A population pharmacokinetic model to predict the individual starting dose of tacrolimus in adult renal transplant recipients.

Br J Clin Pharmacol. 2018 Dec 14;:

Authors: Andrews LM, Hesselink DA, van Schaik RHN, van Gelder T, de Fijter JW, Lloberas N, Elens L, Moes DJAR, de Winter BCM

Abstract
AIMS: The aims of this study were to describe the pharmacokinetics of tacrolimus immediately after kidney transplantation, and to develop a clinical tool for selecting the best starting dose for each patient.
METHODS: Data on tacrolimus exposure were collected for the first three months following renal transplantation. A population pharmacokinetic analysis was conducted using nonlinear mixed-effects modeling (NONMEM). Demographic, clinical and genetic parameters were evaluated as covariates.
RESULTS: A total of 4,527 tacrolimus blood samples collected from 337 kidney transplant recipients were available. Data were best described using a two-compartment model. The mean absorption rate was 3.6 h-1 , clearance was 23.0 L/h (39% IIV), central volume of distribution (Vd) was 692 L (49% IIV) and the peripheral Vd 5340 L (53% IIV). Inter-occasion variability was added to CL (14%). Higher body surface area (BSA), lower serum creatinine, younger age, higher albumin and lower hematocrit levels were identified as covariates enhancing tacrolimus clearance. Cytochrome P450 (CYP) 3A5 expressers had a significantly higher tacrolimus clearance (160%), whereas CYP3A4*22 carriers had a significantly lower clearance (80%). From these significant covariates, age, BSA, CYP3A4 and CYP3A5 genotype were incorporated in a second model to individualize the tacrolimus starting dose: [Formula: see text] Both models were successfully internally and externally validated. A clinical trial was simulated to demonstrate the added value of the starting dose model.
CONCLUSIONS: For a good prediction of tacrolimus pharmacokinetics, age, BSA, CYP3A4 and CYP3A5 genotype are important covariates. These covariates explained 30% of the variability in CL/F. The model proved effective in calculating the optimal tacrolimus dose based on these parameters, and can be used to individualize the tacrolimus dose in the early period after transplantation.

PMID: 30552703 [PubMed - as supplied by publisher]

DPYD, TYMS and MTHFR Genes Polymorphism Frequencies in a Series of Turkish Colorectal Cancer Patients.

J Pers Med. 2018 Dec 13;8(4):

Authors: Amirfallah A, Kocal GC, Unal OU, Ellidokuz H, Oztop I, Basbinar Y

Abstract
Fluoropyrimidine-based chemotherapy is extensively used for the treatment of solid cancers, including colorectal cancer. However, fluoropyrimidine-driven toxicities are a major problem in the management of the disease. The grade and type of the toxicities depend on demographic factors, but substantial inter-individual variation in fluoropyrimidine-related toxicity is partly explained by genetic factors. The aim of this study was to investigate the effect of dihydropyrimidine dehydrogenase (DPYD), thymidylate synthase (TYMS), and methylenetetrahydrofolate reductase (MTHFR) polymorphisms in colorectal cancer patients. Eighty-five patients who were administered fluoropyrimidine-based treatment were included in the study. The DPYD, TYMS and MTHFR polymorphisms were scanned by a next generation Sequenom MassARRAY. Fluoropyrimidine toxicities were observed in 92% of all patients. The following polymorphisms were detected: DPYD 85T>C (29.4% heterozygote mutants, 7.1% homozygote mutants), DPYD IVS 14+1G>A (1.2% heterozygote mutants), TYMS 1494del TTAAAG (38.4% heterozygote mutants, 24.7% homozygote mutants), MTHFR 677C>T (43.5% heterozygote mutants, 9.4% homozygote mutants) and MTHFR 1298A>C (8.2% heterozygote mutants, 2.4% homozygote mutants). A statistically significant association was demonstrated between MTHFR 677C>T and fluoropyrimidine-related toxicity. Furthermore, MTHFR 1298A>C was associated with hematopoietic toxicity. MTHFR polymorphisms may be considered as related factors of fluoropyrimidine toxicity and may be useful as predictive biomarkers for the determination of the colorectal cancer patients who can receive the greatest benefit from fluoropyrimidine-based treatments.

PMID: 30551678 [PubMed]

The exploration of novel Alzheimer's therapeutic agents from the pool of FDA approved medicines using drug repositioning, enzyme inhibition and kinetic mechanism approaches.

Biomed Pharmacother. 2019 Jan;109:2513-2526

Authors: Hassan M, Raza H, Abbasi MA, Moustafa AA, Seo SY

Abstract
Novel drug development is onerous, time consuming and overpriced process with particularly low success and relatively high enfeebling rates. To overcome this burden, drug repositioning approach is being used to predict the possible therapeutic effects of FDA approved drugs in different diseases. Herein, we designed a computational and enzyme inhibitory mechanistic approach to fetch the promising drugs from the pool of FDA approved drugs against AD. The binding interaction patterns and conformations of screened drugs within active region of AChE were confirmed through molecular docking profiles. The possible associations of selected drugs with AD genes were predicted by pharmacogenomics analysis and confirmed through data mining. The stability behaviour of docked complexes (Drugs-AChE) were checked by MD simulations. The possible therapeutic potential of repositioned drugs against AChE were checked by in vitro analysis. Taken together, Cinitapride displayed a comparable results with standard and can be used as possible therapeutic agent in the treatment of AD.

PMID: 30551512 [PubMed - in process]

An introduction to the role of immunology in medical anthropology and molecular epidemiology.

Biomed Pharmacother. 2019 Jan;109:2203-2209

Authors: Ahmadi SAY, Shahsavar F, Anbari K, Rezaian J

Abstract
Medical anthropology is a multi-disciplinary approach to the medical sciences and humanities. Immunology is of the basic medical sciences dealing with anthropology as a science which involves in recognition of self and non-self. We performed this review paper to introduce the role of immunology in medical anthropology and molecular epidemiology. This narrative review was based on the authors' original experience and current literature. We discussed about human leukocyte antigens (HLA) and killer-cell immunoglobulin-like receptors (KIR) and their disease associations. Bioinformatics and biostatistics help us to use this topic in evidence-based medicine. Immunogenetics is an important part of the molecular anthropology being a part of medical anthropology in turn. There were different notions of the integration of immunology and medical anthropology including environmental, ecological and cultural effects, historical and philosophical approaches, immunological biomarkers in different patients, and immunogenetics. Such studies can be used in pharmacogenomics and personalized medicine especially for immunotherapy.

PMID: 30551477 [PubMed - in process]

Pharmacogenomic assessment of herbal drugs in affective disorders.

Biomed Pharmacother. 2019 Jan;109:1148-1162

Authors: Sahoo S, S B

Abstract
Anxiety and depression, the most prevalent psychiatric disorders are co-morbid in nature affecting several people across the world. There is an increase in demand for complementary and alternative medicines, specifically herbal botanicals due to various side effects exhibited by conventional drugs. Herbal drugs mentioned in traditional medicines, face acceptance issues by the medical community due to lack of scientific data regarding their neurochemical pathways. Hence, there has been an increased interest in the quest to unravel the mechanisms of action of herbal psychotropics. With the advancements in "omic technologies" such as genomics, proteomics and metabolomics, research in the field of herbal psychopharmacology has gained momentum, providing a faster and informative platform for thorough evaluation of herbal drugs and formulations. In this article, we have reviewed several medicinal plants and their formulations that have shown potential anxiolytic and anti-depressant activities and have been screened for their biological mechanisms either at the gene, protein or metabolic level.

PMID: 30551365 [PubMed - in process]

Impact of genetic variation on pravastatin systemic exposure in pediatric hypercholesterolemia.

Clin Pharmacol Ther. 2018 Dec 14;:

Authors: Wagner JB, Abdel-Rahman S, Gaedigk R, Gaedigk A, Raghuveer G, Staggs VS, Kauffman R, Van Haandel L, Steven Leeder J

Abstract
This study investigated the impact of SLCO1B1 genotype on pravastatin systemic exposure in hypercholesterolemic children and adolescents. Participants (8-20 years) with at least one allelic variant of SLCO1B1 c.521T>C (521TC, n=15; 521CC, n=2) and wild type controls (521TT, n=15) completed a single oral dose pharmacokinetic study. Inter-individual variability of pravastatin acid (PVA) exposure within SLCO1B1 genotype groups exceeded the ~2-fold difference in mean PVA exposure observed between SLCO1B1 genotype groups (p>0.05, q>0.10). 3'α-iso-pravastatin acid (3α-PVA) and lactone isomer formation in the acidic environment of the stomach prior to absorption also was variable and affected PVA exposure in all genotype groups. The SLCO1B1 c.521 gene variant contributing to variability in systemic exposure to PVA in our pediatric cohort was comparable with previous studies in adults. However, other demographic and physicochemical factors appear to also contribute to inter-individual variability in the dose-exposure relationship. This article is protected by copyright. All rights reserved.

PMID: 30549267 [PubMed - as supplied by publisher]

Neuronal cell adhesion molecule regulating neural systems underlying addiction.

Neuropsychopharmacol Rep. 2018 Dec 13;:

Authors: Ishiguro H, Miyake K, Tabata K, Mochizuki C, Sakurai T, Onaivi ES

Abstract
AIMS: The human NRCAM gene is associated with polysubstance use. Nrcam knockout mice do not acquire a preference for addictive substances. We aimed to elucidate the role of Nrcam in specific neural circuits underlying congenital preference for substances and the acquisition of addiction.
METHODS: We analyzed gene expression patterns of neural molecules to find a common addiction pathway dependent on Nrcam function. We examined monoaminergic, glutamatergic, and GABAergic systems in the brains of Nrcam knockout mice following treatment with methamphetamine (METH) or saline (SAL) using micro-array gene expression analysis, which was replicated using TaqMan gene expression analysis. To find a common addiction pathway, we examined similarities and differences between the expression patterns of molecules in METH-treated mice and in Nrcam knockout mice treated with cocaine (COC).
RESULTS: Glutaminase expression in brain was reduced in Nrcam heterozygous mice after METH and COC treatment, consistent with our previous study. Metabotropic glutamate receptor 2 expression was reduced in Nrcam heterozygous mice that received either METH or COC treatment. Several other molecules could act in independent addiction pathways involving METH or COC. We also found that GABA receptor subunit g2 expression was reduced in Nrcam heterozygous mice that underwent SAL treatment, and that METH treatment attenuated this reduction.
CONCLUSION: Nrcam differentially regulates glutamatergic and GABAergic molecules in naive brains and in brains of animals with acquired addiction. Elucidating the complex neural mechanisms underlying polysubstance use will uncover biological features of addiction and may contribute to the development of effective pharmaceutical treatments.

PMID: 30549257 [PubMed - as supplied by publisher]

Pharmacogenetics and prediction of adverse events in prescription opioid use disorder patients.

Basic Clin Pharmacol Toxicol. 2018 Oct 29;:

Authors: Muriel J, Margarit C, Barrachina J, Ballester P, Flor A, Morales D, Horga JF, Fernández E, Peiró AM

Abstract
The threats involved in the long-term opioid treatment of chronic non-cancer pain (CNCP) have increased notably. Strategies to identify at-risk patients are important because there is no clear evidence showing which screening or deprescription programmes are appropriate. Our aim was to evaluate the evidence provided by pharmacogenetics applied to predict an analgesic toxicity profile in prescription opioid use disorder (POUD) patients participating in an opioid deprescription programme. Pharmacogenetic markers were analysed in an observational, prospective deprescription programme for POUD patients (n = 88) treated for CNCP. It consisted of monitoring visits (baseline, follow-up and final), opioid rotation or discontinuation and the recording of adverse events and suspected adverse drug reactions (ADRs). Variants in OPRM1 (A118G), ABCB1 (C3435T), COMT (G472A), OPRD1 (T921C) and ARRB2 (C8622T) genes were tested by real-time PCR. Ethics committee approved the study. Wild-type OPRM1-AA genotype carriers reported a significantly higher number of adverse events than OPRM1-AG/GG (median [p25-75], 7 [5-11] vs 5 [3-9]), particularly gastrointestinal system events (90% vs 63%) such as nausea (33% vs 0%). Suspected ADRs (affecting 17% of the patients) were three times higher in males than in females (30% vs 11%). The deprescription programme was effective and safe, and it achieved a significant progressive reduction in the morphine equivalent daily dose, strong opioids and other analgesics' use, without causing any changes in pain intensity or opiate abstinence syndrome. OPRM1 gene polymorphisms could identify the risk of gastrointestinal adverse events in POUD patients. Deprescription programmes including pharmacogenetic analysis should be considered during the follow-up of this population.

PMID: 30549211 [PubMed - as supplied by publisher]

Clinical Features Related to Statin-Associated Muscle Symptoms.

Muscle Nerve. 2018 Dec 13;:

Authors: Ochs-Balcom HM, Nguyen LM, Ma C, Isackson PJ, Luzum JA, Kitzmiller JP, Tarnopolsky M, Weisman M, Christopher-Stine L, Peltier W, Wortmann RL, Vladutiu GD

Abstract
INTRODUCTION: Statins reduce cardiovascular disease risk and are generally well-tolerated, yet up to 0.5% of statin-treated patients develop incapacitating muscle symptoms including rhabdomyolysis. Our objective was to identify clinical factors related to statin-associated muscle symptoms (SAMS).
METHODS: Clinical and laboratory characteristics were evaluated in 748 statin-treated Caucasians (634 with SAMS and 114 statin-tolerant controls). Information was collected on statin type, concomitant drug therapies, muscle symptom history, comorbidities and family history. Logistic regression was used to identify associations.
RESULTS: Individuals with SAMS were 3.6 times (OR: 3.60, 95% CI: 2.08-6.22) more likely than statin-tolerant controls to have a family history of heart disease. Additional associations included obesity (OR=3.08, 95% CI: 1.18, 8.05), hypertension (OR=2.24, 95% CI: 1.33, 3.77), smoking (OR=2.08, 95% CI: 1.16, 3.74), and statin type.
DISCUSSION: Careful medical monitoring of statin-treated patients with the associated co-existing conditions may ultimately reduce muscle symptoms and lead to improved compliance. This article is protected by copyright. All rights reserved.

PMID: 30549046 [PubMed - as supplied by publisher]

15 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 2018/12/14

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.

Biomarkers and pathways of chemoresistance and chemosensitivity for personalized treatment of pancreatic adenocarcinoma.

Pharmacogenomics. 2018 Dec 12;:

Authors: Zemanek T, Melichar B, Lovecek M, Soucek P, Mohelnikova-Duchonova B

Abstract
Pancreatic carcinoma is usually diagnosed late when treatment options are limited and is considered a chemo-resistant malignancy. However, early stage, good performance status and specific patient subgroup are thought to have a more favorable prognosis. Search for novel molecular biomarkers, which could predict treatment resistance, represents a major opportunity, but also a challenge in further research. This review summarizes most aspects of individualized therapy of pancreatic cancer including promising biomarkers, BRCA-deficient pancreatic cancer and its etiology. It may be estimated that nearly a third of metastatic pancreatic ductal adenocarcinoma patients could benefit from treatment other than gold standard chemotherapy. Thus, other aspects of an individualized approach concerning the main factors for the choice of the best therapy for individual pancreatic cancer patient (surgery and chemotherapy), as well as the future directions (target therapy and immunotherapy), are also addressed.

PMID: 30539680 [PubMed - as supplied by publisher]

Down-Regulation of APTR and it's Diagnostic Value in Papillary and Anaplastic Thyroid Cancer.

Pathol Oncol Res. 2018 Dec 11;:

Authors: Zhang K, Li C, Liu J, Li Z, Ma C

Abstract
APTR has been employed as a potential biomarker attributing to it was involved in carcinogenesis and malignancy's progression. However, the roles of APTR in papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC) are unclear. In the present study, we aimed to explore the relative expression of APTR in PTC and ATC tissues and the relation between APTR expression and PTC clinicopathological features. We analyzed APTR expression in PTC and ATC by investigating data obtained from the Gene Expression Omnibus (GEO) database. Then, we tested 76-pair PTC and adjacent normal samples by qRT-PCR, and the result was in accordance with the analysis in GEO datasets. Chi-square (χ2) analysis was employed to evaluate the association between APTR and PTC clinical features. These results showed that APTR was negatively related to TNM stages, distant metastasis. In addition, we further evaluated the feasibility of using APTR to detect PTC and ATC patients by the receiver operating characteristic (ROC) and the area under curve (AUC). These findings implied that down-regulation of APTR is correlated with tumorigenesis, also indicated that the potential diagnostic value of APTR for detecting PTC and ATC patients.

PMID: 30539519 [PubMed - as supplied by publisher]

The influence of telmisartan on metformin pharmacokinetics and pharmacodynamics.

J Pharmacol Sci. 2018 Nov 25;:

Authors: Wen J, Zeng M, Liu Z, Zhou H, Xu H, Huang M, Zhang W

Abstract
Metformin is the most widely used drug among type 2 diabetes mellitus patients. However, drug interaction on metformin will influence its glucose-lowering effect or increase its side effect of lactic acidosis. In this study, a randomized, two-stage, crossover study was conducted to unveil the potential drug interaction between metformin and the anti-hypertension drug, telmisartan. Totally, 16 healthy Chinese male volunteers were enrolled. Blood samples from various time-points after drug adminstration were analyzed for metformin quantification. Oral glucose tolerance test (OGTT) was conducted 2 h after metformin administration. The AUC0-12 and Cmax of metformin in subjects co-administrated with telmisartan were significantly lower than with placebo. The geometric mean ratios (value of metformin plus telmisartan phase/value of metformin plus placebo phase) for Cmax and AUC0-12 is 0.7972 (90%CI: 0.7202-0.8824) and 0.8336 (90%CI: 0.7696-0.9028), respectively. Moreover, telmisartan co-administration significantly increased the plasma concentrations of both glucose and insulin at 0.5 h since OGTT (7.64 ± 1.86 mmol/l·min vs 6.77 ± 0.83 mmol/l·min, P = 0.040; 72.91 ± 31.98 μIU/ml·min vs 60.20 ± 24.20 μIU/ml·min, P = 0.037), though the AUC of glucose and insulin after OGTT showed no significant difference. These findings suggested that telmisartan had a significant influence on the Pharmacokinetics of metformin in healthy groups, though the influence on glucose-lowering effect was moderate.

PMID: 30538075 [PubMed - as supplied by publisher]

Synthesis and Biological Evaluation of Novel Indole-Derived Thioureas.

Molecules. 2018 Oct 07;23(10):

Authors: Sanna G, Madeddu S, Giliberti G, Piras S, Struga M, Wrzosek M, Kubiak-Tomaszewska G, Koziol AE, Savchenko O, Lis T, Stefanska J, Tomaszewski P, Skrzycki M, Szulczyk D

Abstract
A series of 2-(1H-indol-3-yl)ethylthiourea derivatives were prepared by condensation of 2-(1H-indol-3-yl)ethanamine with appropriate aryl/alkylisothiocyanates in anhydrous media. The structures of the newly synthesized compounds were confirmed by spectroscopic analysis and the molecular structures of 8 and 28 were confirmed by X-ray crystallography. All obtained compounds were tested for antimicrobial activity against Gram-positive cocci, Gram-negative rods and for antifungal activity. Microbiological evaluation was carried out over 20 standard strains and 30 hospital strains. Compound 6 showed significant inhibition against Gram-positive cocci and had inhibitory effect on the S. aureus topoisomerase IV decatenation activity and S. aureus DNA gyrase supercoiling activity. Compounds were tested for cytotoxicity and antiviral activity against a large panel of DNA and RNA viruses, including HIV-1 and other several important human pathogens. Interestingly, derivative 8 showed potent activity against HIV-1 wild type and variants bearing clinically relevant mutations. Newly synthesized tryptamine derivatives showed also a wide spectrum activity, proving to be active against positive- and negative-sense RNA viruses.

PMID: 30301264 [PubMed - indexed for MEDLINE]

Genetic variations in influx transporter gene SLC22A1 are associated with clinical responses to imatinib mesylate among Malaysian chronic myeloid leukaemia patients.

J Genet. 2018 Sep;97(4):835-842

Authors: Makhtar SM, Husin A, Baba AA, Ankathil R

Abstract
Imatinib mesylate (IM), a well-established gold standard drug in the treatment of chronic myeloid leukaemia (CML), is a synthetic tyrosine kinase inhibitor. Despite excellent efficacy, a significant number of patients on IM therapy develop resistance to IM. Currently, great focus has been laid on the effect of interindividual pharmacogenetic variability on IM treatment responses. IM uptake is mediated by the hOCT1 protein encoded by the solute carrier 22 gene (SLC22A1). The current study investigated the impact of few single-nucleotide polymorphisms (SNPs) of SLC22A1 on mediating resistance and/or good response to IM among 278 Malaysian CML patients (146 IM-resistant group and 132 IM good response group) undergoing IM therapy on 400 mg daily. Our results showed that the allelic frequencies of heterozygous (CG) and homozygous variant (GG) genotypes of SLC22A1 C480G were significantly higher in the IM-resistant group compared with the IM good response group (41.8% versus 30.3% and 10.9% versus 4.5% with P values of 0.047 and 0.048, respectively). On evaluating the association of genotypes with risk of IM resistance development, heterozygous (CG) and homozygous (GG) variant genotypes showed significantly higher risk for developing resistance to IM treatment with odds ratio (OR): 1.901 (95% confidence interval (CI): 1.142-3.163, P = 0.013) and 3.324 (95% CI: 1.235-8.947, P = 0.017), respectively. Two SNPs and two insertions/deletions were detected in exon 7 of SLC22A1. For exon 7, 1222AA carriers together with the presence of both the 8-bp insertion and 3-bp deletion, and M420del alleles showed higher possibility of developing resistance towards IMtreatment. Our results warrant the need of genotyping this SNP in terms of modulating IM treatment in CML patients.

PMID: 30262695 [PubMed - indexed for MEDLINE]

61 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 2018/12/12

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.

17 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 2018/12/07

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.

Pharmacogenetics of Type 2 Diabetes Mellitus, the route toward tailored medicine.

Diabetes Metab Res Rev. 2018 Dec 04;:e3109

Authors: Mannino GC, Andreozzi F, Sesti G

Abstract
Type 2 diabetes mellitus (T2DM) is a chronic disease that has reached the levels of a global epidemic. In order to achieve optimal glucose control it is often necessary to rely on combination therapy of multiple drugs or insulin, because uncontrolled glucose levels result in T2DM progression and enhanced risk of complications and mortality. Several anti-hyperglycemic agents have been developed over time, and T2DM pharmacotherapy should be prescribed based on suitability for the individual patient's characteristics. Pharmacogenetics is the branch of genetics that investigates how our genome influences individual responses to drugs, therapeutic outcomes, and incidence of adverse effects. In this review we evaluated the pharmacogenetic evidences currently available in the literature and we identified the top informative genetic variants associated with response to the most common anti-diabetic drugs: metformin, DPP-4 inhibitors/GLP1R agonists, thiazolidinediones and sulfonylureas/meglitinides. Overall we found 40 polymorphisms for each drug class in a total of 71 loci, and we examined the possibility of encouraging genetic screening of these variants/loci in order to critically implement decision making about the therapeutic approach through precision medicine strategies. It is possible then to anticipate that when the clinical practice will take advantage of the genetic information of the diabetic patients, this will provide a useful resource for the prevention of T2DM progression, enabling the identification of the precise drug that is most likely to be effective and safe for each patient, and the reduction of the economic impact on a global scale.

PMID: 30515958 [PubMed - as supplied by publisher]

HLA testing in the molecular diagnostic laboratory.

Virchows Arch. 2018 Dec 04;:

Authors: Madden K, Chabot-Richards D

Abstract
The human leukocyte antigen (HLA) system is a highly polymorphic family of genes involved in immunity and responsible for identifying self versus non-self. HLA typing is essential for solid organ and bone marrow transplantation as well as in non-transplant settings such as disease association and pharmacogenomics. Typing of HLA genes differs from most molecular testing as, rather than evaluating differences from an accepted "wild-type" gene, it must distinguish between thousands of similar, but distinct alleles. This article will describe the HLA system and nomenclature. We will then discuss clinical uses of HLA typing including solid organ transplantation, hematopoietic stem cell transplantation, evaluation of platelet refractory patients, disease association, and pharmacogenetics. Finally, we describe common molecular methods of HLA typing.

PMID: 30515565 [PubMed - as supplied by publisher]

ABCC10 Plays a Significant Role in the Transport of Gefitinib and Contributes to Acquired Resistance to Gefitinib in NSCLC.

Front Pharmacol. 2018;9:1312

Authors: Zhao H, Huang Y, Shi J, Dai Y, Wu L, Zhou H

Abstract
Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI), is used clinically as first-line therapy in patients with advanced non-small cell lung cancer (NSCLC) with EGFR activating mutations, but the inevitable development of acquired resistance limits its efficacy. In up to 30-40% of NSCLC cases, the mechanism underlying acquired resistance remains unknown. ATP-binding cassette (ABC) transporters are a family of membrane proteins that can significantly influence the bioavailability of numerous drugs, and have confirmed to play an essential role in multidrug resistance (MDR) in cancer chemotherapy. However, their role in acquired resistance to gefitnib in NSCLC has not been well studied. Here, through RNA sequencing (RNA-Seq) technology we assessed the differentially expressed ABC transporters in gefitinib-sensitive (PC9 and H292) and gefitinib-resistant (PC9/GR and H292/GR) NSCLC cells, with ABCC10 identified as a transporter of interest. Both ABCC10 mRNA and protein were significantly increased in acquired gefitinib-resistant NSCLC cells, independent of EGFR mutation status. In vitro transport assay showed that ABCC10 could actively efflux gefitinib, with an efflux ratio (ER) of 7.8. Further results from in vitro cell line models and in vivo xenograft models showed that overexpression of ABCC10 led to a reduction in gefitinib sensitivity through decreasing the intracellular gefitinib accumulation. Our data suggest that ABCC10 has an important role in acquired resistance to gefitinib in NSCLC, which can serve as a novel predictive marker and a potential therapeutic target in gefitinib treatment.

PMID: 30515095 [PubMed]