Int J Mol Sci. 2021 May 21;22(11):5455. doi: 10.3390/ijms22115455.

ABSTRACT

Sigma-1 receptor (chaperone Sigma1R) is an intracellular protein with chaperone functions, which is expressed in various organs, including the brain. Sigma1R participates in the regulation of physiological mechanisms of anxiety (Su, T. P. et al., 2016) and reactions to emotional stress (Hayashi, T., 2015). In 2006, fabomotizole (ethoxy-2-[2-(morpholino)-ethylthio]benzimidazole dihydrochloride) was registered in Russia as an anxiolytic (Seredenin S. and Voronin M., 2009). The molecular targets of fabomotizole are Sigma1R, NRH: quinone reductase 2 (NQO2), and monoamine oxidase A (MAO-A) (Seredenin S. and Voronin M., 2009). The current study aimed to clarify the dependence of fabomotizole anxiolytic action on its interaction with Sigma1R and perform a docking analysis of fabomotizole interaction with Sigma1R. An elevated plus maze (EPM) test revealed that the anxiolytic-like effect of fabomotizole (2.5 mg/kg i.p.) administered to male BALB/c mice 30 min prior EPM exposition was blocked by Sigma1R antagonists BD-1047 (1.0 mg/kg i.p.) and NE-100 (1.0 mg/kg i.p.) pretreatment. Results of initial in silico study showed that fabomotizole locates in the active center of Sigma1R, reproducing the interactions with the site's amino acids common for established Sigma1R ligands, with the ΔGbind value closer to that of agonist (+)-pentazocine in the 6DK1 binding site.

PMID:34064275 | DOI:10.3390/ijms22115455

J Pers Med. 2021 May 21;11(6):446. doi: 10.3390/jpm11060446.

ABSTRACT

Psychiatric disorder management is based on the prescription of psychotropic drugs. Response to them remains often insufficient and varies from one patient to another. Pharmacogenetics explain part of this variability. Pharmacogenetic testing is likely to optimize the choice of treatment and thus improve patients' care, even if concerns and limitations persist. This practice of personalized medicine is not very widespread in France. We conducted a national survey to evaluate the acceptability of this tool by psychiatrists and psychiatry residents in France, and to identify factors associated with acceptability and previous use. The analysis included 397 observations. The mean acceptability score was 10.70, on a scale from 4 to 16. Overall acceptability score was considered as low for 3.0% of responders, intermediate for 80.1% and high for 16.9%. After regression, the remaining factors influencing acceptability independently of the others were prescription and training history and theoretical approach. The attitude of our population seems to be rather favorable, however, obvious deficiencies have emerged regarding perceived skills and received training. Concerns about the cost and delays of tests results also emerged. According to our survey, one of the keys to overcoming the barriers encountered in the integration of pharmacogenetics seems to be the improvement of training and the provision of information to practitioners.

PMID:34064030 | DOI:10.3390/jpm11060446

Pharmaceuticals (Basel). 2021 May 21;14(6):491. doi: 10.3390/ph14060491.

ABSTRACT

Cisplatin is an antineoplastic drug used for the treatment of many solid tumors. Among its various side effects, nephrotoxicity is the most detrimental. In recent years, epigenetic regulation has emerged as a modulatory mechanism of cisplatin-induced nephrotoxicity, involving non-coding RNAs, DNA methylation and histone modifications. These epigenetic marks alter different signaling pathways leading to damage and cell death. In this review, we describe how different epigenetic modifications alter different pathways leading to cell death by apoptosis, autophagy, necroptosis, among others. The study of epigenetic regulation is still under development, and much research remains to fully determine the epigenetic mechanisms underlying cell death, which will allow leading new strategies for the diagnosis and therapy of this disease.

PMID:34063951 | DOI:10.3390/ph14060491

J Pers Med. 2021 May 21;11(6):443. doi: 10.3390/jpm11060443.

ABSTRACT

Chronic disease management often requires use of multiple drug regimens that lead to polypharmacy challenges and suboptimal utilization of healthcare services. While the rising costs and healthcare utilization associated with polypharmacy and drug interactions have been well documented, effective tools to address these challenges remain elusive. Emerging evidence that proactive medication management, combined with pharmacogenomic testing, can lead to improved health outcomes and reduced cost burdens may help to address such gaps. In this report, we describe informatic and bioanalytic methodologies that integrate weak signals in symptoms and chief complaints with pharmacogenomic analysis of ~90 single nucleotide polymorphic variants, CYP2D6 copy number, and clinical pharmacokinetic profiles to monitor drug-gene pairs and drug-drug interactions for medications with significant pharmacogenomic profiles. The utility of the approach was validated in a virtual patient case showing detection of significant drug-gene and drug-drug interactions of clinical significance. This effort is being used to establish proof-of-concept for the creation of a regional database to track clinical outcomes in patients enrolled in a bioanalytically-informed medication management program. Our integrated informatic and bioanalytic platform can provide facile clinical decision support to inform and augment medication management in the primary care setting.

PMID:34063850 | DOI:10.3390/jpm11060443

PLoS Genet. 2021 Jun 1;17(6):e1009593. doi: 10.1371/journal.pgen.1009593. Online ahead of print.

ABSTRACT

Understanding the contribution of genetic variation to drug response can improve the delivery of precision medicine. However, genome-wide association studies (GWAS) for drug response are uncommon and are often hindered by small sample sizes. We present a high-throughput framework to efficiently identify eligible patients for genetic studies of adverse drug reactions (ADRs) using "drug allergy" labels from electronic health records (EHRs). As a proof-of-concept, we conducted GWAS for ADRs to 14 common drug/drug groups with 81,739 individuals from Vanderbilt University Medical Center's BioVU DNA Biobank. We identified 7 genetic loci associated with ADRs at P < 5 × 10-8, including known genetic associations such as CYP2D6 and OPRM1 for CYP2D6-metabolized opioid ADR. Additional expression quantitative trait loci and phenome-wide association analyses added evidence to the observed associations. Our high-throughput framework is both scalable and portable, enabling impactful pharmacogenomic research to improve precision medicine.

PMID:34061827 | DOI:10.1371/journal.pgen.1009593

Eur J Neurol. 2021 Jun 1. doi: 10.1111/ene.14950. Online ahead of print.

ABSTRACT

INTRODUCTION: Charcot-Marie-Tooth (CMT) disease, an untreatable hereditary polyneuropathy, may mimic chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), a treatable neuropathy.

OBJECTIVE: In this retrospective study, we analyzed the characteristics of CMT patients misdiagnosed as CIDP in 16 University Hospitals from 3 countries, compared these patients with a reference group of CIDP patients, and estimated the cost of misdiagnosis.

RESULTS: Amongst 1104 CIDP cases, we identified 35 CMT patients misdiagnosed as CIDP (3.2%). All were initially diagnosed with definite or probable CIDP (EFNS/PNS criteria), and mutations in the PMP22, MPZ and 10 other CMT genes were found in 34%, 31% and 35% of cases respectively. In comparison with a reference group of 35 CIDP patients, CMT patients were younger (median age at disease-onset: 39 vs 56 years), and more frequently had motor weakness at disease onset (80% vs 29%), hearing loss (14% vs 0%), normal brachial plexus imaging (70% vs 40%), lower cerebrospinal fluid protein content (median: 0.5 vs 0.8 g/L), and lower treatment response (20% vs 69%). Treatment cost in these 35 misdiagnosed patients was estimated at 4,6 Million € (M€), whereas the cost of CMT genetic analysis in 1104 patients was estimated at 2,7M€.

CONCLUSION: In this study, 35/1104 (3.2%) of patients initially diagnosed with CIDP had CMT. Importantly, the cost of treating these 35 misdiagnosed patients was significantly higher than the cost of performing CMT genetic analysis in 1104 patients (4,6M€ vs 2,7M€), suggesting that CMT genetic investigations should be more widely used before diagnosing CIDP.

PMID:34060689 | DOI:10.1111/ene.14950

Pharmacogenomics. 2021 Jun 1. doi: 10.2217/pgs-2020-0151. Online ahead of print.

ABSTRACT

Aim: Phenytoin is metabolized through CYP2C9 and CYP2C19. Polymorphisms of CYP2C9 and CYP2C19 may increase plasma concentration and side effects. Materials & methods: Systematic review and meta-analysis were performed to evaluate the effects of CYP2C9 and CYP2C19 polymorphism on pharmacokinetic parameters. PubMed, Science Direct, Cochrane library, and Thai databases were systematically searched. Results: Eight observational studies, comprising a total of 633 patients were included. Michaelis-Menten constant was significantly higher in the polymorphism of CYP2C9IM/CYP2C19EM and CYP2C9IM/CYP2C19IM groups as compared with the control groups (CYP2C9EM/CYP2C19EM) at 2.16 and 1.55 mg/l (p < 0.00001, p < 0.0001). The maximum rate of action was significantly lower in the control groups as compared with the polymorphism of CYP2C9IM/CYP2C19EM and CYP2C9IM/CYP2C19IM groups at 3.10 and 3.53 mg/kg/day (p = 0.00001, <0.0001). Conclusion: The dosage regimen for patients in the CYP2C9IM group to achieve phenytoin therapeutic levels was 2.1-3.4 mg/kg/day.

PMID:34060344 | DOI:10.2217/pgs-2020-0151

Nat Genet. 2021 May 31. doi: 10.1038/s41588-021-00852-9. Online ahead of print.

ABSTRACT

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.

PMID:34059833 | DOI:10.1038/s41588-021-00852-9

NPJ Genom Med. 2021 May 31;6(1):37. doi: 10.1038/s41525-021-00202-y.

ABSTRACT

The success of immunotherapy was overshadowed by its low response rate, and the hot or cold tumor microenvironment was reported to be responsible for it. However, due to the lack of an appropriate method, it is still a huge challenge for researchers to understand the molecular differences between hot and cold tumor microenvironments. Further research is needed to gain deeper insight into the molecular characteristics of the hot/cold tumor microenvironment. A large-scale clinical cohort and single-cell RNA-seq technology were used to identify the molecular characteristics of inflamed or noninflamed tumors. With single-cell RNA sequencing technology, we provided a novel method to dissect the tumor microenvironment into a hot/cold tumor microenvironment to help us understand the molecular differences between hot and cold tumor microenvironments. Compared with cold tumors, hot tumors highly expressed B cell-related genes, such as MS4A1 and CXCR5, neurogenesis-related miRNA such as MIR650, and immune molecule-related lncRNA such as MIR155HG and LINC00426. In cold tumors, the expression of genes related to multiple biological processes, such as the neural system, was significantly upregulated, and methylome analysis indicated that the promoter methylation level of genes related to neurogenesis was significantly reduced. Finally, we investigated the pan-cancer prognostic value of the cold/hot microenvironment and performed pharmacogenomic analysis to predict potential drugs that may have the potential to convert the cold microenvironment into a hot microenvironment. Our study reveals the multiomics characteristics of cold/hot microenvironments. These molecular characteristics may contribute to the understanding of immune exclusion and the development of microenvironment-targeted therapy.

PMID:34059678 | DOI:10.1038/s41525-021-00202-y

Auto Immun Highlights. 2021 May 31;12(1):9. doi: 10.1186/s13317-021-00152-6.

ABSTRACT

OBJECTIVE: To aid in the selection of the most suitable therapeutic option in patients with diagnosis of rheumatoid arthritis according to the phase of disease, through the review of articles that identify omics biological markers.

METHODS: A systematic review in PubMed/Medline databases was performed. We searched articles from August 2014 to September 2019, in English and Spanish, filtered by title and full text; and using the terms "Biomarkers" AND "Rheumatoid arthritis".

RESULTS: This article supplies an exhaustive review from research of objective measurement, omics biomarkers and how disease activity appraise decrease unpredictability in treatment determinations, and finally, economic, and clinical outcomes of treatment options by biomarkers' potential influence. A total of 122 articles were included. Only 92 met the established criteria for review purposes and 17 relevant references about the topic were included as well. Therefore, it was possible to identify 196 potential clinical biomarkers: 22 non-omics, 20 epigenomics, 33 genomics, 21 transcriptomics, 78 proteomics, 4 glycomics, 1 lipidomics and 17 metabolomics.

CONCLUSION: A biomarker is a measurable indicator of some, biochemical, physiological, or morphological condition; evaluable at a molecular, biochemical, or cellular level. Biomarkers work as indicators of physiological or pathological processes, or as a result of a therapeutic management. In the last five years, new biomarkers have been identified, especially the omics, which are those that proceed from the investigation of genes (genomics), metabolites (metabolomics), and proteins (proteomics). These biomarkers contribute to the physician choosing the best therapeutic option in patients with rheumatoid arthritis.

PMID:34059137 | DOI:10.1186/s13317-021-00152-6

Eur J Cancer. 2021 May 28;152:1-3. doi: 10.1016/j.ejca.2021.04.027. Online ahead of print.

NO ABSTRACT

PMID:34058699 | DOI:10.1016/j.ejca.2021.04.027

Clin Transl Sci. 2021 May 31. doi: 10.1111/cts.13057. Online ahead of print.

NO ABSTRACT

PMID:34058073 | DOI:10.1111/cts.13057

Breast Cancer (Dove Med Press). 2021 May 21;13:325-339. doi: 10.2147/BCTT.S308554. eCollection 2021.

ABSTRACT

INTRODUCTION: Breast cancer (BC) is the second most frequent cancer worldwide. It is known that a subset of BC has amplification, and overexpression of the epidermal growth factor receptor (EGFR) and high expression of the insulin-like growth factor receptor-1 (IGF-1R) are correlated with a favorable prognosis. This study aimed to evaluate the prognostic and predictive values of the EGFR and IGF-1R in tumor samples from patients with BC and their correlation with socio-epidemiological features.

PATIENTS AND METHODS: We analyzed socio-epidemiological, clinical-pathological data and tumor tissues from 124 patients with BC undergoing treatment, to assess levels of EGFR and IGF-1R mRNA and protein. The predictive performance included the calculation of area-under-the-curve (AUC) to discriminate groups of patients with high and low mRNA expression associated with survival analysis within each molecular group of BC.

RESULTS: We found a significant expression increase (p <0.001) in EGFR associated with body mass index, angiolymphatic invasion, compromised lymph nodes and follow-up in 58.1% of the triple-negative and HER overexpression tumors. The increase in IGF-IR was significant (p <0.001) in 41.9% of luminal tumors A and B. ROC analysis showed that EGFR had a higher predictive performance (AUC = 0.891) than IGF-1R (AUC = 0.60). The Kaplan-Meier analysis indicated that only the high expression of EGFR was associated with a decreased probability of survival for patients, what did not happen with IGF-1R.

CONCLUSION: Our results suggest that EGFR and IGF-1R expression patterns associated with the clinical characteristics of patients and biological profile influenced the evolution of BC.

PMID:34054308 | PMC:PMC8153070 | DOI:10.2147/BCTT.S308554

Cell Death Discov. 2021 May 29;7(1):126. doi: 10.1038/s41420-021-00508-x.

ABSTRACT

Cancer stem cells (CSCs) are a major cause of tumor treatment resistance, relapse and metastasis. Cancer cells exhibit reprogrammed metabolism characterized by aerobic glycolysis, which is also critical for sustaining cancer stemness. However, regulation of cancer cell metabolism rewiring and stemness is not completely understood. Here, we report that ETV4 is a key transcription factor in regulating glycolytic gene expression. ETV4 loss significantly inhibits the expression of HK2, LDHA as well as other glycolytic enzymes, reduces glucose uptake and lactate release in breast cancer cells. In human breast cancer and hepatocellular carcinoma tissues, ETV4 expression is positively correlated with glycolytic signaling. Moreover, we confirm that breast CSCs (BCSCs) are glycolysis-dependent and show that ETV4 is required for BCSC maintenance. ETV4 is enriched in BCSCs, its knockdown and overexpression suppresses and promotes breast cancer cell stem-like traits, respectively. Mechanistically, on the one hand, we find that ETV4 may enhance glycolysis activity to facilitate breast cancer stemness; on the other, ETV4 activates Sonic Hedgehog signaling by transcriptionally promoting CXCR4 expression. A xenograft assay validates the tumor growth-impeding effect and inhibition of CXCR4/SHH/GLI1 signaling cascade after ETV4 depletion. Together, our study highlights the potential roles of ETV4 in promoting cancer cell glycolytic shift and BCSC maintenance and reveals the molecular basis.

PMID:34052833 | DOI:10.1038/s41420-021-00508-x

J Pharm Biomed Anal. 2021 May 13;202:114134. doi: 10.1016/j.jpba.2021.114134. Online ahead of print.

ABSTRACT

Accurate metabolome measurements are critical for improved insights into breast cancer metabolic disturbances and enhanced exploration of novel therapeutic targets. Nevertheless, conventional functional interpretation is limited by metabolite identification capacity, which diminishes the scientific value of untargeted metabolomics analyses. In this study, we conducted a metabolomics-guided global pathway meta-analysis to investigate the metabolic alterations of breast cancer. Metabolic features were directly investigated in the pathway meta-analysis to identify breast cancer-associated metabolic processes. Conventional pathway analysis was also conducted involving identified metabolites alone. Comparison of the two strategies revealed that the global pathway meta-analysis approach could avoid the loss of functionally relevant information, relative to the conventional analysis findings. Furthermore, the pathway meta-analysis accurately captured alterations in the following components of the breast cancer metabolome: central carbon metabolism, oxidative glutamine metabolism, purine metabolism, nonessential amino acid metabolism, and glutathione metabolism. There were also substantial alterations of fatty acyl carnitine species and fatty acid β-oxidation processes. These pathways contribute to breast cancer initiation, progression, metastasis, and drug resistance. In conclusion, we suggest that global pathway analysis and the conventional approach with identified metabolites should be employed together to maximize the exploration of breast cancer's metabolic landscape.

PMID:34052553 | DOI:10.1016/j.jpba.2021.114134

Clin Ther. 2021 May 26:S0149-2918(21)00199-5. doi: 10.1016/j.clinthera.2021.04.005. Online ahead of print.

NO ABSTRACT

PMID:34052008 | DOI:10.1016/j.clinthera.2021.04.005

Clin Ther. 2021 May 6:S0149-2918(21)00201-0. doi: 10.1016/j.clinthera.2021.04.007. Online ahead of print.

ABSTRACT

PURPOSE: Given the coronavirus disease 2019 (COVID-19) pandemic, there is a global urgency to discover an effective treatment for patients withthis disease. This study aimed to evaluate the effects of the widely used antiparasitic drug ivermectin on outcomes in patients with COVID-19.

METHODS: In this randomized, double-blind clinical trial, patients with COVID-19 admitted to 2 referral tertiary hospitals in Mazandaran, Iran, were randomly divided into 2 groups: intervention and control. In addition to standard treatment for COVID-19, the intervention group received a single weight-based dose (0.2 mg/kg) of ivermectin; the control group received the standard of care. Demographic, clinical, laboratory, and imaging data from participants were recorded at baseline. Patients were assessed daily for symptoms and disease progression. The primary clinical outcome measures were the durations of hospital stay, fever, dyspnea, and cough; and overall clinical improvement.

FINDINGS: Sixty-nine patients were enrolled (mean [SD] ages: ivermectin, 47.63 [22.20] years; control, 45.18 [23.11] years; P = 0.65). Eighteen patients (51.4%) in the ivermectin group and 18 (52.9%) in control group were male (P = 0.90). The mean durations of dyspnea were 2.6 (0.4) days in the ivermectin group and 3.8 (0.4) days in the control group (P = 0.048). Also, persistent cough lasted for 3.1 (0.4) days in the ivermectin group compared to 4.8 (0.4) days in control group (PP = 0.019). The mean durations of hospital stay were 7.1 (0.5) days versus 8.4 (0.6) days in the ivermectin and control groups, respectively (P = 0.016). Also, the frequency of lymphopenia decreased to 14.3% in the ivermectin group and did not change in the control group (P = 0.007).

IMPLICATIONS: A single dose of ivermectin was well-tolerated in symptomatic patients with COVID-19, and important clinical features of COVID-19 were improved with ivermectin use, including dyspnea, cough, and lymphopenia. Further studies with larger sample sizes, different drug dosages, dosing intervals and durations, especially in different stages of the disease, may be useful in understanding the potential clinical benefits ivermectin. Iranian Registry of Clinical Trials identifier: IRCT20111224008507N3.

PMID:34052007 | DOI:10.1016/j.clinthera.2021.04.007

Transl Oncol. 2021 May 26;14(8):101133. doi: 10.1016/j.tranon.2021.101133. Online ahead of print.

ABSTRACT

Patient-derived tumor xenograft (PDX) is now largely recognized as a key preclinical model for cancer research, mimicking patient tumor phenotype and genotype. Immunodeficient mice, well-known to develop spontaneous lymphoma, are required for PDX growth. As for all animal models used for further clinical translation, a robust experimental design is strongly required to lead to conclusive results. Here we briefly report unintentional co-engraftment of mouse lymphoma during expansion of well-established PDXs to illustrate the importance of systematic check of the PDX identity to avoid misinterpretation. Besides, this quality control based on complementary approaches deserves a more detailed description in materials and methods section to ensure experimental validity and reproducibility.

PMID:34051622 | DOI:10.1016/j.tranon.2021.101133

Crit Rev Oncol Hematol. 2021 May 26:103366. doi: 10.1016/j.critrevonc.2021.103366. Online ahead of print.

ABSTRACT

Lenvatinib is a non-selective tyrosine kinase inhibitor with high in vitro potency against vascular endothelial growth factor receptors. Although this drug is used to treat several cancer types, it is the most effective TKI used in patients with thyroid cancer. Lenvatinib is well tolerated and the most common adverse drug reactions can be adequately managed by dose adjustment. Particularly, blood pressure and cardiac function monitoring, as well as antihypertensive treatment optimization, may be required in patients treated with lenvatinib. Dose reduction should be taken into account in patients with body weight <60 kg or severe hepatic failure. No significant change in lenvatinib pharmacokinetics has been observed with other patient-related factors and very few data are available on lenvatinib pharmacogenetics. Lenvatinib can be administered orally regardless of food and no clinically relevant drug-drug interactions have been reported.

PMID:34051303 | DOI:10.1016/j.critrevonc.2021.103366

J Immunother Cancer. 2021 May;9(5):e002521. doi: 10.1136/jitc-2021-002521.

ABSTRACT

Many adverse reactions associated with immune checkpoint inhibitor (ICI) treatments are immunologically driven and may necessitate discontinuation of the ICI. Herein, we present a patient who had been administered the radio contrast media amidotrizoate multiple times without issue but who then developed a Stevens-Johnson syndrome reaction after coadministration of atezolizumab. Causality was confirmed by a positive re-challenge with amidotrizoate and laboratory investigations that implicated T cells. Importantly, the introduction of atezolizumab appears to have altered the immunologic response to amidotrizoate in terms of the tolerance-elicitation continuum. Proof of concept studies demonstrated enhancement of recall responses to a surrogate antigen panel following in-vitro (healthy donors) and in-vivo (ICI patients) administrations of ICIs. Our findings highlight the importance of considering all concomitant medications in patients on ICIs who develop immune-mediated adverse reactions. In the event of some immune-related adverse reactions, it may be critical to identify the culprit antigen-forming entity that the ICIs have altered the perception of rather than simply attribute causality to the ICI itself in order to optimize both patient safety and treatment of malignancies.

PMID:34049931 | DOI:10.1136/jitc-2021-002521