Capecitabine efficacy is correlated with TYMP and RB expression in PDX established from triple-negative breast cancers.

Clin Cancer Res. 2018 Feb 20;:

Authors: Marangoni E, Laurent C, Coussy F, El Botty R, Chateau-Joubert S, Servely JL, de Plater L, Assayag F, Dahmani A, Montaudon E, Némati F, Fleury J, Vacher S, Gentien D, Rapinat A, Foidart P, Sounni NE, Noël A, Salomon A, Lae M, Decaudin D, Roman-Roman S, Bièche I, Piccard M, Reyal F

Abstract
PURPOSE: triple-negative breast cancer (TNBC) patients with residual disease after neoadjuvant chemotherapy have a poor outcome. We developed patient-derived xenografts (PDX) from residual tumors to identify efficient chemotherapies and predictive biomarkers in a context of resistance to anthracyclines and taxanes-based treatments.
EXPERIMENTAL DESIGN: PDX were established from residual tumors of primary breast cancer patients treated in neoadjuvant setting. TNBC PDX were treated by anthracyclines, taxanes, platins and capecitabine. Predictive biomarkers were identified by transcriptomic and immunohistological analysis. Downregulation of RB1 was performed by siRNA in a cell line established from a PDX.
RESULTS: residual TNBC PDX were characterized by a high tumor take, a short latency and a poor prognosis of the corresponding patients. With the exception of BRCA1/2 mutated models, residual PDX were resistant to anthracyclines, taxanes, and platins. Capecitabine, the oral prodrug of 5-FU, was highly efficient in 60% of PDX with two models showing complete responses. Prior treatment of a responder PDX with 5-FU increased expression of thymidylate synthase and decreased efficacy of capecitabine. Transcriptomic and IHC analyses of 32 TNBC PDX, including both residual tumors and treatment-naïve derived tumors, identified RB and TYMP proteins as predictive biomarkers for capecitabine response. Finally, RB1 knockdown in a cell line established from a capecitabine-responder PDX decreased sensitivity to 5-FU treatment.
CONCLUSIONS: we identified capecitabine as efficient chemotherapy in TNBC PDX models established from residual disease and resistant to anthracyclines, taxanes and platins. RB positivity and high expression of TYMP were significantly associated with capecitabine response.

PMID: 29463559 [PubMed - as supplied by publisher]

Defining drug response for stratified medicine.

Drug Discov Today. 2017 Jan;22(1):173-179

Authors: Lonergan M, Senn SJ, McNamee C, Daly AK, Sutton R, Hattersley A, Pearson E, Pirmohamed M

Abstract
The premise for stratified medicine is that drug efficacy, drug safety, or both, vary between groups of patients, and biomarkers can be used to facilitate more targeted prescribing, with the aim of improving the benefit:risk ratio of treatment. However, many factors can contribute to the variability in response to drug treatment. Inadequate characterisation of the nature and degree of variability can lead to the identification of biomarkers that have limited utility in clinical settings. Here, we discuss the complexities associated with the investigation of variability in drug efficacy and drug safety, and how consideration of these issues a priori, together with standardisation of phenotypes, can increase both the efficiency of stratification procedures and identification of biomarkers with the potential for clinical impact.

PMID: 27818254 [PubMed - indexed for MEDLINE]

Managing the Risk of CYP3A Induction in Drug Development: A Strategic Approach.

Drug Metab Dispos. 2017 Jan;45(1):35-41

Authors: Jones BC, Rollison H, Johansson S, Kanebratt KP, Lambert C, Vishwanathan K, Andersson TB

Abstract
Induction of cytochrome P450 (P450) can impact the efficacy and safety of drug molecules upon multiple dosing with coadministered drugs. This strategy is focused on CYP3A since the majority of clinically relevant cases of P450 induction are related to these enzymes. However, the in vitro evaluation of induction is applicable to other P450 enzymes; however, the in vivo relevance cannot be assessed because the scarcity of relevant clinical data. In the preclinical phase, compounds are screened using pregnane X receptor reporter gene assay, and if necessary structure-activity relationships (SAR) are developed. When projects progress toward the clinical phase, induction studies in a hepatocyte-derived model using HepaRG cells will generate enough robust data to assess the compound's induction liability in vivo. The sensitive CYP3A biomarker 4β-hydroxycholesterol is built into the early clinical phase I studies for all candidates since rare cases of in vivo induction have been found without any induction alerts from the currently used in vitro methods. Using this model, the AstraZeneca induction strategy integrates in vitro assays and in vivo studies to make a comprehensive assessment of the induction potential of new chemical entities. Convincing data that support the validity of both the in vitro models and the use of the biomarker can be found in the scientific literature. However, regulatory authorities recommend the use of primary human hepatocytes and do not advise the use of sensitive biomarkers. Therefore, primary human hepatocytes and midazolam studies will be conducted during the clinical program as required for regulatory submission.

PMID: 27777246 [PubMed - indexed for MEDLINE]

Propranolol induced G0/G1/S phase arrest and apoptosis in melanoma cells via AKT/MAPK pathway.

Oncotarget. 2016 10 18;7(42):68314-68327

Authors: Zhou C, Chen X, Zeng W, Peng C, Huang G, Li X, Ouyang Z, Luo Y, Xu X, Xu B, Wang W, He R, Zhang X, Zhang L, Liu J, Knepper TC, He Y, McLeod HL

Abstract
Both preclinical and epidemiology studies associate β-adrenoceptors-blockers (β-blockers) with activity against melanoma. However, the underlying mechanism is still unclear, especially in acral melanoma. In this study, we explored the effect of propranolol, a non-selective β-blocker, on the A375 melanoma cell line, two primary acral melanoma cell lines (P-3, P-6) and mice xenografts. Cell viability assay demonstrated that 50μM-400μM of propranolol inhibited viability in a concentration and time dependent manner with an IC50 ranging from 65.33μM to 148.60μM for 24h -72h treatment, but propranolol (less than 200μM) had no effect on HaCaT cell line. Western blots showed 100μM propranolol significantly reduced the expression of Bcl-2 while increasing the expressions of Bax, cytochrome c, cleaved capase-9 and cleaved caspase-3, and down-regulated the levels of p-AKT, p-BRAF, p-MEK1/2 and p-ERK1/2 in melanoma cells, after a 24h incubation. The in vivo data confirmed the isolation results. Mice received daily ip. administration of propranolol at the dose of 2 mg/kg for 3 weeks and the control group was treated with the same volume of saline. The mean tumor volume at day 21 in A375 xenografts was 82.33 ± 3.75mm3vs. 2044.67 ± 54.57mm3 for the propranolol-treated mice and the control group, respectively, and 31.66 ± 4.67 mm3vs. 1074.67 ± 32.17 mm3 for the P-3 xenografts. Propranolol also reduced Ki67, inhibited phosphorylation of AKT, BRAF, MEK1/2 and ERK1/2 in xenografts. These are the first data to demonstrate that propranolol might inhibit melanoma by activating the intrinsic apoptosis pathway and inactivating the MAPK and AKT pathways.

PMID: 27582542 [PubMed - indexed for MEDLINE]

N-acetylcysteine in a Double-Blind Randomized Placebo-Controlled Trial: Toward Biomarker-Guided Treatment in Early Psychosis.

Schizophr Bull. 2018 Feb 15;44(2):317-327

Authors: Conus P, Seidman LJ, Fournier M, Xin L, Cleusix M, Baumann PS, Ferrari C, Cousins A, Alameda L, Gholam-Rezaee M, Golay P, Jenni R, Woo TW, Keshavan MS, Eap CB, Wojcik J, Cuenod M, Buclin T, Gruetter R, Do KQ

Abstract
Biomarker-guided treatments are needed in psychiatry, and previous data suggest oxidative stress may be a target in schizophrenia. A previous add-on trial with the antioxidant N-acetylcysteine (NAC) led to negative symptom reductions in chronic patients. We aim to study NAC's impact on symptoms and neurocognition in early psychosis (EP) and to explore whether glutathione (GSH)/redox markers could represent valid biomarkers to guide treatment. In a double-blind, randomized, placebo-controlled trial in 63 EP patients, we assessed the effect of NAC supplementation (2700 mg/day, 6 months) on PANSS, neurocognition, and redox markers (brain GSH [GSHmPFC], blood cells GSH levels [GSHBC], GSH peroxidase activity [GPxBC]). No changes in negative or positive symptoms or functional outcome were observed with NAC, but significant improvements were found in favor of NAC on neurocognition (processing speed). NAC also led to increases of GSHmPFC by 23% (P = .005) and GSHBC by 19% (P = .05). In patients with high-baseline GPxBC compared to low-baseline GPxBC, subgroup explorations revealed a link between changes of positive symptoms and changes of redox status with NAC. In conclusion, NAC supplementation in a limited sample of EP patients did not improve negative symptoms, which were at modest baseline levels. However, NAC led to some neurocognitive improvements and an increase in brain GSH levels, indicating good target engagement. Blood GPx activity, a redox peripheral index associated with brain GSH levels, could help identify a subgroup of patients who improve their positive symptoms with NAC. Thus, future trials with antioxidants in EP should consider biomarker-guided treatment.

PMID: 29462456 [PubMed - in process]

The Impact of NOD2 Variants on Fecal Microbiota in Crohn's Disease and Controls Without Gastrointestinal Disease.

Inflamm Bowel Dis. 2018 Feb 15;24(3):583-592

Authors: Kennedy NA, Lamb CA, Berry SH, Walker AW, Mansfield J, Parkes M, Simpkins R, Tremelling M, Nutland S, UK IBD Genetics Consortium, Parkhill J, Probert C, Hold GL, Lees CW

Abstract
Background/Aims: Current models of Crohn's disease (CD) describe an inappropriate immune response to gut microbiota in genetically susceptible individuals. NOD2 variants are strongly associated with development of CD, and NOD2 is part of the innate immune response to bacteria. This study aimed to identify differences in fecal microbiota in CD patients and non-IBD controls stratified by NOD2 genotype.
Methods: Patients with CD and non-IBD controls of known NOD2 genotype were identified from patients in previous UK IBD genetics studies and the Cambridge bioresource (genotyped/phenotyped volunteers). Individuals with known CD-associated NOD2 mutations were matched to those with wild-type genotype. We obtained fecal samples from patients in clinical remission with low fecal calprotectin (<250 µg/g) and controls without gastrointestinal disease. After extracting DNA, the V1-2 region of 16S rRNA genes were polymerase chain reaction (PCR)-amplified and sequenced. Analysis was undertaken using the mothur package. Volatile organic compounds (VOC) were also measured.
Results: Ninety-one individuals were in the primary analysis (37 CD, 30 bioresource controls, and 24 household controls). Comparing CD with nonIBD controls, there were reductions in bacterial diversity, Ruminococcaceae, Rikenellaceae, and Christensenellaceae and an increase in Enterobacteriaceae. No significant differences could be identified in microbiota by NOD2 genotype, but fecal butanoic acid was higher in Crohn's patients carrying NOD2 mutations.
Conclusions: In this well-controlled study of NOD2 genotype and fecal microbiota, we identified no significant genotype-microbiota associations. This suggests that the changes associated with NOD2 genotype might only be seen at the mucosal level, or that environmental factors and prior inflammation are the predominant determinant of the observed dysbiosis in gut microbiota.

PMID: 29462388 [PubMed - in process]

Improving stability of prediction models based on correlated omics data by using network approaches.

PLoS One. 2018;13(2):e0192853

Authors: Tissier R, Houwing-Duistermaat J, Rodríguez-Girondo M

Abstract
Building prediction models based on complex omics datasets such as transcriptomics, proteomics, metabolomics remains a challenge in bioinformatics and biostatistics. Regularized regression techniques are typically used to deal with the high dimensionality of these datasets. However, due to the presence of correlation in the datasets, it is difficult to select the best model and application of these methods yields unstable results. We propose a novel strategy for model selection where the obtained models also perform well in terms of overall predictability. Several three step approaches are considered, where the steps are 1) network construction, 2) clustering to empirically derive modules or pathways, and 3) building a prediction model incorporating the information on the modules. For the first step, we use weighted correlation networks and Gaussian graphical modelling. Identification of groups of features is performed by hierarchical clustering. The grouping information is included in the prediction model by using group-based variable selection or group-specific penalization. We compare the performance of our new approaches with standard regularized regression via simulations. Based on these results we provide recommendations for selecting a strategy for building a prediction model given the specific goal of the analysis and the sizes of the datasets. Finally we illustrate the advantages of our approach by application of the methodology to two problems, namely prediction of body mass index in the DIetary, Lifestyle, and Genetic determinants of Obesity and Metabolic syndrome study (DILGOM) and prediction of response of each breast cancer cell line to treatment with specific drugs using a breast cancer cell lines pharmacogenomics dataset.

PMID: 29462177 [PubMed - in process]

SNPs and STRs in forensic medicine. A strategy for kinship evaluation.

Arch Med Sadowej Kryminol. 2017;67(3):226-240

Authors: Pontes L, Sousa JC, Medeiros R

Abstract
Some emerging technologies are used as strategies for the analyses of single nucleotide polymorphisms (SNPs) that have attracted much interest in recent years, applied to various scientific areas. They have been extensively used as markers to identify genes that underlie complex diseases and also to realize the potential of pharmacogenomics in relation to different drug responses. Additionally, SNPs have been shown to be very useful in forensic genetics resolving all kinds of legal problems, namely crime cases, disaster victim identification and paternity and kinship investigation testing. The low mutation rate of SNPs, makes these markers very suitable for relationship testing. In the great majority of the cases, analyses with the widely used sets of STR markers provide powerful statistical evidence but some of them remain with ambiguous results. Those include cases with complex pedigrees or cases with some problems, like mutations, that are inherent to the use of STRs. At this time several forensic laboratories are using SNPs especially to complement the study of STRs in some of their casework cases. This paper intends to analyze some of our casework examples and to providea data update on the joint use of STRs and autosomal SNPs in the evaluation and kinship calculation, one of the strategies currently used for this purpose, namely reviewing and comparing results published by various working groups.

PMID: 29460612 [PubMed - in process]

Research directions in the clinical implementation of pharmacogenomics - An Overview of US programs and projects.

Clin Pharmacol Ther. 2018 Feb 20;:

Authors: Volpi S, Bult C, Chisholm RL, Deverka PA, Ginsburg GS, Jacob HJ, Kasapi M, McLeod HL, Roden DM, Williams MS, Green ED, Lyman Rodriguez L, Aronson S, Cavallari LH, Denny JC, Dressler L, Johnson JA, Klein TE, Steven Leeder J, Piquette-Miller M, Perera M, Rasmussen-Torvik LJ, Rehm HL, Ritchie MD, Skaar TC, Wagle N, Weinshilboum R, Weitzel KW, Wildin R, Wilson J, Manolio TA, Relling MV

Abstract
Response to a drug often differs widely among individual patients. This variability is frequently observed not only with respect to effective responses but also with adverse drug reactions. Matching patients to the drugs that are most likely to be effective and least likely to cause harm is the goal of effective therapeutics. Pharmacogenomics (PGx) holds the promise of precision medicine through elucidating the genetic determinants responsible for pharmacological outcomes and using them to guide drug selection and dosing. Here, we survey the US landscape of research programs in PGx implementation, review current advances and clinical applications of PGx, summarize the obstacles that have hindered PGx implementation, and identify the critical knowledge gaps and possible studies needed to help to address them. This article is protected by copyright. All rights reserved.

PMID: 29460415 [PubMed - as supplied by publisher]

Pharmacogenetic information in clinical guidelines - the European perspective.

Clin Pharmacol Ther. 2018 Feb 20;:

Authors: Swen JJ, Nijenhuis M, van Rhenen M, de Boer-Veger NJ, Buunk AM, Houwink EJF, Mulder H, Rongen GA, van Schaik RHN, van der Weide J, Wilffert B, Deneer VHM, Guchelaar HJ, Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Pharmacists Association (KNMP)

PMID: 29460273 [PubMed - as supplied by publisher]

Operationalizing the Reciprocal Engagement Model of Genetic Counseling Practice: a Framework for the Scalable Delivery of Genomic Counseling and Testing.

J Genet Couns. 2018 Feb 19;:

Authors: Schmidlen T, Sturm AC, Hovick S, Scheinfeldt L, Scott Roberts J, Morr L, McElroy J, Toland AE, Christman M, O'Daniel JM, Gordon ES, Bernhardt BA, Ormond KE, Sweet K

Abstract
With the advent of widespread genomic testing for diagnostic indications and disease risk assessment, there is increased need to optimize genetic counseling services to support the scalable delivery of precision medicine. Here, we describe how we operationalized the reciprocal engagement model of genetic counseling practice to develop a framework of counseling components and strategies for the delivery of genomic results. This framework was constructed based upon qualitative research with patients receiving genomic counseling following online receipt of potentially actionable complex disease and pharmacogenomics reports. Consultation with a transdisciplinary group of investigators, including practicing genetic counselors, was sought to ensure broad scope and applicability of these strategies for use with any large-scale genomic testing effort. We preserve the provision of pre-test education and informed consent as established in Mendelian/single-gene disease genetic counseling practice. Following receipt of genomic results, patients are afforded the opportunity to tailor the counseling agenda by selecting the specific test results they wish to discuss, specifying questions for discussion, and indicating their preference for counseling modality. The genetic counselor uses these patient preferences to set the genomic counseling session and to personalize result communication and risk reduction recommendations. Tailored visual aids and result summary reports divide areas of risk (genetic variant, family history, lifestyle) for each disease to facilitate discussion of multiple disease risks. Post-counseling, session summary reports are actively routed to both the patient and their physician team to encourage review and follow-up. Given the breadth of genomic information potentially resulting from genomic testing, this framework is put forth as a starting point to meet the need for scalable genetic counseling services in the delivery of precision medicine.

PMID: 29460110 [PubMed - as supplied by publisher]

Leptospirosis in human: Biomarkers in host immune responses.

Microbiol Res. 2018 Mar;207:108-115

Authors: Vk C, Ty L, Wf L, Ywy WS, An S, S Z, A M

Abstract
Leptospirosis remains one of the most widespread zoonotic diseases caused by spirochetes of the genus Leptospira, which accounts for high morbidity and mortality globally. Leptospiral infections are often found in tropical and subtropical regions, with people exposed to contaminated environments or animal reservoirs are at high risk of getting the infection. Leptospirosis has a wide range of clinical manifestations with non-specific signs and symptoms and often misdiagnosed with other acute febrile illnesses at early stage of infection. Despite being one of the leading causes of zoonotic morbidity worldwide, there is still a gap between pathogenesis and human immune responses during leptospiral infection. It still remains obscure whether the severity of the infection is caused by the pathogenic properties of the Leptospira itself, or it is a consequence of imbalance host immune factors. Hence, in this review, we seek to summarize the past and present milestone findings on the biomarkers of host immune response aspects during human leptospiral infection, including cytokine and other immune mediators. A profound understanding of the interlink between virulence factors and host immune responses during human leptospirosis is imperative to identify potential biomarkers for diagnostic and prognostic applications as well as designing novel immunotherapeutic strategies in future.

PMID: 29458845 [PubMed - in process]

[Molecular aspects of vasoprotective peptide KED activity during atherosclerosis and restenosis].

Adv Gerontol. 2016;29(4):646-650

Authors: Kozlov KL, Bolotov II, Linkova NS, Drobintseva AO, Khavinson VK, Dyakonov MM, Kozina LS

Abstract
Peptide KED (Lys-Glu-Asp) has vasoprotective effects and is effective substance in treatment of of atherosclerosis and other cardio-vascular disorders in elderly people. One of the probable mechanisms of biological activity of this peptide is epigenetic genes regulation. These genes can coding proteins, which are markers of endothelium functional activity. The goal of investigation was to study the KED peptide effect on signal molecules expression in normal, atherosclerotic and restenotic endothelium in vitro. It was shown, that KED peptide has normalized endothelin-1 expression, which increased during atherosclerosis and restenosis. KED peptide also restorates cells interactions by connexin expression. Geroprotective effect of KED peptide is realized by increasing of sirtuin1 expression, which has took part in DNA reparation.

PMID: 28539025 [PubMed - indexed for MEDLINE]

Leveraging the Learning Health Care Model to Improve Equity in the Age of Genomic Medicine.

Learn Health Syst. 2018 Jan;2(1):

Authors: Blizinsky KD, Bonham VL

Abstract
To fully achieve the goals of a genomics-enabled learning health care system, purposeful efforts to understand and reduce health disparities and improve equity of care are essential. This paper highlights three major challenges facing genomics-enabled learning health care systems, as they pertain to ancestrally diverse populations: inequality in the utility of genomic medicine; lack of access to pharmacogenomics in clinical care; and inadequate incorporation of social and environmental data into the electronic health care record (EHR). We advance a framework that can not only be used to directly improve care for all within the learning health system, but can also be used to focus on the needs to address racial and ethnic health disparities and improve health equity.

PMID: 29457138 [PubMed]

Effects of Cytochrome P450 Single Nucleotide Polymorphisms on Methadone Metabolism and Pharmacodynamics.

Biochem Pharmacol. 2018 Feb 16;:

Authors: Ahmad T, Valentovic MA, Rankin GO

Abstract
Methadone is a synthetic, long-acting opioid with a single chiral center forming two enantiomers, (R)-methadone and (S)-methadone, each having specific pharmacological actions. Concentrations of (R)- and (S)-methadone above therapeutic levels have the ability to cause serious, life-threatening, and fatal side effects. This toxicity can be due in part to the pharmacogenetics of an individual, which influences the pharmacokinetic and pharmacodynamic properties of the drug. Methadone is primarily metabolized in the liver by cytochrome P450 (CYP) enzymes, predominately by CYP2B6, followed by CYP3A4, 2C19, 2D6, and to a lesser extent, CYP2C18, 3A7, 2C8, 2C9, 3A5, and 1A2. Single nucleotide polymorphisms (SNPs) located within CYPs have the potential to play an important role in altering methadone metabolism and pharmacodynamics. Several SNPs in the CYP2B6, 3A4, 2C19, 2D6, and 3A5 genes result in increases in methadone plasma concentrations, decreased N-demethylation, and decreased methadone clearance. In particular, carriers of CYP2B6∗6/∗6 may have a greater risk for detrimental adverse effects, as methadone metabolism and clearance are diminished in these individuals. CYP2B6∗4, on the other hand, has been observed to decrease plasma concentrations of methadone due to increased methadone clearance. The involvement, contribution, and understanding the role of SNPs in CYP2B6, and other CYP genes, in methadone metabolism can improve the therapeutic uses of methadone in patient outcome and the development of personalized medicine.

PMID: 29458047 [PubMed - as supplied by publisher]

Population pharmacokinetics and pharmacogenomics of apixaban in Japanese adult patients with atrial fibrillation.

Br J Clin Pharmacol. 2018 Feb 19;:

Authors: Ueshima S, Hira D, Kimura Y, Fujii R, Tomitsuka C, Yamane T, Tabuchi Y, Ozawa T, Itoh H, Ohno S, Horie M, Terada T, Katsura T

Abstract
AIMS: This study aimed to analyse the effects of genetic polymorphisms in drug transporters and metabolising enzymes, and clinical laboratory data on the pharmacokinetic parameters of apixaban.
METHODS: Data were collected from 81 Japanese patients with atrial fibrillation. Pharmacogenomic data were stratified by ABCB1, ABCG2, and CYP3A5 polymorphisms. The pharmacokinetic profile of apixaban was described by a one-compartment model with first-order absorption. Population pharmacokinetic analysis was conducted using non-linear mixed effect modelling (NONMEM™) program.
RESULTS: The non-linear relationship between oral clearance (CL/F) of apixaban and creatinine clearance (Ccr) was observed. The population mean of CL/F for a typical patient (Ccr value of 70 mL/min) with the CYP3A5*1/*1 and ABCG2 421C/C or C/A genotypes was estimated to be 3.06 L/h. When Ccr values were set to the typical value, the population mean of CL/F was 1.52 times higher in patients with the CYP3A5*1/*1 genotype compared with patients with the CYP3A5*1/*3 or *3/*3 genotype, while the population mean of CL/F was 1.49 times higher in patients with the ABCG2 421C/C or C/A genotype compared with patients with the ABCG2 421A/A genotype. However, no covariates affected the population mean of the apparent volume of distribution (Vd/F) of apixaban. The population mean of Vd/F was estimated to be 24.7 L.
CONCLUSION: The present study suggests that the ABCG2 421A/A and CYP3A5*3 genotypes and renal function are considered to be intrinsic factors affecting apixaban pharmacokinetics. These findings may provide useful information for precision medicine using apixaban, to avoid the risk of adverse reactions.

PMID: 29457840 [PubMed - as supplied by publisher]

Novel approach for CES1 genotyping: integrating single nucleotide variants and structural variation.

Pharmacogenomics. 2018 Feb 19;:

Authors: Bjerre D, Berg Rasmussen H

Abstract
AIM: Development of a specific procedure for genotyping of CES1A1 (CES1) and CES1A2, a hybrid of CES1A1  and the pseudogene CES1P1.
MATERIALS & METHODS: The number of CES1A1 and CES1A2  copies and that of CES1P1  were determined using real-time PCR. Long range PCRs followed by secondary PCRs allowed sequencing of single nucleotide variants in CES1A1 and CES1A2. Results & conlusion: A procedure consisting of two main steps was developed. Its first main step, the copy number determination, informed about presence of CES1A2 . This information enabled choice of PCR in the second main step, which selectively amplified CES1A1 and, if present, also CES1A2, for subsequent sequencing. Examination of 501 DNA samples suggested that our procedure is specific with potential for personalization of drug treatments.

PMID: 29457755 [PubMed - as supplied by publisher]

Kinase-targeted cancer therapies: progress, challenges and future directions.

Mol Cancer. 2018 Feb 19;17(1):48

Authors: Bhullar KS, Lagarón NO, McGowan EM, Parmar I, Jha A, Hubbard BP, Rupasinghe HPV

Abstract
The human genome encodes 538 protein kinases that transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are associated with human cancer initiation and progression. The recent development of small-molecule kinase inhibitors for the treatment of diverse types of cancer has proven successful in clinical therapy. Significantly, protein kinases are the second most targeted group of drug targets, after the G-protein-coupled receptors. Since the development of the first protein kinase inhibitor, in the early 1980s, 37 kinase inhibitors have received FDA approval for treatment of malignancies such as breast and lung cancer. Furthermore, about 150 kinase-targeted drugs are in clinical phase trials, and many kinase-specific inhibitors are in the preclinical stage of drug development. Nevertheless, many factors confound the clinical efficacy of these molecules. Specific tumor genetics, tumor microenvironment, drug resistance, and pharmacogenomics determine how useful a compound will be in the treatment of a given cancer. This review provides an overview of kinase-targeted drug discovery and development in relation to oncology and highlights the challenges and future potential for kinase-targeted cancer therapies.

PMID: 29455673 [PubMed - in process]

Systematic Cell-Based Phenotyping of Missense Alleles.

Methods Mol Biol. 2017;1601:215-228

Authors: Thormählen AS, Runz H

Abstract
Sequencing of the protein-coding genome, the exome, has proven powerful to unravel links between genetic variation and disease for both Mendelian and complex conditions. Importantly, however, the increasing number of sequenced human exomes and mapping of disease-associated alleles is accompanied by a simultaneous, yet exponential increase in the overall number of rare and low frequency alleles identified. For most of these novel alleles, biological consequences remain unknown since reliable experimental approaches to better characterize their impact on protein function are only slowly emerging.Here we review a scalable, cell-based strategy that we have recently established to systematically profile the biological impact of rare and low frequency missense variants in vitro. By applying this approach to missense alleles identified through cohort-level exome sequencing in the low-density lipoprotein receptor (LDLR) we are able to distinguish rare alleles that predispose to familial hypercholesterolemia and myocardial infarction from alleles without obvious impact on LDLR levels or functions. We propose that systematic implementation of such and similar strategies will significantly advance our understanding of the protein-coding human genome and how rare and low frequency genetic variation impacts on health and disease.

PMID: 28470529 [PubMed - indexed for MEDLINE]

Donor and recipient P450 gene polymorphisms influence individual pharmacological effects of tacrolimus in Chinese liver transplantation patients.

Int Immunopharmacol. 2018 Feb 14;57:18-24

Authors: Liu J, Ouyang Y, Chen D, Yao B, Lin D, Li Z, Zang Y, Liu H, Fu X

Abstract
The immunosuppressant drug tacrolimus (Tac) used for the prevention of immunological rejection is a metabolic substrate of cytochrome P450 enzymes. This study was designed to evaluate the short-term and long-term potential influence of single-nucleotide polymorphisms (SNPs) in CYP450 genes of liver transplant (LT) recipients as well as the donors on individual pharmacological effects of Tac and to guide individualized-medication from the perspective of pharmacogenomics. Twenty-one SNPs of the CYP450 gene were genotyped for both recipients and donors in 373 LT patients receiving Tac-based immunosuppressants. The Tac concentration/dosage ratio (C/D) was evaluated from the initial medication until one year after LT. The C/D ratio was significantly higher when the donor and/or recipient genotype of CYP3A5 rs776746 was G/G or rs15524 was T/T or rs4646450 was C/C all through one year after transplantation. Comparing the effect of donor gene variants of rs776746, rs15524, and rs4646450 on Tac C/D ratios with the recipients, statistically significant differences were found between the donor T/T group and the recipient T/T group in rs15524 at 1 month and 6 months, and at 6 months, the donor C/C group differed from the recipient C/C group in rs4646450. In conclusion, rs776746, rs15524, and rs4646450 of CYP3A5 had a significant influence on Tac pharmacological effects for both the initial use and long-term use. The donor liver genotype and the recipient intestine genotype contribute almost equally in the short-term, but the donor genotype had a greater effect than the recipient genotype at 6 months. Personalized Tac treatment after LT should be based on the CYP3A5 genotype.

PMID: 29454235 [PubMed - as supplied by publisher]