Lessons from clinical implementation of a preemptive pharmacogenetic panel as part of a testing pilot program with an employer-sponsored medical plan.

This manuscript reports on a pilot program focused on implementing pharmacogenetic testing within the framework of an employer-sponsored medical plan at University of Florida (UF) Health. The aim was to understand the challenges associated with program implementation and to gather insights into patient attitudes towards PGx testing. The pilot program adopted a partially preemptive approach, targeting patients on current prescriptions for medications with relevant gene-drug associations.

Implementation of CYP2C19 genotyping to guide proton pump inhibitor use at an academic health center.

Purpose: To describe the implementation of CYP2C19 testing into clinical practice at University of Florida (UF) Health Gainesville hospital to guide proton pump inhibitor (PPI) dosing and the lessons learned from this experience.

Summary: Different CYP2C19 genotypes are associated with variability in PPI plasma concentrations and intragastric pH, which may contribute to the risk of treatment failure due to subtherapeutic concentrations and adverse effects (eg, infection, bone fracture, renal dysfunction) with sustained supratherapeutic concentrations. Based on evidence available prior to the availability of pertinent Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, the UF Health Precision Medicine Program (PMP) developed clinical recommendations, provided through automated alerts at the time of a PPI order, to (1) increase the PPI dose for individuals with genotypes linked to increased CYP2C19 enzyme activity (ie, rapid and ultrarapid metabolizers) to improve the likelihood of drug effectiveness and (2) decrease the dose for individuals with decreased CYP2C19 activity (ie, intermediate and poor metabolizers) to reduce the risk of harm.

Mothering from the Inside Out: Results of a community-based randomized efficacy trial testing a mentalization-based parenting intervention for mothers with addictions.

Mothering from the Inside Out (MIO) is a mentalization-based parenting intervention developed to address challenges common among mothers experiencing substance use disorders (SUDs) and previously deemed effective when delivered by research clinicians. This randomized clinical trial was designed to test the efficacy of MIO when delivered by community-based addiction counselors in Connecticut, USA. Ninety-four mothers [M(SD)age = 31.

Assessment of a Manual Method versus an Automated, Probability-Based Algorithm to Identify Patients at High Risk for Pharmacogenomic Adverse Drug Outcomes in a University-Based Health Insurance Program.

We compared patient cohorts selected for pharmacogenomic testing using a manual method or automated algorithm in a university-based health insurance network. The medication list was compiled from claims data during 4th quarter 2018. The manual method selected patients by number of medications by the health system's list of medications for pharmacogenomic testing.

Multisite investigation of strategies for the clinical implementation of pre-emptive pharmacogenetic testing.

Purpose: The increased availability of clinical pharmacogenetic (PGx) guidelines and decreasing costs for genetic testing have slowly led to increased utilization of PGx testing in clinical practice. Pre-emptive PGx testing, where testing is performed in advance of drug prescribing, is one means to ensure results are available at the time of prescribing decisions. However, the most efficient and effective methods to clinically implement this strategy remain unclear.

Patients with geographic barriers to health care access are prescribed a higher proportion of drugs with pharmacogenetic testing guidelines.

Pharmacogenetic (PGx) testing may be particularly beneficial in medically underserved populations by reducing the number of appointments required to optimize drug therapy and increasing the effectiveness of less expensive off-patent drugs. The objective of this study was to identify patient populations with poor health care access and assess prescribing trends for drugs with published PGx testing guidelines. We used electronic health record data from 67,753 University of Florida Health patients, geographic access scores calculated via the 2-step floating catchment area method, and a composite measure of socioeconomic status.

Characterization of CYP3A pharmacogenetic variation in American Indian and Alaska Native communities, targeting CYP3A4*1G allele function.

The frequencies of genetic variants in the CYP3A4 and CYP3A5 genes differ greatly across global populations, leading to profound differences in the metabolic activity of these enzymes and resulting drug metabolism rates, with important consequences for therapeutic safety and efficacy. Yet, the impact of genetic variants on enzyme activity are incompletely described, particularly in American Indian and Alaska Native (AIAN) populations. To characterize genetic variation in CYP3A4 and CYP3A5 and its effect on enzyme activity, we partnered with AIAN people living in two regions of Alaska: Yup'ik Alaska Native people living in the Yukon-Kuskokwim Delta region of rural southwest Alaska and AIAN people receiving care at the Southcentral Foundation in Anchorage, Alaska.

Transfer learning enables prediction of CYP2D6 haplotype function.

Cytochrome P450 2D6 (CYP2D6) is a highly polymorphic gene whose protein product metabolizes more than 20% of clinically used drugs. Genetic variations in CYP2D6 are responsible for interindividual heterogeneity in drug response that can lead to drug toxicity and ineffective treatment, making CYP2D6 one of the most important pharmacogenes. Prediction of CYP2D6 phenotype relies on curation of literature-derived functional studies to assign a functional status to CYP2D6 haplotypes.

Interrogation of CYP2D6 Structural Variant Alleles Improves the Correlation Between CYP2D6 Genotype and CYP2D6-Mediated Metabolic Activity.

The cytochrome P450 2D6 (CYP2D6) gene locus is challenging to accurately genotype due to numerous single nucleotide variants and complex structural variation. Our goal was to determine whether the CYP2D6 genotype-phenotype correlation is improved when diplotype assignments incorporate structural variation, identified by the bioinformatics tool Stargazer, with next-generation sequencing data. Using CYP2D6 activity measured with substrates dextromethorphan and metoprolol, activity score explained 40% and 34% of variability in metabolite formation rates, respectively, when diplotype calls incorporated structural variation, increasing from 36% and 31%, respectively, when diplotypes did not incorporate structural variation.

Stargazer: a software tool for calling star alleles from next-generation sequencing data using CYP2D6 as a model.

Purpose: Genotyping CYP2D6 is important for precision drug therapy because the enzyme it encodes metabolizes approximately 25% of drugs, and its activity varies considerably among individuals. Genotype analysis of CYP2D6 is challenging due to its highly polymorphic nature. Over 100 haplotypes (star alleles) have been defined for CYP2D6, some involving a gene conversion with its nearby nonfunctional but highly homologous paralog CYP2D7.

Mothering From the Inside Out: Results of a second randomized clinical trial testing a mentalization-based intervention for mothers in addiction treatment.

Mothers with histories of alcohol and drug addiction have shown greater difficulty parenting young children than mothers with no history of substance misuse. This study was the second randomized clinical trial testing the efficacy of Mothering From the Inside Out (MIO), a 12-week mentalization-based individual therapy designed to address psychological deficits commonly associated with chronic substance use that also interfere with the capacity to parent young children. Eighty-seven mothers caring for a child between 11 and 60 months of age were randomly assigned to receive 12 sessions of MIO versus 12 sessions of parent education (PE), a psychoeducation active control comparison.

miR-206 Inhibits Stemness and Metastasis of Breast Cancer by Targeting MKL1/IL11 Pathway.

Effective targeting of cancer stem cells is necessary and important for eradicating cancer and reducing metastasis-related mortality. Understanding of cancer stemness-related signaling pathways at the molecular level will help control cancer and stop metastasis in the clinic. By analyzing miRNA profiles and functions in cancer development, we aimed to identify regulators of breast tumor stemness and metastasis in human xenograft models and examined their effects on self-renewal and invasion of breast cancer cells To discover the direct targets and essential signaling pathways responsible for miRNA functions in breast cancer progression, we performed microarray analysis and target gene prediction in combination with functional studies on candidate genes (overexpression rescues and pheno-copying knockdowns).

P-Glycoprotein Transport of Neurotoxic Pesticides.

P-glycoprotein (P-gp) has been associated with a number of neurodegenerative diseases, including Parkinson's disease, although the mechanisms remain unclear. Altered transport of neurotoxic pesticides has been proposed in Parkinson's disease, but it is unknown whether these pesticides are P-gp substrates. We used three in vitro transport models, stimulation of ATPase activity, xenobiotic-induced cytotoxicity, and inhibition of rhodamine-123 efflux, to evaluate P-gp transport of diazinon, dieldrin, endosulfan, ivermectin, maneb, 1-methyl-4-phenyl-4-phenylpyridinium ion (MPP(+)), and rotenone.

Absence of P-glycoprotein transport in the pharmacokinetics and toxicity of the herbicide paraquat.

Genetic variation in the multidrug resistance gene ABCB1, which encodes the efflux transporter P-glycoprotein (P-gp), has been associated with Parkinson disease. Our goal was to investigate P-gp transport of paraquat, a Parkinson-associated neurotoxicant. We used in vitro transport models of ATPase activity, xenobiotic-induced cytotoxicity, transepithelial permeability, and rhodamine-123 inhibition.

MicroRNA-30c inhibits human breast tumour chemotherapy resistance by regulating TWF1 and IL-11.

Chemotherapy resistance frequently drives tumour progression. However, the underlying molecular mechanisms are poorly characterized. Epithelial-to-mesenchymal transition has been shown to correlate with therapy resistance, but the functional link and signalling pathways remain to be elucidated.

MicroRNA-30c targets cytoskeleton genes involved in breast cancer cell invasion.

Metastasis remains a significant challenge in treating cancer. A better understanding of the molecular mechanisms underlying metastasis is needed to develop more effective treatments. Here, we show that human breast tumor biomarker miR-30c regulates invasion by targeting the cytoskeleton network genes encoding twinfilin 1 (TWF1) and vimentin (VIM).

Removal of lactate dehydrogenase-elevating virus from human-in-mouse breast tumor xenografts by cell-sorting.

Lactate dehydrogenase-elevating virus (LDV) can infect transplantable mouse tumors or xenograft tumors in mice through LDV-contaminated mouse biological materials, such as Matrigel, or through mice infected with LDV. LDV infects specifically mouse macrophages and alters immune system and tumor phenotype. The traditional approaches to remove LDV from tumor cells, by transplanting tumors into rats or culturing tumor cells in vitro, are inefficient, labor-intensive and time-consuming.