JMIR Form Res. 2022 Aug 17. doi: 10.2196/36759. Online ahead of print.

ABSTRACT

Multi-cohort projects in medicine provide an opportunity to investigate scientific questions beyond the boundaries of a single institution, and to increase sample size for more reliable results. However, the complications of these kinds of collaborations arise during management, with many administrative hurdles. Hands-on approaches and lessons learned from previous collaborations provide solutions for optimized collaboration models. Here, we use our experience in running the Swiss multi-cohort project PGX-link to show the strategy we used to tackle different challenges from project set up to getting the relevant permits, including ethics approval. We set PGX-link into an international context, since our struggles were similar to those encountered during the SYNCHROS project. We provide ad-hoc solutions for cohorts, general project management strategies, and suggestions for unified protocols between cohorts that would ease current management hurdles. Project managers are not necessarily familiar with medical projects, and even if they are, they are not aware of the intricacies behind decision making, and consequently of the time needed to set up multi-cohort collaborations. This paper is meant to be a brief overview of what we went through with our multi-cohort project and provides the necessary practices for future managers.

PMID:35976179 | DOI:10.2196/36759

BJPsych Open. 2022 Aug 17;8(5):e157. doi: 10.1192/bjo.2022.554.

ABSTRACT

There is growing evidence for the use of pharmacogenomics in psychotropic prescribing. People with intellectual disabilities are disproportionately prescribed psychotropics and are at risk of polypharmacy. There is an urgent need for safeguards to prevent psychotropic overprescribing but it is equally crucial that this population is not left behind in such exciting initiatives. Understanding how genetic variations affect medications is a step towards personalised medicine. This may improve personalised prescribing for people with intellectual disabilities, especially given the high rate of psychiatric and behavioural problems in this population. Our editorial explores opportunities and challenges that pharmacogenomics offers for the challenges of polypharmacy and overprescribing of psychotropics in people with intellectual disabilities.

PMID:35975635 | DOI:10.1192/bjo.2022.554

Pestic Biochem Physiol. 2022 Aug;186:105152. doi: 10.1016/j.pestbp.2022.105152. Epub 2022 Jun 20.

ABSTRACT

Chemical or drug treatments are successfully used to treat parasitic nematode infections that impact human, animal and plant health. Many of these exert their effects through modifying neural function underpinning behaviours essential for parasite viability. Selectivity against the parasite may be achieved through distinct pharmacological properties of the parasite nervous system, as exemplified by the success of the ivermectin which target a glutamate-gated chloride channel found only in invertebrates. Despite the success of the ivermectins, emerging resistance and concerns around eco-toxicity are driving the search for new nematocidal chemicals or drugs. Here, we describe the potential of a 5-HT-gated chloride channel MOD-1, which is involved in vital parasite behaviours with constrained distribution in the invertebrate phyla. This ion channel has potential pharmacophores that could be targeted by new nematocidal chemicals and drugs. We have developed a microtiter based bioassay for MOD-1 pharmacology based on its ectopic expression in the Caenorhabditis elegans essential neuron M4. We have termed this technology 'PhaGeM4' for 'Pharmacogenetic targeting of M4 neuron'. Exposure of transgenic worms harbouring ectopically expressed MOD-1 to 5-HT results in developmental arrest. By additional expression of a fluorescence marker in body wall muscle to monitor growth we demonstrate that this assay is suitable for the identification of receptor agonists and antagonists. Indeed, the developmental progression is a robustly quantifiable bioassay that resolves MOD-1 activation by quipazine, 5-carboxyamidotryptamine and fluoxetine and highlight methiothepin as a potent antagonist. This assay has the intrinsic ability to highlight compounds with optimal bioavailability and furthermore to filter out off-target effects. It can be extended to the investigation of other classes of membrane receptors and modulators of neuronal excitation. This approach based on heterologous modulation of the essential M4 neuron function offers a route to discover new effective and selective anthelmintics potentially less confounded by disruptive environmental impact.

PMID:35973757 | DOI:10.1016/j.pestbp.2022.105152

J Transl Med. 2022 Aug 16;20(1):371. doi: 10.1186/s12967-022-03557-7.

ABSTRACT

BACKGROUND: Despite the increasing number of treatment options, reliable prognostic/predictive biomarkers are still missing for patients affected by metastatic clear cell renal cell carcinoma (mccRCC).

METHODS: Patients with mccRCC undergoing standard first line treatment were enrolled. Blood (12 ml) was drawn at treatment baseline and circulating free DNA (cfDNA) was extracted from plasma. Next-generation sequencing (NGS) was performed on cfDNA using the Oncomine Pan-Cancer Cell-Free Assay and clinical outcomes were correlated with liquid biopsy findings.

RESULTS: A total of 48 patients were enrolled, 12 received immunotherapy and 36 received a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI). A cfDNA cut-off of 0.883 ng/μl stratified patients based on progression-free survival (PFS) and overall survival (OS) (p = 0.001 and p = 0.008, respectively). cfDNA amount was also correlated with best response (p = 0.006). Additional cfDNA cut-points divided patients into short, intermediate and long responders, with PFS of 4.87 vs 9.13 vs 23.1 months, respectively (p < 0.001). PFS resulted to be significantly shorter in carriers of mutant TP53 compared to not carriers (p = 0.04). Patients with high cfDNA levels and mutant TP53 have the worst PFS, while patients with low cfDNA amounts and no mutations in TP53 displayed the longest PFS (p = 0.004).

CONCLUSIONS: The present study demonstrates that cfDNA and TP53 are potential predictive biomarkers of response in mccRCC to be further explored in larger and/or prospective studies.

PMID:35974365 | DOI:10.1186/s12967-022-03557-7

Encephale. 2022 Aug 13:S0013-7006(22)00124-5. doi: 10.1016/j.encep.2022.03.011. Online ahead of print.

ABSTRACT

OBJECTIVES: Several international guidelines for the pharmacological treatment of posttraumatic stress disorder (PTSD) have been published. However, it is unclear whether clinicians use these procedures in their daily practice. We compared the psychopharmacological prescription patterns in a Swiss adult psychiatric center with international clinical guidelines at admission and discharge.

METHODS: Retrospective chart review study between 2005 and 2015 of adult patients with PTSD and no other documented psychiatric comorbidity.

RESULTS: Fifty-two outpatients and 21 inpatients were included; 47% had at least one psychopharmacological treatment at admission. Among them, 47% had one or several antidepressants, mainly escitalopram (31%, n=5) or citalopram. At discharge, 68% had at least one psychopharmacological treatment. Among them, 76% had at least one antidepressant, mainly escitalopram (34%, n=13) or mirtazapine (21%, n=8). They were compared to the guidelines of the Department of Veterans Affairs and Department of Defense (VA/DoD), showing 19% of the patients treated with antidepressants at admission were in agreement with the guidelines (sertraline, fluoxetine, paroxetine, venlafaxine), and 26% at discharge. In addition, we found prescriptions of benzodiazepines (62% at admission and 50% at discharge), antipsychotics (12% and 22%), Z-drugs (zolpidem, zopiclone: 15 and 40%) and a few pregabalin prescriptions (n=4).

CONCLUSIONS: Clinicians in this study frequently prescribed antidepressants to treat PTSD, as recommended. However, most of the antidepressants used were not recommended in the VA/DoD guidelines. Benzodiazepines and Z-drugs remained widely used, although they are not recommended.

PMID:35973850 | DOI:10.1016/j.encep.2022.03.011

Hum Mol Genet. 2022 Aug 16:ddac193. doi: 10.1093/hmg/ddac193. Online ahead of print.

ABSTRACT

Advances in genomics have led to the identification of many risk loci with hundreds of genes and thousands of DNA variants associated with neuropsychiatric disorders. A significant barrier to understanding the genetic underpinnings of complex diseases is the lack of functional characterization of risk genes and variants in biological systems relevant to human health and connecting disease-associated variants to pathological phenotypes. Characterizing gene and DNA variant functions requires genetic perturbations followed by molecular and cellular assays of neurobiological phenotypes. However, generating null or mutant alleles is low throughput, making it impossible to characterize disease-associated variants in large quantities efficiently. CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) screens can be leveraged to dissect the biological consequences of the tested genes and variants in their native context. Nevertheless, testing non-coding variants associated with complex diseases remains non-trivial. In this review, we first discuss the current challenges of interpreting the function of the non-coding genome and approaches to prioritizing disease-associated variants in the context of the 3D epigenome. Second, we provide a brief overview of high throughput CRISPRi and CRISPRa screening strategies applicable for characterizing non-coding sequences in appropriate biological systems. Lastly, we discuss the promising prospects of using CRISPR-based technologies to dissect DNA sequences associated with neuropsychiatric diseases.

PMID:35972825 | DOI:10.1093/hmg/ddac193

Acta Oncol. 2022 Aug 16:1-4. doi: 10.1080/0284186X.2022.2109423. Online ahead of print.

NO ABSTRACT

PMID:35972781 | DOI:10.1080/0284186X.2022.2109423

Pharmacogenomics. 2022 Aug 16. doi: 10.2217/pgs-2022-0078. Online ahead of print.

ABSTRACT

Specific HLA associations with drug hypersensitivity may vary between geographic regions and ethnic groups. There are little to no data related to HLA-drug hypersensitivity on populations who reside in the Greater Middle East (GME), a vast region spanning from Morocco in the west to Pakistan in the east. In this review, the authors intended to summarize the significant HLA alleles associated with hypersensitive drug reactions induced by different drugs, as have been found in different populations, and to summarize the prevalence of these alleles in the specific and diverse populations of the GME. For example, HLA-B*57:01 allele prevalence, associated with abacavir-induced hypersensitivity, ranges from 1% to 3%, and HLA-DPB1*03:01 prevalence, associated with aspirin-induced asthma, ranges from 10% to 14% in the GME population. Studying pharmacogenomic associations in the ethnic groups of the GME may allow the discovery of new associations, confirm ones found with a low evidence rate and enable cost-effectiveness analysis of allele screening before drug use.

PMID:35971864 | DOI:10.2217/pgs-2022-0078

Pharmacogenomics. 2022 Aug 16. doi: 10.2217/pgs-2022-0079. Online ahead of print.

ABSTRACT

Aim: This work examined whether ARG1 (rs2781659, rs2781667, rs2246012 and rs17599586) and ARG2 (rs3742879 and rs10483801) single-nucleotide polymorphisms (SNPs) are associated with antihypertensive therapy responsiveness in preeclampsia (PE) and their effects on arginase isoforms and nitrite concentrations in responsive and nonresponsive patients. Methods: SNP genotypes were determined by TaqMan assays. Plasma arginase levels were measured by ELISA and nitrite concentrations were measured using an ozone-based chemiluminescence assay. Results: The G allele for ARG2 rs3742879 (A>G) was less frequent in nonresponsive compared with responsive patients (15.5% vs 24.7%) and the G carriers of the nonresponsive subgroup had lower arginase 2 (9.2 ± 7.5 ng/ml vs 19.1 ± 17.3 ng/ml) and higher nitrite concentrations (110.2 ± 52.8 nM vs 78.5 ± 37.9 nM) than carriers of the AA genotype (all p < 0.05). Conclusion: ARG2 SNP rs3742879 is associated with diminished arginase 2 levels and increased nitric oxide formation in nonresponsive PE patients.

PMID:35971863 | DOI:10.2217/pgs-2022-0079

Basic Clin Pharmacol Toxicol. 2022 Aug 16. doi: 10.1111/bcpt.13779. Online ahead of print.

ABSTRACT

Genetic factors have long been recognized as important determinants of inter-individual variability in drug efficacy and toxicity. However, despite the increasing number of established gene-drug associations, candidate polymorphisms can only explain a fraction of the genetically encoded functional variability in drug disposition. Advancements in genetic profiling methods now allow to analyse the landscape of human pharmacogenetic variations comprehensively, which opens new opportunities to identify novel factors that could explain the "missing heritability". Here, we provide an updated overview of the landscape of pharmacogenomic variability based on recent analyses of population-scale sequencing projects. We then summarize the current state-of-the-art how the functional consequences of variants with unknown effects can be quantitatively estimated while discussing challenges and peculiarities that are specific to pharmacogenes. In the last sections, we discuss the importance of considering ethnogeographic diversity to provide equitable benefits of pharmacogenomics and summarize current roadblocks for the implementation of sequencing-based guidance of clinical decision-making. Based on the current state of the field, we conclude that testing is likely to gradually shift from the interrogation of selected candidate polymorphisms to comprehensive sequencing, which allows to consider the full spectrum of pharmacogenomic variations for a true personalization of genomic prescribing.

PMID:35971800 | DOI:10.1111/bcpt.13779

Pharmacogenomics. 2022 Aug 15. doi: 10.2217/pgs-2022-0044. Online ahead of print.

ABSTRACT

Introduction: Atorvastatin exhibits wide interindividual variability in treatment response, limiting the drug efficacy in coronary artery disease patients. Aim: To study the effect of genetic variants involved in atorvastatin transport/metabolism and correlate their lipid-lowering efficacy. Materials & methods: Genotyping was performed using 5'-hydrolysis probe method (n = 412), and the study evaluated the treatment response in 86 patients. Results: Significant reduction in total cholesterol and low-density lipoprotein cholesterol (LDL-C) were observed in SLCO1B1-rs4149056, rs4363657 and ABCB1-rs1045642 genotypes. The combined genotypes of ABCB1 and SLCO1B1 showed a strong synergistic effect in reducing the total cholesterol and LDL-C. Diabetes and smoking were observed to influence the LDL-C reduction. Conclusion: The genetic variants of SLCO1B1 and ABCB1 predict the lipid-lowering efficacy of atorvastatin, and this may be useful in genotype-guided statin therapy for coronary artery disease patients.

PMID:35968761 | DOI:10.2217/pgs-2022-0044

Expert Rev Clin Pharmacol. 2022 Aug 13. doi: 10.1080/17512433.2022.2112949. Online ahead of print.

ABSTRACT

INTRODUCTION: The efficacy of antidepressants for patients with major depressive disorder (MDD) varies from individual to individual, making the prediction of therapeutic outcomes difficult. Better methods for predicting antidepressant outcomes are needed. However, complex interactions between biological, psychological, and environmental factors affect outcomes, presenting immense computational challenges for prediction. Using machine learning (ML) techniques with pharmacogenomics data provides one pathway towards individualized prediction of therapeutic outcomes of antidepressants.

AREAS COVERED: This report systematically reviews the methods, results, and limitations of individual studies of ML and pharmacogenomics for predicting response and/or remission with antidepressants in patients with MDD. Future directions for research and pragmatic considerations for the clinical implementation of ML-based pharmacogenomic algorithms are also discussed.

EXPERT OPINION: ML methods utilizing pharmacogenomic and clinical data demonstrate promising results for predicting short-term antidepressant response. However, predictions of antidepressant treatment outcomes depend on contextual factors that ML algorithms may not be able to capture. As such, ML-driven prediction is best viewed as a companion to clinical judgment, not its replacement. Successful implementation and adoption of methods predicting antidepressant response warrants provider education about ML and close collaborations between computing scientists, pharmacogenomic experts, health system engineers, laboratory medicine experts and clinicians.

PMID:35968639 | DOI:10.1080/17512433.2022.2112949

Front Cardiovasc Med. 2022 Jul 28;9:887705. doi: 10.3389/fcvm.2022.887705. eCollection 2022.

ABSTRACT

Radiotherapy (RT) is one of the pillars of cancer therapy. High-dose radiation exposure on the thorax is mainly used in the context of adjuvant RT after breast surgery, in lung and esophageal cancer, and as a complement to systemic treatment in lymphoma. Due to the anatomical proximity, the heart inevitably receives some radiation that can result in acute and chronic cardiotoxicity, leading to heart failure, coronary artery disease, pericardial and valvular heart disease. Current evidence suggests there is no safe radiation dose to the heart, which poses a need for early recognition of RT-induced cardiac injury to initiate cardioprotective treatment and prevent further damage. Multimodality cardiac imaging provides a powerful tool to screen for structural and functional abnormalities secondary to RT. Left ventricular ejection fraction, preferably with three-dimensional echocardiography or cardiovascular magnetic resonance (CMR), and global longitudinal strain with speckle-tracking echocardiography are currently the key parameters to detect cardiotoxicity. However, several novel imaging parameters are tested in the ongoing clinical trials. CMR parametric imaging holds much promise as T1, T2 mapping and extracellular volume quantification allow us to monitor edema, inflammation and fibrosis, which are fundamental processes in RT-induced cardiotoxicity. Moreover, the association between serum biomarkers, genetic polymorphisms and the risk of developing cardiovascular disease after chest RT has been demonstrated, providing a platform for an integrative screening approach for cardiotoxicity. The present review summarizes contemporary evidence of RT-induced cardiac injury obtained from multimodality imaging-echocardiography, cardiovascular computed tomography, CMR and nuclear cardiology. Moreover, it identifies gaps in our current knowledge and highlights future perspectives to screen for RT-induced cardiotoxicity.

PMID:35966531 | PMC:PMC9366112 | DOI:10.3389/fcvm.2022.887705

Front Oncol. 2022 Jul 29;12:972718. doi: 10.3389/fonc.2022.972718. eCollection 2022.

NO ABSTRACT

PMID:35965582 | PMC:PMC9372610 | DOI:10.3389/fonc.2022.972718

Allergol Int. 2022 Aug 11:S1323-8930(22)00081-8. doi: 10.1016/j.alit.2022.07.003. Online ahead of print.

NO ABSTRACT

PMID:35965193 | DOI:10.1016/j.alit.2022.07.003

Chem Biol Interact. 2022 Aug 11:110097. doi: 10.1016/j.cbi.2022.110097. Online ahead of print.

ABSTRACT

Remdesivir (RDV, Veklury®) is an FDA-approved prodrug for the treatment of hospitalized patients with COVID-19. Recent in vitro studies have indicated that human carboxylesterase 1 (CES1) is the major metabolic enzyme catalyzing RDV activation. COVID-19 treatment for hospitalized patients typically also involves a number of antibiotics and anti-inflammatory drugs. Further, individuals who are carriers of a CES1 variant (polymorphism in exon 4 codon 143 [G143E]) may experience impairment in their ability to metabolize therapeutic agents which are CES1 substrates. The present study assessed the potential influence of nine therapeutic agents (hydroxychloroquine, ivermectin, erythromycin, clarithromycin, roxithromycin, trimethoprim, ciprofloxacin, vancomycin, and dexamethasone) commonly used in treating COVID-19 and 5 known CES1 inhibitors on the metabolism of RDV. Additionally, we further analyzed the mechanism of inhibition of cannabidiol (CBD), as well as the impact of the G143E polymorphism on RDV metabolism. An in vitro S9 fraction incubation method and in vitro to in vivo pharmacokinetic scaling were utilized. None of the nine therapeutic agents evaluated produced significant inhibition of RDV hydrolysis; CBD was found to inhibit RDV hydrolysis by a mixed type of competitive and noncompetitive partial inhibition mechanism. In vitro to in vivo modeling suggested a possible reduction of RDV clearance and increase of AUC when coadministration with CBD. The same scaling method also suggested a potentially lower clearance and higher AUC in the presence of the G143E variant. In conclusion, a potential CES1-mediated DDI between RDV and the nine assessed medications appears unlikely. However, a potential CES1-mediated DDI between RDV and CBD may be possible with sufficient exposure to the cannabinoid. Patients carrying the CES1 G143E variant may exhibit a slower biotransformation and clearance of RDV. Further clinical studies would be required to evaluate and characterize the clinical significance of a CBD-RDV interaction.

PMID:35964681 | DOI:10.1016/j.cbi.2022.110097

Cancer Cell Int. 2022 Aug 13;22(1):256. doi: 10.1186/s12935-022-02667-y.

NO ABSTRACT

PMID:35964054 | DOI:10.1186/s12935-022-02667-y

Pharmacogenomics J. 2022 Aug 13. doi: 10.1038/s41397-022-00286-4. Online ahead of print.

ABSTRACT

This pilot study is aimed at implementing an approach for comprehensive clinical pharmacogenomics (PGx) profiling. Fifty patients with cardiovascular diseases and 50 healthy individuals underwent whole-exome sequencing. Data on 1800 PGx genes were extracted and analyzed through deep filtration separately. Theoretical drug induced phenoconversion was assessed for the patients, using sequence2script. In total, 4539 rare variants (including 115 damaging non-synonymous) were identified. Four publicly available PGx bioinformatics algorithms to assign PGx haplotypes were applied to nine selected very important pharmacogenes (VIP) and revealed a 45-70% concordance rate. To ensure availability of the results at point-of-care, actionable variants were stored in a web-hosted database and PGx-cards were developed for quick access and handed to the study subjects. While a comprehensive clinical PGx profile could be successfully extracted from WES data, available tools to interpret these data demonstrated inconsistencies that complicate clinical application.

PMID:35963939 | DOI:10.1038/s41397-022-00286-4

BMC Cancer. 2022 Aug 13;22(1):884. doi: 10.1186/s12885-022-09989-0.

ABSTRACT

BACKGROUND: Hepatocellular carcinoma (HCC) is a fatal disease characterized by early genetic alterations in telomerase reverse transcriptase promoter (TERTp) and β-catenin (CTNNB1) genes and immune cell activation in the tumor microenvironment. As a novel approach, we wanted to assess patient survival influenced by combined presence of mutations and densities of CD8+ cytotoxic T cells.

METHODS: Tissue samples were obtained from 67 HCC patients who had undergone resection. We analysed CD8+ T cells density, TERTp mutations, rs2853669 polymorphism, and CTNNB1 mutations. These variables were evaluated for time to recurrence (TTR) and disease free survival (DFS).

RESULTS: TERTp mutations were found in 75.8% and CTNNB1 mutations in 35.6% of the patients. TERTp mutations were not associated with survival but polymorphism rs2853669 in TERTp was associated with improved TTR and DFS. CTNNB1 mutations were associated with improving TTR. High density of CD8+ T-lymphocytes in tumor center and invasive margin correlated with longer TTR and DFS. Combined genetic and immune factors further improved survival showing higher predictive values. E.g., combining CTNNB1 mutations and high density of CD8+ T-lymphocytes in tumor center yielded HRs of 0.12 (0.03-0.52), p = 0.005 for TTR and 0.25 (0.09-0.74), p = 0.01 for DFS.

CONCLUSION: The results outline a novel integrative approach for prognostication through combining independent predictive factors from genetic and immune cell profiles. However, larger studies are needed to explore multiple cell types in the tumor microenvironment.

PMID:35962322 | DOI:10.1186/s12885-022-09989-0

Ir J Med Sci. 2022 Aug 13. doi: 10.1007/s11845-022-03112-9. Online ahead of print.

ABSTRACT

Patients presenting with degenerative spinal changes are often poor surgical candidates due to associated co-morbidities, frailty, or sarcopenia. Additionally, surgeries of a degenerative spine can prove difficult due to the distortion of normal surgical anatomy. Therefore, many patients are managed conservatively with a variety of modalities, including over-the-counter and prescription medications. Nevertheless, several patients do not experience adequate relief from pain with analgesic medications, precipitating multiple hospital visits, and usage of resources. As a result, back pain is regarded as a major economic burden, with total costs of associated treatment exceeding $100 billion annually. Pharmacogenetics is a relatively novel method of evaluating an individual's response to analgesic medications, through analysis of germline polymorphisms. It entails obtaining a genetic sample, often via buccal swab or peripheral blood sample, and genetic analysis achieved through either polymerase chain reaction +/- Sanger sequencing, microassays, restriction length fragment polymorphism analysis, or genetic library preparation and next generation sequencing. The potential efficacy of pharmacogenetic analysis has been highlighted across several specialities to date. However, a paucity of evidence exists regarding spine surgery populations. Nevertheless, regular prospective pharmacogenetic analysis may ultimately prove beneficial when concerning degenerative spinal cohorts due to aforementioned surgical and economic considerations. The purpose of this narrative review is to outline how metaboliser profile variants affect the pharmacokinetics of specific analgesia used to treat back pain, and to discuss the current potential and limitations of employing regular pharmacogenetic analysis for spine surgery populations with degenerative conditions.

PMID:35962253 | DOI:10.1007/s11845-022-03112-9