Front Pharmacol. 2022 Apr 4;13:831099. doi: 10.3389/fphar.2022.831099. eCollection 2022.

ABSTRACT

Cisplatin (DDP) is a well-known anticancer drug used for the treatment of numerous human cancers in solid organs, including bladder, breast, cervical, head and neck squamous cell, ovarian, among others. Its most important mode of action is the DNA-platinum adducts formation, inducing DNA damage response, silencing or activating several genes to induce apoptosis; these mechanisms result in genetics and epigenetics modifications. The ability of DDP to induce tumor cell death is often challenged by the presence of anti-apoptotic regulators, leading to chemoresistance, wherein many patients who have or will develop DDP-resistance. Cancer cells resist the apoptotic effect of chemotherapy, being a problem that severely restricts the successful results of treatment for many human cancers. In the last 30 years, researchers have discovered there are several types of RNAs, and among the most important are non-coding RNAs (ncRNAs), a class of RNAs that are not involved in protein production, but they are implicated in gene expression regulation, and representing the 98% of the human genome non-translated. Some ncRNAs of great interest are long ncRNAs, circular RNAs, and microRNAs (miRs). Accumulating studies reveal that aberrant miRs expression can affect the development of chemotherapy drug resistance, by modulating the expression of relevant target proteins. Thus, identifying molecular mechanisms underlying chemoresistance development is fundamental for setting strategies to improve the prognosis of patients with different types of cancer. Therefore, this review aimed to identify and summarize miRs that modulate chemoresistance in DDP-resistant in the top five deadliest cancer, both in vitro and in vivo human models.

PMID:35444536 | PMC:PMC9015654 | DOI:10.3389/fphar.2022.831099

Mol Psychiatry. 2022 Apr 20. doi: 10.1038/s41380-022-01572-0. Online ahead of print.

ABSTRACT

Antipsychotic drugs are the mainstay in the treatment of schizophrenia. However, one-third of patients do not show adequate improvement in positive symptoms with non-clozapine antipsychotics. Additionally, approximately half of them show poor response to clozapine, electroconvulsive therapy, or other augmentation strategies. However, the development of novel treatment for these conditions is difficult due to the complex and heterogenous pathophysiology of treatment-resistant schizophrenia (TRS). Therefore, this review provides key findings, potential treatments, and a roadmap for future research in this area. First, we review the neurobiological pathophysiology of TRS, particularly the dopaminergic, glutamatergic, and GABAergic pathways. Next, the limitations of existing and promising treatments are presented. Specifically, this article focuses on the therapeutic potential of neuromodulation, including electroconvulsive therapy, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and deep brain stimulation. Finally, we propose multivariate analyses that integrate various perspectives of the pathogenesis, such as dopaminergic dysfunction and excitatory/inhibitory imbalance, thereby elucidating the heterogeneity of TRS that could not be obtained by conventional statistics. These analyses can in turn lead to a precision medicine approach with closed-loop neuromodulation targeting the detected pathophysiology of TRS.

PMID:35444257 | DOI:10.1038/s41380-022-01572-0

Mol Genet Genomics. 2022 Apr 19. doi: 10.1007/s00438-022-01892-4. Online ahead of print.

ABSTRACT

Mutations in the LDL receptor gene LDLR cause familial hypercholesterolemia (FH); however, the pharmacogenomics of specific LDLR mutations remains poorly understood. The goals of this study were to identify the genetic cause of a three-generation Chinese family affected with autosomal dominant FH, and to investigate the response of FH patients in the family to statin and evolocumab. Whole exome sequencing of the FH family with four patients and six unaffected members identified a heterozygous splicing mutation (c.1187-2A>G) in LDLR. The mutation co-segregated with FH in the family, providing strong genetic evidence to support its pathogenicity. The proband was a 48-year-old male FH patient who had an acute myocardial infarction (MI) and ventricular fibrillation (VF), and showed LDL-C of 5.23 mmol/L. A combination of life style modifications on food and exercise and treatment with rosuvastatin reduced his LDL-C to 2.05-2.80 mmol/L. Addition of ezetimibe did not improve rosuvastatin therapy, but addition of evolocumab further reduced LDL-C by 70% to 0.7 mmol/L at the first time and by 67% to 1.31 mmol/L at the second time. Rosuvastatin also reduced LDL-C for proband's father and sister by 40% and 43-63%, respectively. Lovastatin alone or addition to rosuvastatin treatment did not have any effect on LDL-C for the proband and his son. Both patients carry ApoE 3/4 genotype and SLCO1B1 rs4149056 TT genotype. These results suggest that combined treatment with rosuvastatin (but not lovastatin or ezetimibe) and evolocumab can control LDL-C to meet the LDL-C treatment goal for patients with LDLR splicing mutation c.1187-2A>G.

PMID:35441343 | DOI:10.1007/s00438-022-01892-4

Pharmacogenomics. 2022 Apr 20. doi: 10.2217/pgs-2022-0004. Online ahead of print.

ABSTRACT

Aim: Molecular alterations in drug targets may result in differential drug activity. Therefore, the authors aimed to characterize how molecular alterations in drug targets were assessed during drug development. Materials & methods: The authors analyzed nonclinical and clinical study reports submitted to the US FDA for novel drugs approved in 2020 to determine if in vitro studies, animal models or clinical studies assessed molecular alterations in the drug target. Results & conclusion: Assessment of the impact of molecular alterations in drug targets on drug activity varies considerably depending on the type of assessment and therapeutic area. Premarket assessment of drug target molecular alterations is common in the oncology setting, less frequent in the genetic disease setting and rare for other diseases.

PMID:35440173 | DOI:10.2217/pgs-2022-0004

Blood. 2022 Apr 19:blood.2021015108. doi: 10.1182/blood.2021015108. Online ahead of print.

ABSTRACT

Differentiation blockade is a hallmark of AML. Strategy to overcome such blockade is a promising approach against the disease. Lack of understanding underlying mechanisms hampers development of such strategy. Dysregulated ribonucleotide reductase (RNR) is considered a druggable target in proliferative cancers susceptible to deoxynucleoside triphosphates (dNTPs) depletion. Herein, we report an unanticipated discovery that hyperactivating RNR enables differentiation and decreases leukemia cell growth. We integrate pharmacogenomics and metabolomics analyses to identify that pharmacologically (e.g., nelarabine) or genetically upregulating RNR subunit M2 (RRM2) level, creates a dNTP pool imbalance and overcomes differentiation arrest. Moreover, R-loop mediated DNA replication stress signaling is responsible for RRM2 activation by nelarabine treatment. Further aggravating dNTP imbalance by depleting the dNTP hydrolase SAM domain and HD domain-containing protein 1 (SAMHD1) enhances ablation of leukemia stem cells by RRM2 hyperactivation. Mechanistically, excessive activation of ERK signaling downstream of the imbalance contributes to cellular outcomes of RNR hyperactivation. A CRISPR screen identifies a synthetic lethal interaction between loss of DUSP6, an ERK negative regulator, and nelarabine treatment. These data demonstrate that dNTP homeostasis governs leukemia maintenance, and combination of DUSP inhibition and nelarabine represents a therapeutic strategy.

PMID:35439288 | DOI:10.1182/blood.2021015108

IEEE J Biomed Health Inform. 2022 Apr 19;PP. doi: 10.1109/JBHI.2022.3168289. Online ahead of print.

ABSTRACT

Exploring the prognostic classification and biomarkers in Head and Neck Squamous Carcinoma (HNSC) is of great clinical significance. We hybridized three prominent strategies to comprehensively characterize the molecular features of HNSC. We constructed a 15-gene signature to predict patients death risk with an average AUC of 0.744 for 1-, 3-, and 5-year on TCGA-HNSC training set, and average AUCs of 0.636, 0.584, 0.755 in GSE65858, GSE-112026, CPTAC-HNSCC datasets, respectively. By combined with NMF clustering and consensus clustering of fraction of tumor immune cell infiltration (ICI) in the tumor microenvironment (TME), we captured a more refined biological characteristics of HNSC, and observed a prognosis heterogeneity in high tumor immunity patients. By matching tumor subset-specific expression signatures to drug-induced cell line expression profiles from large-scale pharmacogenomic databases in the OCTAD workspace, we identified a group of HNSC patients featured with poor prognosis and demonstrated that the individuals in this group are likely to receive increased drug sensitivity to reverse differentially expressed disease signature genes. This trend is especially highlighted among those with higher death risk and tumour immunity.

PMID:35439152 | DOI:10.1109/JBHI.2022.3168289

Br J Clin Pharmacol. 2022 Apr 18. doi: 10.1111/bcp.15357. Online ahead of print.

ABSTRACT

AIM: To determine whether the known single nucleotide polymorphisms in adrenoreceptor associated genes affect the hemodynamic response to dobutamine in critically ill neonates.

METHODS: Alleles in the known genetic single nucleotide polymorphisms in β1 and β2 adrenoceptor (AR) genes and Gs protein α-subunit gene (GNAS) possibly affecting inotropic effect were identified in patients of neonatal dobutamine pharmacokinetic-pharmacodynamic study. Linear mixed-effect models were used to describe the effect of genetic polymorphisms to heart rate (HR), left ventricular output (LVO) and right ventricular output (RVO) during dobutamine treatment.

RESULTS: 26 neonates (5 term, 21 preterm) were studied. Dobutamine plasma concentration and exposure time respective HR (adjusted to gestational age) is dependent on β1-AR Arg389Gly polymorphism so that in G/G (Gly) homozygotes and G/C heterozygotes dobutamine increases HR more than in C/C (Arg) homozygotes, with parameter estimate (95% CI) of 38.3 (15.8 - 60.7) bpm per AUC of 100 μg L-1 h, p=0.0008. LVO (adjusted to antenatal glucocorticoid administration and illness severity) and RVO (adjusted to gestational age and illness severity) is dependent on GNAS c.393C>T polymorphism so that in T/T homozygotes and C/T heterozygotes but not in C/C homozygotes LVO and RVO increase with dobutamine treatment, 24.5 (6.2 - 42.9) mL kg-1 min-1 per AUC of 100 μg L-1 h, p=0.0095 and 33.2 (12.1 - 54.3) mL kg-1 min-1 per AUC of 100 μg L-1 h, p=0.0025, respectively.

CONCLUSION: In critically ill neonates, β1-AR Arg389Gly and GNAS c.393C>T polymorphisms may play a role in the haemodynamic response to dobutamine during the first hours and days of life.

PMID:35437830 | DOI:10.1111/bcp.15357

Urol Oncol. 2022 Apr 15:S1078-1439(22)00102-8. doi: 10.1016/j.urolonc.2022.03.011. Online ahead of print.

ABSTRACT

INTRODUCTION & AIMS: Monitoring testosterone (T) levels is recommended to assess the effectiveness of androgen deprivation therapy (ADT) in advanced prostate cancer. T levels below 20 ng/dL have been associated with better outcomes. Three main measures for T exist including radioimmunoassay (RIA), chemiluminescence assay (CLIA) and mass spectrometry (MS). While CLIA and RIA are ubiquitous, MS is regarded as the reference standard. We set out to determine the discordance of T measurements amongst men on ADT.

METHODS: A retrospective review of men with prostate cancer on ADT for ≥3 months was conducted. Serum samples were split in triplicate. Observational data was reported and T measurements were compared analyzing for variability looking for categorical concordance. Over and under-estimation rates were calculated.

RESULTS: Ninety-five patients were included with a mean age of 70 (50-92) years. Mean ADT duration was 24.1 (3-144) months. Ninety-five percent of patients had T ≤20ng/dL by MS and CLIA as compared to only 80% by RIA. After subdividing into T categories of ≤20, 20 to 50 and ≥50 ng/dL concordance analysis showed that 4.3% and 18.9% of T measured by MS would have a different category result when remeasured by CLIA (Kappa 0.84) or RIA (Kappa 0.50) respectively. CLIA and RIA overestimated T in 66.7% of patients with T <20 ng/dL measured by MS. Conversely CLIA and RIA underestimated T in only 4.4% of cases with T >20 ng/dL measured by MS.

CONCLUSIONS: There is significant variability in T measured with RIA, CLIA and MS. CLIA and RIA overestimated T levels in majority of patients leaving a concern of misdiagnosing truly castrate patients as being inadequately treated.

PMID:35437219 | DOI:10.1016/j.urolonc.2022.03.011

Pharmacogenomics J. 2022 Apr 18. doi: 10.1038/s41397-022-00277-5. Online ahead of print.

ABSTRACT

There is an increasing demand for supporting the adoption of rapid whole-genome sequencing (rWGS) by demonstrating its real-world value. We aimed to assess the cost-effectiveness of rWGS in critically ill pediatric patients with diseases of unknown cause. Data were collected prospectively of patients admitted to the Nicklaus Children's Hospital's intensive care units from March 2018 to September 2020, with rWGS (N = 65). Comparative data were collected in a matched retrospective cohort with standard diagnostic genetic testing. We determined total costs, diagnostic yield (DY), and incremental cost-effectiveness ratio (ICER) adjusted for selection bias and right censoring. Sensitivity analyses explored the robustness of ICER through bootstrapping. rWGS resulted in a diagnosis in 39.8% while standard testing in 13.5% (p = 0.026). rWGS resulted in a mean saving per person of $100,440 (SE = 26,497, p < 0.001) and a total of $6.53 M for 65 patients. rWGS in critically ill pediatric patients is cost-effective, cost-saving, shortens diagnostic odyssey, and triples the DY of traditional approaches.

PMID:35436997 | DOI:10.1038/s41397-022-00277-5

Ann Transl Med. 2022 Mar;10(6):369. doi: 10.21037/atm-22-291.

ABSTRACT

BACKGROUND AND OBJECTIVE: Bronchial asthma, a common respiratory disease in children and young adults, is characterized by hyperresponsiveness and reversible narrowing of the airways which manifest clinically as shortness of breath, cough, and/or wheezing. Although its pathogenic mechanism remains unknown, it's known that asthma patients have substantial interindividual variability in drug responsiveness, among which genetic factors play key roles. For improving the understanding of the biological mechanism of asthma and useful recognition of diagnostic and therapeutic targets, and the main purpose of this article is to optimize drug selection by analyzing genes associated with different drug responsiveness in asthmatic patients through the use of genomic techniques.

METHODS: β2-agonists, inhaled corticosteroids (ICS), and leukotriene modulators are the most commonly used to treat asthma, and major genetic variations associated with differential response to these three drugs were identified via candidate gene association analysis, genome-wide association study (GWAS), and RNA sequencing.

KEY CONTENT AND FINDINGS: Genomics focuses on the effects of genetic variations in a group of genes. Most current studies have focused on the effect of single gene polymorphisms on drug efficacy, but the pharmacogenomics of asthma is inherently complex, with each factor having a small effect on drug responsiveness, and no single locus has yet been able to predict the variability in drug responsiveness.

CONCLUSIONS: According to epidemiological researches, a worldwide increase in the prevalence of bronchial asthma over the past four decades was shown. Genomic approaches can be used to screen for genetic variants associated with drug response. Stratifying patients prior to treatment helps to optimize drug selection, maximize the effectiveness of individual treatment, and improve clinical outcomes.

PMID:35434004 | PMC:PMC9011285 | DOI:10.21037/atm-22-291

Front Genet. 2022 Mar 31;13:836636. doi: 10.3389/fgene.2022.836636. eCollection 2022.

ABSTRACT

Introduction: MicroRNAs are small noncoding RNAs with potential regulatory roles in hypertension and drug response. The presence of many of these RNAs in biofluids has spurred investigation into their role as possible biomarkers for use in precision approaches to healthcare. One of the major challenges in clinical translation of circulating miRNA biomarkers is the limited replication across studies due to lack of standards for data normalization techniques for array-based approaches and a lack of consensus on an endogenous control normalizer for qPCR-based candidate miRNA profiling studies. Methods: We conducted genome-wide profiling of 754 miRNAs in baseline plasma of 36 European American individuals with uncomplicated hypertension selected from the PEAR clinical trial, who had been untreated for hypertension for at least one month prior to sample collection. After appropriate quality control with amplification score and missingness filters, we tested different normalization strategies such as normalization with global mean of imputed and unimputed data, mean of restricted set of miRNAs, quantile normalization, and endogenous control miRNA normalization to identify the method that best reduces the technical/experimental variability in the data. We identified best endogenous control candidates with expression pattern closest to the mean miRNA expression in the sample, as well as by assessing their stability using a combination of NormFinder, geNorm, Best Keeper and Delta Ct algorithms under the Reffinder software. The suitability of the four best endogenous controls was validated in 50 hypertensive African Americans from the same trial with reverse-transcription-qPCR and by evaluating their stability ranking in that cohort. Results: Among the compared normalization strategies, quantile normalization and global mean normalization performed better than others in terms of reducing the standard deviation of miRNAs across samples in the array-based data. Among the four strongest candidate miRNAs from our selection process (miR-223-3p, 19b, 106a, and 126-5p), miR-223-3p and miR-126-5p were consistently expressed with the best stability ranking in the validation cohort. Furthermore, the combination of miR-223-3p and 126-5p showed better stability ranking when compared to single miRNAs. Conclusion: We identified quantile normalization followed by global mean normalization to be the best methods in reducing the variance in the data. We identified the combination of miR-223-3p and 126-5p as potential endogenous control in studies of hypertension.

PMID:35432462 | PMC:PMC9008777 | DOI:10.3389/fgene.2022.836636

Front Pharmacol. 2022 Apr 1;13:866827. doi: 10.3389/fphar.2022.866827. eCollection 2022.

ABSTRACT

Originating in ancient India, Ayurveda is an alternative medicinal approach that provides substantial evidence for a theoretical-level analysis of all aspects of life. Unlike modern medicine, Ayurveda is based upon tridoshas (Vata, pitta, and Kapha) and Prakriti. On the other hand, the research of all the genes involved at the proteomics, metabolomics, and transcriptome levels are referred to as genomics. Geoclimatic regions (deshanupatini), familial characteristics (kulanupatini), and ethnicity (jatiprasakta) have all been shown to affect phenotypic variability. The combination of genomics with Ayurveda known as ayurgenomics provided new insights into tridosha that may pave the way for precision medicine (personalized medicine). Through successful coordination of "omics," Prakriti-based treatments can help change the existing situation in health care. Prakriti refers to an individual's behavioral trait, which is established at the moment of birth and cannot be fully altered during one's existence. Ayurvedic methodologies are based on three Prakriti aspects: aushadhi (medication), vihara (lifestyle), and ahara (diet). A foundation of Prakriti-based medicine, preventative medicine, and improvement of life quality with longevity can be accomplished through these ayurvedic characteristics. In this perspective, we try to understand prakriti's use in personalized medicine, and how to integrate it with programs for drug development and discovery.

PMID:35431922 | PMC:PMC9011054 | DOI:10.3389/fphar.2022.866827

Colomb Med (Cali). 2021 Sep 30;52(3):e2074569. doi: 10.25100/cm.v52i3.4569. eCollection 2021 Jul-Sep.

ABSTRACT

OBJECTIVE: This study aimed to correlate the genetic profile of the NUDT15 and TPMT genes with the side effects of the treatment of pediatric patients with acute lymphoid leukemia who were undergoing maintenance therapy at a tertiary care hospital in 2017.

METHODS: This was an analytical, longitudinal, observational study in which the genotypes of the genes of interest were determined by PCR allelic discrimination with TaqMan® probes in patients receiving chemotherapy during the maintenance phase in the Pediatric Hematology and Oncology Unit in 2017. Sociodemographic and clinical data corresponding to the first six months of their maintenance chemotherapy were collected, and the correlation between the genotypes obtained and the development of side effects during the maintenance phase of chemotherapy in these patients was evaluated.

RESULTS: Seventy pediatric patients were included in the study. Genetic analyses were carried out of these for NUDT15 and TPMT (rs1800462 and rs1800460) on 68 patients, while for the rs1142345 polymorphism, typing was achieved in 42 patients. 4/68 patients were heterozygous for NUDT15, and the same number of patients were heterozygous for rs1800462 and rs1142345, while for rs1800460, 6 heterozygous patients were identified. No statistically significant association was identified between the genetic variants and the outcomes of interest.

CONCLUSION: Studies with a larger population size are needed and the evaluation of other genetic variants that may influence the development of side effects during maintenance chemotherapy.

PMID:35431360 | PMC:PMC8973308 | DOI:10.25100/cm.v52i3.4569

Biomed Pharmacother. 2022 Apr 13;150:112952. doi: 10.1016/j.biopha.2022.112952. Online ahead of print.

ABSTRACT

Mendelian randomization (MR) is an epidemiological method that uses genetic variants to proxy an exposure predicting its causal association with an outcome. It occupies a valuable niche between observational studies and randomized trials. MR applications expanded lately, facilitated by the availability of big data, to include disease risk causation prediction, supporting evidence of prior observational data, identifying new drug targets, and drug repurposing. Concurrently, the last decade witnessed the growth of pharmacogenomics (PGx) research as a cornerstone in precision medicine. PGx research, conducted at discovery and implementation levels, resulted in validated PGx biomarkers and tests. Despite many clinically relevant PGx associations that could be translated into clinical applications, worldwide implementation is lagging far behind. The current review examines the intersection zones between MR and PGx research. MR can provide supporting evidence that allows generalizing PGx findings supporting its implementation. Interchangeability, PGx research can fuel MR studies with libraries of genetic variants of validated biological relevance. Furthermore, PGx and MR exhibit a synergistic relationship in drug discovery that can accelerate identifying new targets and repurposing old drugs. Interdisciplinary research applied by PGx researchers, epidemiologists with MR experience, and data scientists' collaborations can unlock unforeseen opportunities in accelerating precision medicine acquisition.

PMID:35429744 | DOI:10.1016/j.biopha.2022.112952

Pain Ther. 2022 Apr 16. doi: 10.1007/s40122-022-00374-0. Online ahead of print.

ABSTRACT

The abuse of opioids has become one of the most serious concerns in the world. Opioid use can cause serious adverse reactions, including respiratory depression, postoperative nausea and vomiting, itching, and even death. These adverse reactions are also important complications of clinical application of opioid drugs that may affect patient safety and recovery. Due to the fear of adverse reactions of opioids, clinicians often do not dare to use opioids in an adequate or appropriate amount, thus affecting the clinical medication strategy and the quality of treatment for patients. The prediction of adverse reactions to opioids is one of the most concerned problems in clinical practice. At present, the correlation between gene polymorphism and the efficacy of opiates has been widely studied and preliminarily confirmed, but the research on the effect of gene polymorphism on the adverse reactions of opiates is relatively limited. Existing studies have made encouraging progress in predicting the incidence and severity of adverse opioid reactions and clinical management by using genetic testing, but most of these studies are single-center, small-sample clinical studies or animal experiments, which have strong limitations. When the same receptor or enzyme is studied by different experimental methods, different or even opposite conclusions can be drawn. These phenomena indicate that the correlation between gene polymorphism and adverse opioid reaction still needs further research and demonstration. At present, it is still too early to use genetic testing to predict opioid adverse reactions in clinic. In this paper, the correlation between gene polymorphism and adverse opioid reactions and a small number of clinical applications were reviewed in terms of pharmacokinetics and pharmacodynamics, in order to provide some suggestions for future research and clinical drug decision making.

PMID:35429333 | DOI:10.1007/s40122-022-00374-0

Pharmacotherapy. 2022 Apr 16. doi: 10.1002/phar.2684. Online ahead of print.

ABSTRACT

Dexmedetomidine is titrated to achieve sedation in the pediatric and cardiovascular intensive care units (PICU, CVICU). In adults, dexmedetomidine response has been associated with an ADRA2A polymorphism (rs1800544); CC genotype is associated with an increased sedative response compared to GC and GG. To date, this has not been studied in children. We conducted a pilot study to determine if ADRA2A genotype is associated with dexmedetomidine response in critically ill children. Forty intubated PICU or CVICU patients who received dexmedetomidine as a continuous infusion for at least 2 days were genotyped for ADRA2A with a custom designed TaqMan® Assay. Ten (25%) patients were wildtype (GG), 15 (37.5%) were heterozygous (GC), and 15 (37.5%) were homozygous variant (CC). The maximum dexmedetomidine doses (mCg/kg/hr) were not different between genotype groups CC (1, range 0.3-1.2), GC (1, 0.3-1.3), and GG (0.8, 0.3-1.2), (p=0.37); mean dexmedetomidine doses also were not different for these respective genotype groups CC (0.68, 0.24-1.07), GC (0.72, 0.22-0.98), and GG (0.58, 0.3-0.94), (p=0.67). These findings did not confirm results from adult studies where ADRA2A polymorphisms correlate with dexmedetomidine response, therefore highlighting the need for pediatric studies to validate pharmacogenomics (PGx) findings in adults prior to implementation in pediatrics.

PMID:35429176 | DOI:10.1002/phar.2684

Clin Pharmacol Ther. 2022 Apr 16. doi: 10.1002/cpt.2612. Online ahead of print.

ABSTRACT

The ABCD-GENE score was developed to identify patients at risk for diminished antiplatelet effects with clopidogrel after percutaneous coronary intervention (PCI) and utilizes Age, Body mass index, Chronic kidney disease, Diabetes and CYP2C19 GENEtic variants. The objective of this study was to validate the ability of ABCD-GENE score to predict risk for atherothrombotic events in a diverse, real-world population of clopidogrel-treated PCI patients who received clinical CYP2C19 genotyping to guide antiplatelet therapy. A total of 2341 adult patients who underwent PCI, were genotyped for CYP2C19, and received treatment with clopidogrel across four institutions were included (mean age 64±12 years, 35% female, 20% Black). The primary outcome was major atherothrombotic events, defined as the composite of all-cause death, myocardial infarction, ischemic stroke, stent thrombosis, or revascularization for unstable angina within 12 months following PCI. Major adverse cardiovascular events (MACE), defined as the composite of cardiovascular death, myocardial infarction, ischemic stroke, or stent thrombosis, was assessed as the secondary outcome. Outcomes were compared between patients with an ABCD-GENE score ≥10 versus <10. The risk of major atherothrombotic events was higher in patients with an ABCD-GENE score ≥10 (n=505) versus <10 (n=1836; 24.6 versus 14.7 events per 100 patient-years, adjusted hazard ratio (HR), 1.66; 95% CI, 1.23-2.25; p<0.001). The risk for MACE was also higher among patients with a score ≥10 versus <10 (16.7 versus 10.1 events per 100 patient-years, adjusted HR, 1.59; 95% CI, 1.11-2.30; p=0.013). Our diverse, real-world data demonstrate diminished clopidogrel effectiveness in PCI patients with an ABCD-GENE score ≥10.

PMID:35429163 | DOI:10.1002/cpt.2612

Res Social Adm Pharm. 2022 Apr 9:S1551-7411(22)00123-1. doi: 10.1016/j.sapharm.2022.04.002. Online ahead of print.

ABSTRACT

INTRODUCTION: Pharmacogenomics (PGx) uses DNA to predict an individual's response to a medicine. Internationally, the delivery of PGx is frequently via community pharmacies, who can take a saliva sample, send it off for analysis and contribute to the final clinical decision making. No similar service has been set up in England.

AIM: To identify the barriers, enablers and Behaviour Change Techniques (BCTs) to inform a service specification for delivery of a community pharmacy based PGx service in England.

METHOD: This qualitative co-design research study was designed in three stages using action-orientated theory-based frameworks and tools. The first stage mapped perceptions, barriers to, and enablers for, implementing a community pharmacy based PGx service, derived from a previous qualitative study onto the Theoretical Domains Framework (TDF). The second stage utilised the Theory and Techniques Tool (TTT) to link the identified TDF domain with corresponding BCTs. The final stage used a Delphi survey followed by a Nominal Group Technique session to facilitate community pharmacists selecting their preferred BCTs to include in a service specification.

RESULTS: The existing qualitative data were mapped onto six TDF domains: Knowledge, Skills, Social/professional role and identity, Optimism, Beliefs about Consequences, and Environmental context and resources. Forty-six BCTs were identified using the TTT and the consensus methods resulted in nine selected BCTs: Review outcome goal(s), Feedback on behaviour, Instruction on how to perform behaviour, Demonstration of the behaviour, Credible source and Adding objects to the environment.

CONCLUSION: Using a range of action-orientated theoretical frameworks and tools, pragmatic BCTs have been identified as part of a co-design process, which can now be used as the basis to develop a service specification for the implementation of a PGx testing service in a community pharmacy setting in England.

PMID:35428579 | DOI:10.1016/j.sapharm.2022.04.002

Drug Resist Updat. 2022 Apr 5;62:100832. doi: 10.1016/j.drup.2022.100832. Online ahead of print.

ABSTRACT

Small-molecule kinase inhibitors (SMKIs) represent the cornerstone in the treatment of non-small cell lung cancer (NSCLC) patients harboring genetic driver mutations. Because of the introduction of SMKIs in the last decades, treatment outcomes have drastically improved. Their treatment efficacy, the development of drug resistance as well as untoward toxicity, all suffer from large patient variability. This variability can be explained, at least in part, by their oral route of administration, which leads to a large inter- and intra-patient variation in bioavailability based on differences in absorption. Additionally, drug-drug and food-drug interactions are frequently reported. These interactions could modulate SMKI efficacy and/or untoward toxicity. Furthermore, the large patient variability could be explained by the presence of germline variations in target receptor domains, metabolizing enzymes, and drug efflux transporters. Knowledge about these predictor variations is crucial for handling SMKIs in clinical practice, and for selecting the most optimal therapy. In the current review, the literature search included all SMKIs registered for locally-advanced and metastatic NSCLC by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA) until March 24th, 2022. The BIM deletion showed a significantly decreased PFS and OS for East-Asian patients treated with gefitinib, and has the potential to be clinically relevant for other SMKIs as well. Furthermore, we expect most relevance from the ABCG2 34 G>A and CYP1A1 variations during erlotinib and gefitinib treatment. Pre-emptive CYP2D6 testing before starting gefitinib treatment can also be considered to prevent severe drug-related toxicity. These and other germline variations are summarized and discussed, in order to provide clear recommendations for clinical practice.

PMID:35427871 | DOI:10.1016/j.drup.2022.100832

Semin Cancer Biol. 2022 Apr 12:S1044-579X(22)00096-7. doi: 10.1016/j.semcancer.2022.04.002. Online ahead of print.

ABSTRACT

Epidermal Growth Factor Receptor (EGFR) enacts major roles in the maintenance of epithelial tissues. However, when EGFR signaling is altered, it becomes the grand orchestrator of epithelial transformation, and hence one of the most world-wide studied tyrosine kinase receptors involved in neoplasia, in several tissues. In the last decades, EGFR-targeted therapies shaped the new era of precision-oncology. Despite major advances, the dream of converting solid tumors into a chronic disease is still unfulfilled, and long-term remission eludes us. Studies investigating the function of this protein in solid malignancies have revealed numerous ways how tumor cells dysregulate EGFR function. Starting from preclinical models (cell lines, organoids, murine models) and validating in clinical specimens, EGFR-related oncogenic pathways, mechanisms of resistance, and novel avenues to inhibit tumor growth and metastatic spread enriching the therapeutic portfolios, were identified. Focusing on non-small cell lung cancer (NSCLC), where EGFR mutations are major players in the adenocarcinoma subtype, we will go over the most relevant discoveries that led us to understand EGFR and beyond, and highlight how they revolutionized cancer treatment by expanding the therapeutic arsenal at our disposal.

PMID:35427766 | DOI:10.1016/j.semcancer.2022.04.002