Opportunities for pharmacists to integrate pharmacogenomics into clinical practice.

Pharmacogenomics J. 2019 Dec 04;:

Authors: Wang YT, Merl MY, Yang J, Zhu ZX, Li GH

Abstract
Many medical centers in the United States have implemented pharmacogenomics (PGx) programs to integrate PGx into clinical practice. The roles of pharmacists in optimizing medication use based on genetic testing results are emergently evolving. A literature search was conducted to assess pharmacists' roles in pharmacogenetics/pharmacogenomics or precision/personalized medicine programs. Fifteen PGx pharmacy practice models implemented in eleven hospitals and one community pharmacy in the U.S. were selected for evaluation. Pharmacists perform results interpretation, genotype-guided medication selection and adjustment, medication acquisition, adverse reactions monitoring, and patient education. Institutions that are interested in implementing a PGx program should plan the strategies to overcome the challenges, such as educational knowledge gaps, informatics, and reimbursement issues. Strong institutional support, well-defined goals, standardized procedures, and strategies to educate clinicians and patients are the prerequisites to comprehensively deliver genomic data for individualized drug therapy.

PMID: 31796890 [PubMed - as supplied by publisher]

Genomic testing is best integrated into clinical practice when it is actionable.

Per Med. 2019 Dec 04;:

Authors: Hendricks-Sturrup RM, Linsky A, Lu CY, Vassy JL

PMID: 31795838 [PubMed - as supplied by publisher]

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pharmacogenomics

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22 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/12/04

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Copy number variation profiling in pharmacogenes using panel-based exome resequencing and correlation to human liver expression.

Hum Genet. 2019 Nov 30;:

Authors: Tremmel R, Klein K, Battke F, Fehr S, Winter S, Scheurenbrand T, Schaeffeler E, Biskup S, Schwab M, Zanger UM

Abstract
Structural variants including copy number variations (CNV) have gained widespread attention, especially in pharmacogenomics but for several genes functional relevance and clinical evidence are still lacking. Detection of CNVs in next-generation sequencing data is challenging but offers widespread applications. We developed a cohort-based CNV detection workflow to extract CNVs from read counts of targeted NGS of 340 genes involved in absorption, distribution, metabolism and excretion (ADME) of drugs. We applied our method to 150 human liver tissue samples and correlated identified CNVs to mRNA expression levels. In total, we identified 445 deletions (73%) and 167 duplications (27%) in 36 pharmacogenes including all well-known CNVs of CYPs, GSTs, SULTs, UGTs, numerous described rare CNVs of CYP2E1, SLC16A3 or UGT2B15 as well as novel observations, e.g., for SLC22A12, SLC22A17 and GPS2 (G Protein Pathway Suppressor 2). We were able to fine-map complex CNVs of CYP2A6 and CYP2D6 with exon resolution. Correlation analysis confirmed known expression patterns for common CNVs and suggested an influence on expression variability for some rare CNVs. Our straightforward CNV detection workflow can be easily applied to any NGS coverage data and helped to analyze CNVs in an ADME-NGS panel of 340 pharmacogenes to improve genotype-phenotype correlations.

PMID: 31786673 [PubMed - as supplied by publisher]

Flavonoid aglycone-oriented data-mining in high-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry: efficient and targeted profiling of flavonoids in Scutellaria barbata.

Anal Bioanal Chem. 2019 Nov 30;:

Authors: Fu Q, Tong C, Guo Y, Xu J, Shi F, Shi S, Xiao Y

Abstract
The high-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (HPLC-QTOF-MS/MS) technique is a powerful tool for compound identification in complex natural products. However, untargeted MS/MS data analysis needs skillful experience and sometimes neglects minor compounds, which are co-eluted with major ones or overshadowed by the matrix. Flavonoids are the main bioactive components in Scutellaria barbata, and the total flavonoid content is 47.02 ± 3.23 mg QE/g DW. Although some flavonoid aglycones and their O-glycosides have been found in S. barbata, comprehensive profiling of flavonoids is unknown. Therefore, we report a flavonoid aglycone-oriented data-mining strategy for efficient and targeted profiling of flavonoids in S. barbata. The strategy includes four steps: (1) HPLC-QTOF-MS analysis of S. barbata; (2) construction of a flavonoid aglycone-based database according to biosynthetic pathway analysis and reported data; (3) extraction of through flavonoid aglycone-based ion chromatography; (4) identification of targeted flavonoids by MS/MS analysis. As a result, 45 flavonoids, including 24 flavones, 1 flavonol, 13 flavanones, and 7 flavanonols, were unambiguously or tentatively identified, while 20 of them were reported in S. barbata for the first time. Moreover, 14 available flavonoids were sensitively, precisely, and accurately determined by standard calibration curves, with limit of detection at 0.06 to 1.55 μg/g, limit of quantification at 0.16 to 3.70 μg/g, relative standard deviation (RSD) less than 9.0% for intra- and inter-day variations, and recovery at 92.6-108.1%. The matrix did not obviously suppress or enhance the ionization of 14 flavonoids, and finally their contents ranging from 0.04 to 4.49 mg/g in S. barbata were successfully achieved. Collectively, our results demonstrate that an efficient, reliable, and valuable strategy has been provided to rapidly and sensitively screen, profile, and quantify chemical components of complex natural products. Graphical abstract.

PMID: 31786643 [PubMed - as supplied by publisher]

Toward Personalized Medicine Implementation: Survey of Military Medicine Providers in the Area of Pharmacogenomics.

Mil Med. 2019 Dec 02;:

Authors: DeLuca J, Selig D, Poon L, Livezey J, Oliver T, Barrett J, Turner C, Hellwig L

Abstract
INTRODUCTION: Personalized medicine is the right treatment, to the right patient, at the right dose. Knowledge of genetic predisposition to variable metabolism and distribution of drugs within the body is currently available as pharmacogenomic testing and is one of the pillars of personalized medicine. Pharmacogenomic testing is growing. It has become part of guidelines for dosing on FDA labels and has been used by health care organizations to improve outcomes and reduce adverse events. Additionally, it has been FDA approved for direct-to-consumer purchase and has been cause of concern of patient self-dosing and medication changes. Presumably in the near future, pharmacogenomics will be impressed upon the military health system (MHS) provider from either a top-down, command requested, or from a bottom-up, patient requested, approach. To date, widespread implementation of pharmacogenomic testing does not seem to be established within the MHS. This survey sheds light on the knowledge, exposure, use, comfort, and interest among family medicine providers in the MHS. It compares similar results in other national and international surveys and compares results among a small subset of residents to staff.
MATERIALS AND METHODS: The questions were part of a larger survey conducted by the Clinical Investigations Committee of the Uniformed Services Academy of Family Physicians (USAFP) at the USAFP 2019 annual meeting. The study received approval from the Uniformed Services University Institutional Review Board. Submitted questions were written using multiple choice, fill-in, five-point Likert scale, and best answer. Direct results are reported as well as chi-square statistics for categorical data with statistical significance to attain a P-value of < 0.05.
RESULTS: Among the 532 USAFP-registered conference attendees eligible to complete the survey, 387 attendees responded to the survey, for a response rate of 72.7%. Some results included were a knowledge question in which 37% of respondents answered correctly. Less than half of respondents agreed that they could define pharmacogenomics, and resident respondents were more likely to have received teaching in graduate medical education. Additionally, 12% of providers responded to being exposed to direct-to-consumer results, and 28% of those exposed were influenced to change medications, while 14% were influenced to change medications on multiple occasions. Chi-square comparisons resulted in statistically significant direct relationships to exposure to direct to consumer testing, previous training, and confidence of those that answered the knowledge question correctly.
CONCLUSIONS: This survey establishes a baseline for the possible needs associated with implementation of a pharmacogenomic program, and it argues an actionable level for the use of pharmacogenomics among the patient population within the MHS.

PMID: 31786583 [PubMed - as supplied by publisher]

Cytochrome P450 2C9 polymorphism: Effect of amino acid substitutions on protein flexibility in the presence of tamoxifen.

Comput Biol Chem. 2019 Nov 17;:107166

Authors: Manish M, Lynn AM, Mishra S

Abstract
Tamoxifen is a prodrug and cytochrome P450 2C9 (CYP2C9) has a significant role in the formation of a therapeutically more potent metabolite (4-hydroxytamoxifen) than tamoxifen. Since CYP2C9 exhibits genetic polymorphism, it may contribute to different phenotypic drug response. Moreover, it may be misleading if the possibility of heterogeneous clinical observations of pharmacogenetic investigations is ignored. Above all, clinical investigation of all the polymorphic variants is beyond the scope of a pharmacogenetic study. Therefore, in order to understand the genotype-phenotype association, it is aimed to study the interatomic interactions of amino acid substitutions in CYP2C9 variants in the presence of tamoxifen. Computational structural biology approach was adopted to study the effect of amino acid substitutions of polymorphic variants of CYP2C9 R144C (*2), I359 L (*3), D360E (*5), R150H (*8), R335W (*11) and L90 P (*13) on the flexibility of the enzyme in the presence of tamoxifen. The mutations were selected based on previously determined associations on genotype and clinical outcome of drugs. Against the above plane, docking of tamoxifen was performed with the crystal structure representing the wild-type form of the enzyme. The docked conformation of tamoxifen was favourable for 4-hydroxylation with the site of metabolism within 5 Å of oxyferrylheme consistent with the drug metabolism pathway of tamoxifen. Further, the effect of amino acid substitutions CYP2C9 variants on the protein flexibility in the presence of tamoxifen in 4-hydroxy orientation was evaluated by molecular dynamics (MD) simulations. Distinct protein flexibility modulations between variants were observed in F/G segment constituting the substrate access/egress channels, helix B' involved with substrate specificity and helix I associated with the holding of substrates. Root Mean Square Fluctuation analysis of the trajectories of variants exhibited fluctuations in F/G segment, B' and I helix. Dominant motions in the structure were identified by performing Principal Component Analysis on trajectories and the porcupine plot depicted displaced F/G segment in variants. Thus, the interatomic interaction study of CYP2C9 variants in the presence of tamoxifen predicts the plausible effect of the investigated variants on the therapeutic outcome of tamoxifen. It is presumed that the observations of the study would be meaningful to understand tamoxifen pharmacogenetics.

PMID: 31785970 [PubMed - as supplied by publisher]

miR-181a-2* expression is different amongst carcinomas from the colorectal serrated route.

Mutagenesis. 2019 Nov 30;:

Authors: Kondelova A, Alburquerque-González B, Vychytilova-Faltejskova P, García-Solano J, Prochazka V, Kala Z, Pérez F, Slaby O, Conesa-Zamora P

Abstract
Serrated adenocarcinoma (SAC) and colorectal carcinomas showing histological and molecular features of high-level of microsatellite instability (hmMSI-H) are both end points of the serrated pathway of colorectal carcinogenesis. Despite common features (right-sided location, CpG island methylation phenotype and BRAF mutation) there are no studies comparing the microRNA (miRNA) expression profiles in SACs and hmMSI-H. The microtranscriptome from 12 SACs and 8 hmMSI-H were analysed using Affymetrix GeneChip miRNA 3.0 arrays and differentially enriched functions involving immune response were observed from this comparison. miR-181a-2* was found significantly more expressed in hmMSI-H than in SAC and higher expression of this miRNA in microsatellite unstable colorectal cancer were corroborated by Real-Time PCR in an extended series (61 SAC, 21 hmMSI-H). An analysis of genes possibly regulated by miR-181a-2* was carried out and, amongst these, an inverse correlation of NAMPT with miR-181a-2* expression was observed, whereas, for TRAF1 and SALL1, additional regulation mechanisms involving CpG island methylation were observed. miR-181a-2* is associated with particular histological and molecular features of colorectal carcinomas within the serrated pathological pathway and might play a role in the immune responses of microsatellite instability carcinomas.

PMID: 31784758 [PubMed - as supplied by publisher]

Research advances in the association of drug-induced liver injury with polymorphisms in human leukocyte antigen.

Int Immunopharmacol. 2019 Nov 26;:106037

Authors: Ma Q, Yang W, Wang L, Ma L, Jing Y, Wang J, Liu X

Abstract
Drug-induced liver injury is an important adverse drug reaction. Due to the lack of specificity in clinical symptoms and pathological features, there are still no reliable diagnostic biomarkers, so drug-induced liver injury is a diagnosis of exclusion. The article reviews the relevant advances in the association between novel human leukocyte antigen gene polymorphisms and drug-induced liver injury in order to identify potential biomarkers and provide a new method for the prediction and diagnosis of drug-induced liver injury. Henceforth, while studying the association between them, it will also need that the large sample and prospective studies to gain supporting evidence to implement translational application, so as to improve the safety and effectiveness of medication and achieve individualized treatment.

PMID: 31784402 [PubMed - as supplied by publisher]

Impact of CYP2C19 genotype and drug interactions on voriconazole plasma concentrations: a spain pharmacogenetic-pharmacokinetic prospective multicenter study.

Pharmacotherapy. 2019 Nov 29;:

Authors: Blanco Dorado S, Maroñas O, Latorre-Pellicer A, Rodríguez Jato T, López-Vizcaíno A, Gómez Márquez A, Bardán García B, Belles Medall D, Barbeito Castiñeiras G, Pérez Del Molino Bernal ML, Campos-Toimil M, Otero Espinar F, Blanco Hortas A, Durán Piñeiro G, Zarra Ferro I, Carracedo Á, Lamas MJ, Fernández-Ferreiro A

Abstract
BACKGROUND: Voriconazole, a first-line agent for the treatment of invasive fungal infections, is mainly metabolized by cytochrome P450 (CYP) 2C19. A significant portion of patients fail to achieve therapeutic voriconazole trough concentrations, with a consequently increased risk of therapeutic failure.
OBJECTIVE: To show the association between subtherapeutic voriconazole concentrations and factors affecting voriconazole pharmacokinetics: CYP2C19 genotype and drug-drug interactions.
METHODS: Adults receiving voriconazole for antifungal treatment or prophylaxis were included in a multicenter prospective study conducted in Spain. The prevalence of subtherapeutic voriconazole troughs were analyzed in the rapid metabolizer and ultra-rapid metabolizer patients (RMs and UMs, respectively), and compared with the rest of the patients. The relationship between voriconazole concentration, CYP2C19 phenotype, adverse events (AEs), and drug-drug interactions was also assessed.
RESULTS: In this study 78 patients were included with a wide variability in voriconazole plasma levels with only 44.8% of patients attaining trough concentrations within the therapeutic range of 1 and 5.5 µg/ml. The allele frequency of *17 variant was found to be 29.5%. Compared with patients with other phenotypes, RMs and UMs had a lower voriconazole plasma concentration (RM/UM: 1.85±0.24 µg/ml versus other phenotypes: 2.36±0.26 µg/ml, ). Adverse events were more common in patients with higher voriconazole concentrations (p<0.05). No association between voriconazole trough concentration and other factors (age, weight, route of administration, and concomitant administration of enzyme inducer, enzyme inhibitor, glucocorticoids, or proton pump inhibitors) was found.
CONCLUSION: These results suggest the potential clinical utility of using CYP2C19 genotype-guided voriconazole dosing to achieve concentrations in the therapeutic range in the early course of therapy. Larger studies are needed to confirm the impact of pharmacogenetics on voriconazole pharmacokinetics.

PMID: 31782536 [PubMed - as supplied by publisher]

Letermovir Resistance Analysis in a Clinical Trial of Cytomegalovirus Prophylaxis for Hematopoietic Stem Cell Transplant Recipients.

J Infect Dis. 2019 Nov 29;:

Authors: Douglas CM, Barnard R, Holder D, Leavitt R, Levitan D, Maguire M, Nickle D, Teal V, Wan H, van Alewijk DCJG, van Doorn LJ, Chou S, Strizki J

Abstract
BACKGROUND: Letermovir (LET), a cytomegalovirus (CMV) deoxyribonucleic acid (DNA) terminase inhibitor, was recently approved for prophylaxis of CMV infection in adult CMV-seropositive recipients of allogeneic hematopoietic stem cell transplantation. Cytomegalovirus genotyping was performed to identify LET-resistance-associated variants (RAVs) among subjects in a Phase 3 trial.
METHODS: The CMV UL56 and UL89 genes, encoding subunits of CMV DNA terminase, were sequenced from plasma collected from subjects with clinically significant CMV infection (CS-CMVi). Novel variants were evaluated by recombinant phenotyping to assess their potential to confer resistance to LET.
RESULTS: Genotyping was successful for 50 of 79 LET subjects with CS-CMVi. Resistance-associated variants (encoding pUL56 V236M and C325W) were detected independently in subjects 1 and 3 who experienced CS-CMVi while receiving LET prophylaxis, and 2 other variants (encoding pUL56 E237G and R369T) were detected >3 weeks after subjects 2 and 3, respectively, had discontinued LET prophylaxis and received preemptive therapy with ganciclovir.
CONCLUSIONS: The detected incidence of CMV resistance among subjects who received LET as prophylaxis in this Phase 3 trial was low. The LET RAVs that were detected mapped to the CMV UL56 gene at positions associated with reduced susceptibility to LET based on resistance selections in cell culture.

PMID: 31781762 [PubMed - as supplied by publisher]

Immunological Aspects of Graves' Ophthalmopathy.

Biomed Res Int. 2019;2019:7453260

Authors: Łacheta D, Miśkiewicz P, Głuszko A, Nowicka G, Struga M, Kantor I, Poślednik KB, Mirza S, Szczepański MJ

Abstract
The body's autoimmune process is involved in the development of Graves' disease (GD), which is manifested by an overactive thyroid gland. In some patients, autoreactive inflammatory reactions contribute to the development of symptoms such as thyroid ophthalmopathy, and the subsequent signs and symptoms are derived from the expansion of orbital adipose tissue and edema of extraocular muscles within the orbit. The autoimmune process, production of antibodies against self-antigens such as TSH receptor (TSHR) and IGF-1 receptor (IGF-1R), inflammatory infiltration, and accumulation of glycosaminoglycans (GAG) lead to edematous-infiltrative changes in periocular tissues. As a consequence, edema exophthalmos develops. Orbital fibroblasts seem to play a crucial role in orbital inflammation, tissue expansion, remodeling, and fibrosis because of their proliferative activity as well as their capacity to differentiate into adipocytes and myofibroblasts and production of GAG. In this paper, based on the available medical literature, the immunological mechanism of GO pathogenesis has been summarized. Particular attention was paid to the role of orbital fibroblasts and putative autoantigens. A deeper understanding of the pathomechanism of the disease and the involvement of immunological processes may give rise to the introduction of new, effective, and safe methods of treatment or monitoring of the disease activity.

PMID: 31781640 [PubMed - in process]

Chaihu-Shugan-San Reinforces CYP3A4 Expression via Pregnane X Receptor in Depressive Treatment of Liver-Qi Stagnation Syndrome.

Evid Based Complement Alternat Med. 2019;2019:9781675

Authors: He Z, Fan R, Zhang C, Tang T, Liu X, Luo J, Cui H, Wang Y, Lu R, Gan P

Abstract
Backgrounds. Chaihu-Shugan-San (CSS) is a classic traditional Chinese herbal prescription for treating depression. However, the underlying mechanism of the Chinese syndrome-specific efficacy of CSS is poorly understood. Aim of the Study. From traditional Chinese medicine and pharmacogenetics perspectives, the present study aimed to investigate the antidepressant effects of CSS on a mouse model of Liver-Qi Stagnation (LQS) syndrome and its underlying mechanisms. Methods and Materials. We used two main mouse models of depressive syndromes in the study, including LQS and liver stagnation and spleen deficiency (LSSD) syndrome. Tail suspension and forced swimming tests were used to evaluate the effects of CSS on animal behaviour. The expression level of the CYP450 enzyme from liver microsomes was analysed by western blot (WB) analysis and quantitative real-time polymerase chain reaction (qRT-PCR). More specifically, we analysed the key compounds of CSS that are responsible for CYP450 regulation via bioinformatics. Ultimately, luciferase assays were employed to confirm the prediction in vitro. Results. CSS remarkably reduced the immobile time in LQS rather than in LSSD mice. Although CSS significantly upregulated CYP2C9 in mice with both syndromes, activated translation of CYP3A4 induced by CSS was only observed in the LQS group. Bioinformatics analysis revealed that the unique regulation of CYP3A4 was responsible for the effects of glycyrrhetinic acid (GA) from CSS. Further luciferase assays confirmed the enhancement of CYP3A4 expression via the pregnane X receptor (PXR) pathway in vitro. Conclusions. CSS specifically upregulates the translation of CYP3A4 via the PXR pathway in depressed LQS mice. GA, a bioactive compound that originates from CSS, contributes to this activation. This work provides novel insight into Chinese syndrome-based therapy for depression.

PMID: 31781287 [PubMed]

Pharmacogenetics of amfepramone in healthy Mexican subjects reveals potential markers for tailoring pharmacotherapy of obesity: results of a randomised trial.

Sci Rep. 2019 Nov 28;9(1):17833

Authors: Gómez-Silva M, Piñeyro-Garza E, Vargas-Zapata R, Gamino-Peña ME, León-García A, de León MB, Llerena A, León-Cachón RBR

Abstract
Amfepramone (AFP) is an appetite-suppressant drug used in the treatment of obesity. Nonetheless, studies on interindividual pharmacokinetic variability and its association with genetic variants are limited. We employed a pharmacokinetic and pharmacogenetic approach to determine possible metabolic phenotypes of AFP and identify genetic markers that could affect the pharmacokinetic variability in a Mexican population. A controlled, randomized, crossover, single-blind, two-treatment, two-period, and two sequence clinical study of AFP (a single 75 mg dose) was conducted in 36 healthy Mexican volunteers who fulfilled the study requirements. Amfepramone plasma levels were measured using high-performance liquid chromatography mass spectrometry. Genotyping was performed using real-time PCR with TaqMan probes. Four AFP metabolizer phenotypes were found in our population: slow, normal, intermediate, and fast. Additionally, two gene polymorphisms, ABCB1-rs1045642 and CYP3A4-rs2242480, had a significant effect on AFP pharmacokinetics (P < 0.05) and were the predictor factors in a log-linear regression model. The ABCB1 and CYP3A4 gene polymorphisms were associated with a fast metabolizer phenotype. These results suggest that metabolism of AFP in the Mexican population is variable. In addition, the genetic variants ABCB1-rs1045642 and CYP3A4-rs2242480 may partially explain the AFP pharmacokinetic variability.

PMID: 31780765 [PubMed - in process]

Roles of aminoacyl-tRNA synthetases in immune regulation and immune diseases.

Cell Death Dis. 2019 Nov 28;10(12):901

Authors: Nie A, Sun B, Fu Z, Yu D

Abstract
Aminoacyl-tRNA synthetases (ARSs) play a vital role in protein synthesis by linking amino acids to their cognate transfer RNAs (tRNAs). This typical function has been well recognized over the past few decades. However, accumulating evidence reveals that ARSs are involved in a wide range of physiological and pathological processes apart from translation. Strikingly, certain ARSs are closely related to different types of immune responses. In this review, we address the infection and immune responses induced by pathogen ARSs, as well as the potential anti-infective compounds that target pathogen ARSs. Meanwhile, we describe the functional mechanisms of ARSs in the development of immune cells. In addition, we focus on the roles of ARSs in certain immune diseases, such as autoimmune diseases, infectious diseases, and tumor immunity. Although our knowledge of ARSs in the immunological context is still in its infancy, research in this field may provide new ideas for the treatment of immune-related diseases.

PMID: 31780718 [PubMed - in process]

Combined genetic mutations and DNA-methylated genes as biomarkers for endometrial cancer detection from cervical scrapings.

Clin Epigenetics. 2019 Nov 28;11(1):170

Authors: Liew PL, Huang RL, Wu TI, Liao CC, Chen CW, Su PH, Wang HC, Weng YC, Lai HC

Abstract
BACKGROUND: Endometrial cancer is a common gynecologic cancer. Noninvasive molecular biomarkers for triage of high-risk patients for invasive procedures are needed. Based on the success of cytological Pap smear screening, cervical scrapings are a good source of DNA for molecular testing. In addition to genetic lesions, DNA methylation is a promising biomarker. We assessed the usefulness of combining genetic and epigenetic biomarkers from cervical scrapings to detect endometrial carcinomas.
METHODS: We performed a retrospective case-control study of 96 consecutive cervical scrapings from patients with abnormal uterine bleeding who underwent surgery for diagnostic evaluation. Thirty and 16 cases were diagnosed with type I and type II endometrial cancers, respectively. The remaining non-cancer cases included normal endometrium (n = 12), benign uterine lesions (n = 20), and endometrial hyperplasia (n = 18). Quantitative methylation-specific PCR and mass spectrometry were used for DNA methylation and genetic mutation analysis. Logistic regression was used to evaluate the clinical performance of these candidate biomarkers.
RESULTS: We tested the effectiveness of the methylation status of four genes (BHLHE22, CDO1, TBX5, and HAND2) in endometrial cancer detection. The area under the receiver operating characteristic curves ranged from 0.703 to 0.878, and panels of hypermethylated BHLHE22/CDO1/HAND2 (87.0% sensitivity and 86.0% specificity) and BHLHE22/CDO1/TBX5 (89.1% sensitivity and 80.0% specificity) showed significant differences and could distinguish benign from malignant endometrial lesions. The sensitivity and specificity in endometrial cancer detection for BHLHE22/CDO1 were 84.8% and 88.0%, respectively. Both type I and II endometrial carcinomas could be detected using a BHLHE22/CDO1-based methylation profile, suggesting that they may have common epigenomes. Moreover, PTEN and TP53 mutations were found in 63.3% of type I and 93.6% of type II endometrial cancers. Unexpectedly, PTEN and TP53 mutations were commonly found in cervical scrapings of the normal endometrium (25% and 33.3%, respectively) and in cases with benign uterine lesions (10% and 50%, respectively). Finally, combinations of any one mutation of PTEN and TP53 mutations had a sensitivity of 91.3%, but a specificity of only 42.0%.
CONCLUSIONS: Adding PTEN/TP53 mutation testing to BHLHE22/CDO1-based methylation testing did not improve the detection of endometrial cancer.

PMID: 31779688 [PubMed - in process]

Clinically Significant Drug-Drug Interactions with Agents for Attention-Deficit/Hyperactivity Disorder.

CNS Drugs. 2019 Nov 27;:

Authors: Schoretsanitis G, de Leon J, Eap CB, Kane JM, Paulzen M

Abstract
This article provides an overview of the pharmacokinetic drug-drug interactions (DDIs) for agents prescribed for attention-deficit/hyperactivity disorder (ADHD). Polypharmacy in the treatment of patients with ADHD leads to high exposures to DDIs and possibly adverse safety outcomes. We performed a systematic search of DDI reports for ADHD agents in Embase and Medline. We also searched for agents in the pharmacological pipeline, which include (1) mazindol, molindone and viloxazine, which were previously prescribed for other indications; (2) centanafadine and AR-08, never before approved; and (3) two extracts (Polygala tenuifolia extract and the French maritime pine bark extracts). The identified literature included case reports, cross-sectional, cross-over and placebo-controlled studies of patient cohorts and healthy volunteers. The DDIs were classified as follows: ADHD agents acting as perpetrators, i.e., affecting the clearance of co-prescribed agents (victim drugs), or ADHD agents being the victim drugs, being affected by other agents. Ratios for changes in pharmacokinetic parameters before and after the DDI were used as a rough estimate of the extent of the DDI. Alcohol may increase plasma dextroamphetamine concentrations by presystemic effects. Until studies are done to orient clinicians regarding dosing changes, clinicians need to be aware of the potential for cytochrome P450 (CYP) 2D6 inhibitors to increase amphetamine levels, which is equivalent to increasing dosages. Atomoxetine is a wide therapeutic window drug. The CYP2D6 poor metabolizers who do not have CYP2D6 activity had better atomoxetine response, but also an increased risk of adverse effects. CYP2D6 inhibitors have been used to increase atomoxetine response in CYP2D6 extensive metabolizers. Guanfacine is mainly metabolized by CYP3A4, which can be induced and inhibited. The package insert recommends that in guanfacine-treated patients, after adding potent CYP3A4 inducers, the guanfacine dose should be doubled; after adding potent CYP3A4 inhibitors the guanfacine dose should be halved. Based on a phenobarbital case report and our experience with CYP3A4-metabolized antipsychotics, these correction factors may be too low. According to two case reports, carbamazepine is a clinically relevant inducer of methylphenidate (MPH). A case series study suggested that MPH may be associated with important elevations in imipramine concentrations. Due to the absence of or limitations in the data, no comments for clinicians can be provided on the pharmacokinetic DDIs for clonidine, centanafadine, mazindol, molindone, AR-08, P. tenuifolia extract and the French maritime pine bark extracts. According to currently available data, clinicians should not expect that ADHD drugs modify each other's serum concentrations. A summary table for clinicians provides our current recommendations on pharmacokinetic DDIs of ADHD agents based on our literature review and the package inserts; whenever it was possible, we provide information on serum concentrations and dose correction factors. There will be a need to periodically update these recommendations and these correction factors as new knowledge becomes available.

PMID: 31776871 [PubMed - as supplied by publisher]

The Era of Pharmacogenomics.

Acta Sci Cancer Biol. 2019 Jul;3(7):14-16

Authors: L L

Abstract
The sequencing of the complete human genome led to a before and after in medicine and, specifically, in oncological treatments. Nowadays, we are getting closer to what we call personalized medicine, where it is necessary to know the individual biochemical mechanisms of each patient. The future predicts a precision medicine based on markers of toxicity and pharmacogenomics.

PMID: 31773113 [PubMed]

CLEC4M is associated with poor prognosis and promotes cisplatin resistance in NSCLC patients.

J Cancer. 2019;10(25):6374-6383

Authors: Tan LM, Li X, Qiu CF, Zhu T, Hu CP, Yin JY, Zhang W, Zhou HH, Liu ZQ

Abstract
Cisplatin-based chemotherapy is the foundation of treatment for major non-small cell lung cancer (NSCLC) patients. However, cisplatin resistance is still a challenging issue, and the molecular mechanisms underlying this resistance remain to be fully explored. CLEC4M, a Ca2+-dependent C-type lectin, has recently been found to correlate with tumourigenesis. This study mainly focused on whether CLEC4M impacts clinical prognosis and how CLEC4M contributes to cisplatin resistance in NSCLC. Our results found that CLEC4M was correlated with poor prognosis in patients with lung cancer. In addition, a positive association between CLEC4M expression and the IC50 values of cisplatin was found, which suggests that CLEC4M may impact cisplatin sensitivity. In vitro results from cultured A549 and H1299 cells confirmed that CLEC4M could enhance cisplatin resistance, while CLEC4M knockdown led to higher sensitivity to cisplatin in these cells. Further experiments showed that the underlying mechanisms included inhibition of cisplatin-induced cell apoptosis by CLEC4M and improved DNA repair capacity by upregulating XPA and ERCC1 expression. In addition, CLEC4M was able to promote cell migration with or without cisplatin treatment. Collectively, these findings suggest the potential clinical significance of CLEC4M inhibition in overcoming cisplatin resistance in NSCLC patients.

PMID: 31772670 [PubMed]