (IQR 29·2-41·4) from inclusion and 26·0 months (13·8-34·3) from random assignment. Median progression-free survival from random assignment was 11·9 months (95% CI 9·1-13·6) in the fulvestrant and palbociclib group versus 5·7 months (3·9-7·5) in the aromatase inhibitor and palbociclib group (stratified HR 0·61, 0·43-0·86; p=0·0040). The most frequent grade 3 or worse haematological adverse events were neutropenia (715 [70·3%] of 1017 patients), lymphopenia (66 [6·5%]), and thrombocytopenia (20 [2·0%]). The most common grade 3 or worse adverse events in step 2 were neutropenia (35 [41·7%] of 84 patients in the aromatase inhibitor and palbociclib group vs 39 [44·3%] of 88 patients in the fulvestrant and palbociclib group) and lymphopenia (three [3·6%] vs four [4·5%]). 31 (3·1%) patients had grade 3 or worse serious adverse events related to treatment in the overall population. Three (1·7%) of 172 patients randomly assigned had one serious adverse event in step 2: one (1·2%) grade 4 neutropenia and one (1·2%) grade 3 fatigue among 84 patients in the aromatase inhibitor and palbociclib group, and one (1·1%) grade 4 neutropenia among 88 patients in the fulvestrant and palbociclib group. One death by pulmonary embolism in step 1 was declared as being treatment related.

INTERPRETATION: PADA-1 is the first prospective randomised trial showing that the early therapeutic targeting of bESR1mut results in significant clinical benefit. Additionally, the original design explored in PADA-1 might help with tackling acquired resistance with new drugs in future trials.

FUNDING: Pfizer.

PMID:36183733 | DOI:10.1016/S1470-2045(22)00555-1

Oncologist. 2022 Oct 1:oyac202. doi: 10.1093/oncolo/oyac202. Online ahead of print.

ABSTRACT

BACKGROUND: Glioblastoma (GBM) has a poor prognosis, and patients with epidermal growth factor receptor (EGFR) amplification have an even worse prognosis. Nimotuzumab is an EGFR monoclonal antibody thought to play a significant role in the treatment of GBM. This paper presents a retrospective cohort study that evaluates the clinical efficacy and safety of nimotuzumab in GBM.

MATERIALS AND METHODS: A total of 56 newly diagnosed patients with EGFR-positive GBM were included in our study. The patients were divided into radiotherapy (RT) + temozolomide (TMZ) + nimotuzumab (39 patients) and RT + TMZ (17 patients) groups based on whether or not nimotuzumab was added during RT. Progression-free survival (PFS), overall survival (OS), and toxicities were assessed.

RESULTS: The median follow-up time was 27.9 months (95% confidence interval [CI], 25.1-30.8). The median PFS was 12.4 months (95% CI, 7.8-17.0) and 8.2 months (95% CI, 6.1-10.3) in the 2 groups, respectively, P = .052. The median OS was 27.3 months (95% CI, 19.0-35.6) and 16.7 months (95% CI, 11.1-22.2), respectively, P = .018. In patients with unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter, the PFS and OS were significantly better in patients treated with nimotuzumab than in those without nimotuzumab (median PFS: 19.3 vs 6.7 months, P = .001; median OS: 20.2 vs 13.8 months, P = .026). During the treatment period, no statistically significant difference in toxicity was noted between the 2 groups.

CONCLUSION: Our retrospective cohort study suggests the efficacy of Nimotuzumab combined with concurrent RT with TMZ in patients with newly diagnosed EGFR-positive GBM, and specifically those with unmethylated MGMT promoter. Further prospective studies are warranted to validate our findings. Besides, nimotuzumab demonstrated good safety and tolerability.

PMID:36181764 | DOI:10.1093/oncolo/oyac202

Asian J Psychiatr. 2022 Sep 26;77:103272. doi: 10.1016/j.ajp.2022.103272. Online ahead of print.

NO ABSTRACT

PMID:36181755 | DOI:10.1016/j.ajp.2022.103272

Medicine (Baltimore). 2022 Sep 30;101(39):e30635. doi: 10.1097/MD.0000000000030635.

ABSTRACT

BACKGROUND: CpG island methylator phenotype (CIMP) was closely related to the degree of pathological differentiation of tumors, and it's an important determinant of glioma pathogenicity. However, the molecular and pathological features of CIMP-positive glioma have not been fully elucidated. In addition, CIMP have been reported to be a useful prognostic marker in several human cancers, yet its prognostic value in gliomas is still controversial. Therefore, we aimed to evaluate gene mutations and pathological features of CIMP-positive glioma and explore the prognostic value of CIMP in gliomas.

METHODS: We comprehensively searched PubMed, Embase, and MEDLINE for studies describing gene mutations, pathological features and overall survival of gliomas stratified by CIMP status. Odds ratios (OR), hazard ratios (HR), and their 95% confidence intervals (CI) were used to estimate the correlation between CIMP and the outcome parameters.

RESULTS: Twelve studies with 2386 gliomas (1051 CIMP-positive and 1335 CIMP-negative) were included. Our results showed that CIMP was more frequent in isocitrate dehydrogenase 1 (IDH1)-mutated gliomas (OR 229.07; 95% CI 138.72-378.26) and 1p19q loss of heterozygosis (LOH) gliomas (OR 5.65; 95% CI 2.66-12.01). Pathological analysis showed that CIMP was common in low-malignant oligodendroglioma (OR 5.51; 95% CI 3.95-7.70) with molecular features including IDH1 mutations and 1p19q LOH, but rare in glioblastoma (OR 0.14; 95% CI 0.10-0.19). However, CIMP showed no obvious correlation with anaplastic oligoastrocytomas (OR 1.57; 95% CI 1.24-2.00) or oligoastrocytomas (OR 0.79; 95% CI 0.35-1.76). Concerning the prognosis, we found that CIMP-positive gliomas had longer overall survival (HR 0.57; 95% CI 0.97-0.16) than CIMP-negative gliomas.

CONCLUSIONS: CIMP could be used as a potential independent prognostic indicator for glioma.

PMID:36181110 | DOI:10.1097/MD.0000000000030635

Clin Epigenetics. 2022 Sep 30;14(1):124. doi: 10.1186/s13148-022-01340-5.

ABSTRACT

BACKGROUND AND PURPOSE: The neurological course after stroke is highly variable and is determined by demographic, clinical and genetic factors. However, other heritable factors such as epigenetic DNA methylation could play a role in neurological changes after stroke.

METHODS: We performed a three-stage epigenome-wide association study to evaluate DNA methylation associated with the difference between the National Institutes of Health Stroke Scale (NIHSS) at baseline and at discharge (ΔNIHSS) in ischaemic stroke patients. DNA methylation data in the Discovery (n = 643) and Replication (n = 62) Cohorts were interrogated with the 450 K and EPIC BeadChip. Nominal CpG sites from the Discovery (p value < 10-06) were also evaluated in a meta-analysis of the Discovery and Replication cohorts, using a random-fixed effect model. Metabolic pathway enrichment was calculated with methylGSA. We integrated the methylation data with 1305 plasma protein expression levels measured by SOMAscan in 46 subjects and measured RNA expression with RT-PCR in a subgroup of 13 subjects. Specific cell-type methylation was assessed using EpiDISH.

RESULTS: The meta-analysis revealed an epigenome-wide significant association in EXOC4 (p value = 8.4 × 10-08) and in MERTK (p value = 1.56 × 10-07). Only the methylation in EXOC4 was also associated in the Discovery and in the Replication Cohorts (p value = 1.14 × 10-06 and p value = 1.3 × 10-02, respectively). EXOC4 methylation negatively correlated with the long-term outcome (coefficient = - 4.91) and showed a tendency towards a decrease in EXOC4 expression (rho = - 0.469, p value = 0.091). Pathway enrichment from the meta-analysis revealed significant associations related to the endocytosis and deubiquitination processes. Seventy-nine plasma proteins were differentially expressed in association with EXOC4 methylation. Pathway analysis of these proteins showed an enrichment in natural killer (NK) cell activation. The cell-type methylation analysis in blood also revealed a differential methylation in NK cells.

CONCLUSIONS: DNA methylation of EXOC4 is associated with a worse neurological course after stroke. The results indicate a potential modulation of pathways involving endocytosis and NK cells regulation.

PMID:36180927 | DOI:10.1186/s13148-022-01340-5

J Transl Med. 2022 Sep 30;20(1):438. doi: 10.1186/s12967-022-03651-w.

ABSTRACT

BACKGROUND: Diverse drug vulnerabilities owing to the Chromatin regulators (CRs) genetic interaction across various cancers, but the identification of CRs genetic interaction remains challenging.

METHODS: In order to provide a global view of the CRs genetic interaction in cancer cells, we developed a method to identify potential drug response-related CRs genetic interactions for specific cancer types by integrating the screen of CRISPR-Cas9 and pharmacogenomic response datasets.

RESULTS: Totally, 625 drug response-related CRs synthetic lethality (CSL) interactions and 288 CRs synthetic viability (CSV) interactions were detected. Systematically network analysis presented CRs genetic interactions have biological function relationship. Furthermore, we validated CRs genetic interactions induce multiple omics deregulation in The Cancer Genome Atlas. We revealed the colon adenocarcinoma patients (COAD) with mutations of a CRs set (EP300, MSH6, NSD2 and TRRAP) mediate a better survival with low expression of MAP2 and could benefit from taxnes. While the COAD patients carrying at least one of the CSV interactions in Vorinostat CSV module confer a poor prognosis and may be resistant to Vorinostat treatment.

CONCLUSIONS: The CRs genetic interaction map provides a rich resource to investigate cancer-associated CRs genetic interaction and proposes a powerful strategy of biomarker discovery to guide the rational use of agents in cancer therapy.

PMID:36180906 | DOI:10.1186/s12967-022-03651-w

Clin Pharmacokinet. 2022 Sep 30. doi: 10.1007/s40262-022-01174-7. Online ahead of print.

ABSTRACT

The inter-individual differences in cancer susceptibility are somehow correlated with the genetic differences that are caused by the polymorphisms. These genetic variations in drug-metabolizing enzymes/drug-inactivating enzymes may negatively or positively affect the pharmacokinetic profile of chemotherapeutic agents that eventually lead to pharmacokinetic resistance and toxicity against anti-cancer drugs. For instance, the CYP1B1*3 allele is associated with CYP1B1 overexpression and consequent resistance to a variety of taxanes and platins, while 496T>G is associated with lower levels of dihydropyrimidine dehydrogenase, which results in severe toxicities related to 5-fluorouracil. In this context, a pharmacogenomics approach can be applied to ascertain the role of the genetic make-up in a person's response to any drug. This approach collectively utilizes pharmacology and genomics to develop effective and safe medications that are devoid of resistance problems. In addition, recently reported genomics studies revealed the impact of many single nucleotide polymorphisms in tumors. These studies emphasized the importance of single nucleotide polymorphisms in drug-metabolizing enzymes on the effect of anti-tumor drugs. In this review, we discuss the pharmacogenomics aspect of polymorphisms in detail to provide an insight into the genetic manipulations in drug-metabolizing enzymes that are responsible for pharmacokinetic resistance or toxicity against well-known anti-cancer drugs. Special emphasis is placed on different deleterious single nucleotide polymorphisms and their effect on pharmacokinetic resistance. The information provided in this report may be beneficial to researchers, especially those who are working in the field of biotechnology and human genetics, in rationally manipulating the genetic information of patients with cancer who are undergoing chemotherapy to avoid the problem of pharmacokinetic resistance/toxicity associated with drug-metabolizing enzymes.

PMID:36180817 | DOI:10.1007/s40262-022-01174-7

Nature. 2022 Sep 30. doi: 10.1038/s41586-022-05165-3. Online ahead of print.

ABSTRACT

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

PMID:36180795 | DOI:10.1038/s41586-022-05165-3

Br J Clin Pharmacol. 2022 Sep 30. doi: 10.1111/bcp.15551. Online ahead of print.

ABSTRACT

AIM: Patients on treatment with oral fixed dose imatinib are frequently under- or over-exposed to the drug. We investigated the association between the gene activity score (GAS) of imatinib-metabolizing cytochromes (CYP3A4, CYP3A5, CYP2D6, CYP2C9, CYP2C19, CYP2C8) and imatinib and nor-imatinib exposure. We also investigated the impact of concurrent drug-drug-interactions (DDIs) on the association between GAS and imatinib exposure.

METHODS: Serial plasma samples were collected from 33 GIST patients treated with imatinib 400 mg daily within a prospective clinical trial. Imatinib and nor-imatinib Ctrough were quantified by LC-MS/MS. Genetic polymorphisms with a functional impact on imatinib-metabolizing cytochromes were identified and a GAS was calculated for each gene. A DDIs-adjusted GAS was also generated.

RESULTS: Imatinib and nor-imatinib Ctrough were measured in 161 plasma samples. CYP2D6 GAS and metabolizer status based on genotype were associated with imatinib and (imatinib+nor-imatinib) Ctrough . CYP2D6 poor and intermediate metabolizers were predicted to have a lower nor-imatinib/imatinib metabolic ratio than normal metabolizers (0.197 and 0.193 versus 0.247, p=0.0205), whereas CYP2C8*3 carriers had a higher ratio than CYP2C8*1/*1 patients (0.263 vs 0.201, p=0.0220). CYP2C9 metabolizer status was inversely related to the metabolic ratio with an effect probably driven by the linkage disequilibrium between CYP2C9*2 and CYP2C8*3. The CYP2D6 DDIs-adjusted GAS was still predictive of imatinib exposure.

DISCUSSION: These findings highlight that CYP2D6 plays a major role in imatinib pharmacokinetics, but other players (i.e., CYP2C8) may influence imatinib exposure. These findings could drive the selection of patients more susceptible to imatinib under or over-exposure that could be candidate to personalized treatment and intensified monitoring strategies.

PMID:36178950 | DOI:10.1111/bcp.15551

Front Cardiovasc Med. 2022 Sep 13;9:964721. doi: 10.3389/fcvm.2022.964721. eCollection 2022.

ABSTRACT

Circulating endothelial progenitor cells (EPCs) play an important role in the repair processes of damaged vessels, favoring re-endothelization of stented vessels to minimize restenosis. EPCs number and function is diminished in patients with type 2 diabetes, a known risk factor for restenosis. Considering the impact of EPCs in vascular injury repair, we conducted a meta-analysis of microarray to assess the transcriptomic profile and determine target genes during the differentiation process of EPCs into mature ECs. Five microarray datasets, including 13 EPC and 12 EC samples were analyzed, using the online tool ExpressAnalyst. Differentially expressed genes (DEGs) analysis was done by Limma method, with an | log2FC| > 1 and FDR < 0.05. Combined p-value by Fisher exact method was computed for the intersection of datasets. There were 3,267 DEGs, 1,539 up-regulated and 1,728 down-regulated in EPCs, with 407 common DEGs in at least four datasets. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed enrichment for terms related to "AGE-RAGE signaling pathway in diabetic complications." Intersection of common DEGs, KEGG pathways genes and genes in protein-protein interaction network (PPI) identified four key genes, two up-regulated (IL1B and STAT5A) and two down-regulated (IL6 and MAPK11). MicroRNA enrichment analysis of common DEGs depicted five hub microRNA targeting 175 DEGs, including STAT5A, IL6 and MAPK11, with hsa-miR-124 as common regulator. This group of genes and microRNAs could serve as biomarkers of EPCs differentiation during coronary stenting as well as potential therapeutic targets to improve stent re-endothelization, especially in diabetic patients.

PMID:36176980 | PMC:PMC9513120 | DOI:10.3389/fcvm.2022.964721

Acta Pharm Sin B. 2022 Sep;12(9):3639-3649. doi: 10.1016/j.apsb.2022.02.006. Epub 2022 Feb 15.

ABSTRACT

Hepatotoxicity is a common side effect for patients treated with gefitinib, but the related pathogenesis is unclear and lacks effective predictor and management strategies. A multi-omics approach integrating pharmacometabolomics, pharmacokinetics and pharmacogenomics was employed in non-small cell lung cancer patients to identify the effective predictor for gefitinib-induced hepatotoxicity and explore optional therapy substitution. Here, we found that patients with rs4946935 AA, located in Forkhead Box O3 (FOXO3) which is a well-known autophagic regulator, had a higher risk of hepatotoxicity than those with the GA or GG variant (OR = 18.020, 95%CI = 2.473 to 459.1784, P = 0.018) in a gefitinib-concentration dependent pattern. Furthermore, functional experiments identified that rs4946935_A impaired the expression of FOXO3 by inhibiting the promotor activity, increasing the threshold of autophagy initiation and inhibiting the autophagic activity which contributed to gefitinib-induced liver injury. In contrast, erlotinib-induced liver injury was independent on the variant and expression levels of FOXO3. This study reveals that FOXO3 mutation, leading to autophagic imbalance, plays important role in gefitinib-induced hepatotoxicity, especially for patients with high concentration of gefitinib. In conclusion, FOXO3 mutation is an effective predictor and erlotinib might be an appropriately and well-tolerated treatment option for patients carrying rs4946935 AA.

PMID:36176901 | PMC:PMC9513443 | DOI:10.1016/j.apsb.2022.02.006

Acta Pharm Sin B. 2022 Sep;12(9):3513-3528. doi: 10.1016/j.apsb.2022.04.017. Epub 2022 May 10.

ABSTRACT

Recent insights collectively suggest the important roles of lysyl oxidase (LysOX) in the pathological processes of several acute and chronic neurological diseases, but the molecular regulatory mechanisms remain elusive. Herein, we explore the regulatory role of LysOX in the seizure-induced ferroptotic cell death of neurons. Mechanistically, LysOX promotes ferroptosis-associated lipid peroxidation in neurons via activating extracellular regulated protein kinase (ERK)-dependent 5-lipoxygenase (Alox5) signaling. In addition, overexpression of LysOX via adeno-associated viral vector (AAV)-based gene transfer enhances ferroptosis sensitivity and aggravates seizure-induced hippocampal damage. Our studies show that pharmacological inhibition of LysOX with β-aminopropionitrile (BAPN) significantly blocks seizure-induced ferroptosis and thereby alleviates neuronal damage, while the BAPN-associated cardiotoxicity and neurotoxicity could further be reduced through encapsulation with bioresponsive amorphous calcium carbonate-based nanocarriers. These findings unveil a previously unrecognized LysOX-ERK-Alox5 pathway for ferroptosis regulation during seizure-induced neuronal damage. Suppressing this pathway may yield therapeutic implications for restoring seizure-induced neuronal injury.

PMID:36176900 | PMC:PMC9513491 | DOI:10.1016/j.apsb.2022.04.017

Front Pharmacol. 2022 Sep 13;13:953142. doi: 10.3389/fphar.2022.953142. eCollection 2022.

ABSTRACT

Implementation strategies for pharmacogenetic testing have been largely limited to major academic medical centers and large health systems, threatening to exacerbate healthcare disparities for rural and tribal populations. There exists a need in Montana (United States)-a state where two-thirds of the population live in rural areas and with a large proportion of tribal residents-to develop novel strategies to make pharmacogenetic testing more broadly available. We established partnerships between University of Montana (UM) and three early adopter sites providing patient-centered care to historically neglected populations. We conducted 45 semi-structured interviews with key stakeholders at each site and solicited participant feedback on the utility of a centralized pharmacogenetic service at UM offering consultations to patients and providers statewide via telehealth. For settings serving rural patients-tribal and non-tribal-participants described healthcare facilities without adequate infrastructure, personnel, and funding to implement pharmacogenetic services. Participants serving tribal communities stressed the need for ethical practices for collecting biospecimens and returning genetic results to patients, largely due to historical and contemporary traumas experienced by tribal populations with regard to genetic research. Participants expressed that pharmacogenetic testing could benefit patients by achieving therapeutic benefit sooner, reducing the risk of side effects, and improving adherence outcomes for patients with limited access to follow-up services in remote areas. Others expressed concern that financial barriers to pharmacogenetic testing for patients of lower socioeconomic status would further exacerbate inequities in care. Participants valued the role of telehealth to deliver pharmacogenetic consults from a centralized service at UM, describing the ability to connect providers and patients to resources and expertise as imperative to driving successful pharmacogenetic implementation. Our results support strategies to improve access to pharmacogenetic testing for neglected patient populations and create opportunities to reduce existing healthcare inequities. By exploring critical challenges for pharmacogenetic implementation focused on serving underserved communities, this work can help guide equitable frameworks to serve as a model for other resource-limited settings looking to initiate pharmacogenetic testing.

PMID:36176435 | PMC:PMC9514788 | DOI:10.3389/fphar.2022.953142

Chin Med. 2022 Sep 29;17(1):114. doi: 10.1186/s13020-022-00672-x.

ABSTRACT

BACKGROUND: A biennial or perennial plant of the Apiaceae family, Eryngium caeruleum M. Bieb. is traditionally used in medicine as an antitoxic, diuretic, digestive, anti-inflammatory and analgesic drug. This plant is widely distributed in temperate regions around the world. Young leaves of the plant are used in cooking as aromatic cooked vegetables in various local products in Iran.

PURPOSE: The current review aimed to highlight complete and updated information about the Eryngium caeruleum species, regarding botanical, ethnopharmacological, phytochemical data, pharmacological mechanisms as well as some nutritional properties. All this scientific evidence supports the use of this species in complementary medicine, thus opening new therapeutic perspectives for the treatment of some diseases.

METHODS: The information provided in this updated review is collected from several scientific databases such as PubMed/Medline, ScienceDirect, Mendeley, Scopus, Web of Science and Google Scholar. Ethnopharmacology books and various professional websites were also researched.

RESULTS: The phytochemical composition of the aerial parts and roots of E. caeruleum is represented by the components of essential oil (EO), phenolic compounds, saponins, protein, amino acids, fiber, carbohydrates, and mineral elements. The antioxidant, antimicrobial, antidiabetic, antihypoxic, and anti-inflammatory properties of E. caeruleum have been confirmed by pharmacological experiments with extracts using in vitro and in vivo methods. The syrup E. caeruleum relieved dysmenorrhea as effectively as Ibuprofen in the blinded, randomized, placebo-controlled clinical study.

CONCLUSION: Current evidence from experimental pharmacological studies has shown that the different bioactive compounds present in the species E. caeruleum have multiple beneficial effects on human health, being potentially active in the treatment of many diseases. Thus, the traditional uses of this species are supported based on evidence. In future, translational and human clinical studies are necessary to establish effective therapeutic doses in humans.

PMID:36175969 | DOI:10.1186/s13020-022-00672-x

Environ Toxicol Pharmacol. 2022 Sep 26:103979. doi: 10.1016/j.etap.2022.103979. Online ahead of print.

ABSTRACT

The study aimed to examine the genetic contribution to buprenorphine (BUP) treatment in individuals with opioid use disorder (OUD), with a specific focus on BDNF and OPRM1 genes. A total of 113 controls and 111 OUD patients receiving sublingual BUP/naloxone were enrolled. OPRM1 A118G and BDNF Val66Met polymorphisms were investigated by PCR-FRLP. Plasma BDNF and beta-endorphin levels were assessed by ELISA kits in both groups. Blood BUP levels were measured by LC-MS/MS and normalized with daily BUP dose (BUP/D). OPRM1 A118G and BDNF Val66Met polymorphisms didn't have an effect on plasma beta-endorphin and BDNF levels in OUD patients, respectively. Interestingly, OUD patients had significantly higher plasma BDNF and lower beta-endorphin levels compared to the controls (p<0.001). A negative and significant correlation between plasma BUP/D and BDNF levels was found. Age onset of first use was associated with OPRM1 A118G polymorphism. The findings indicated that sublingual BUP/naloxone may increase plasma BDNF levels, but may decrease beta-endorphin levels in individuals with OUD. Plasma BDNF level seemed to be decreased in a BUP/D concentration-dependent manner.

PMID:36174909 | DOI:10.1016/j.etap.2022.103979

Science. 2022 Sep 30;377(6614):eabn7065. doi: 10.1126/science.abn7065. Epub 2022 Sep 30.

ABSTRACT

Because nonopioid analgesics are much sought after, we computationally docked more than 301 million virtual molecules against a validated pain target, the α2A-adrenergic receptor (α2AAR), seeking new α2AAR agonists chemotypes that lack the sedation conferred by known α2AAR drugs, such as dexmedetomidine. We identified 17 ligands with potencies as low as 12 nanomolar, many with partial agonism and preferential Gi and Go signaling. Experimental structures of α2AAR complexed with two of these agonists confirmed the docking predictions and templated further optimization. Several compounds, including the initial docking hit '9087 [mean effective concentration (EC50) of 52 nanomolar] and two analogs, '7075 and PS75 (EC50 4.1 and 4.8 nanomolar), exerted on-target analgesic activity in multiple in vivo pain models without sedation. These newly discovered agonists are interesting as therapeutic leads that lack the liabilities of opioids and the sedation of dexmedetomidine.

PMID:36173843 | DOI:10.1126/science.abn7065

Asian Pac J Cancer Prev. 2022 Sep 1;23(9):3061-3069. doi: 10.31557/APJCP.2022.23.9.3061.

ABSTRACT

INTRODUCTION: Several studies have shown an association between 5-fluorouracil toxicity and variations in the dihydropyrimidine dehydrogenase (DPYD) gene.

OBJECTIVES: This cross-sectional study aims to elucidate the association between genetic variations in the DPYD gene and 5-fluorouracil toxicity among Jordanians with colorectal cancer (CRC).

METHODS: 80 CRC Patients were recruited to screen for mutations in the DPYD gene using the Sanger sequencing technique. Sequencing results were analyzed using Mutation Surveyor software, and mutational effects were predicted by the Mutation Tester bioinformatics tool.

RESULTS: Three reported variants (c.85T>C, c.1740+40A>G, c.1740+39C>T) and one novel (g.97515583_97515584insA) variant were identified in this study. Results showed a significant association between these variants and toxicity to 5-Fluorouracil with P-values 0.002, 0.005, 0.019, 0.017, respectively. However, there was no significant association between variants and cancer free survival.

CONCLUSION: The present study identified several variants in the DPYD gene among Jordanians with colorectal cancer, which are associated with toxicity to 5-Fluorouracil treatment.

PMID:36172669 | DOI:10.31557/APJCP.2022.23.9.3061

Psychiatr Danub. 2022 Sep;34(Suppl 8):31-37.

ABSTRACT

BACKGROUND: Individuals who have suffered from novel coronavirus disease (COVID-19) are at risk for developing post-COVID neuropsychiatric disorders, which are an integral part of the Long COVID syndrome. Depression and/or anxiety are considered the most common psychiatric disorders after experiencing COVID-19. Certain antiepileptic drugs, notably, carbamazepine (CMZ), are effective in the treatment of mood disorders, especially as mood stabilizers in bipolar affective disorder (BAD), but the efficacy of CMZ in Long COVID remains to be established. The aim of the review was to investigate pharmacogenetic predictors of safety and efficacy of CMZ in patients with depressive symptoms of Long COVID during the post-infection period.

SUBJECTS AND METHODS: We carried out a systematic search for publications in English and Russian on the safety and efficacy of CMZ in depressive disorders of different etiologies in the PubMed, Web of Science, Springer, Clinical Keys, Google Schooler, E-Library databases using keywords and combined word searches (carbamazepine, COVID-19, depression, epilepsy, post-COVID-syndrome) for the period from January 01,2020 to June 10, 2022.

RESULTS: We review the main adverse drug reactions (ADRs) associated with CMZ, drug-drug interactions, and genetic predictors of the development of ADR. Here, we consider as risk factors, candidate genes for CMZ metabolism, CMZ transport, immunohistocompatibility genes, and candidate genes for QT prolongation.

CONCLUSIONS: The choice of antidepressant treatment for patients with Long COVID is fraught because of the frequent occurrence of subclinical (interictal) epileptiform activity in the EEG. Consequently, antidepressant medications with a proconvulsant effect are contraindicated for Long COVID patients. CMZ may be a promising alternative for the treatment of depressive disorders in Long COVID states, given its mood-stabilizer, antidepressant, and antiepileptic profile.

PMID:36170698