Whole exome sequencing reveals novel somatic alterations in neuroblastoma patients with chemotherapy.

Cancer Cell Int. 2018;18:21

Authors: Duan C, Wang H, Chen Y, Chu P, Xing T, Gao C, Yue Z, Zheng J, Jin M, Gu W, Ma X

Abstract
Background: We ought to explore the acquired somatic alterations, shedding light on genetic basis of somatic alterations in NB patients with chemotherapy.
Methods: Marrow blood samples from NB patients were collected before treatment, after the 2nd and 4th chemotherapy for baseline research and continuous monitoring by whole exome sequencing. Plasma cell free DNA (cfDNA) was prepared for baseline research. Finger nail cells were extracted as self control. The clinical data was analyzed.
Results: From December 2014 to February 2016, 27 cases of children with stage IV NB were diagnosed. The follow up time ranged from 5 to 25 months, with a median follow up time of 17 months, 20 patients were stable, one patient died of pulmonary embolism during surgery, six patients died of disease progression. Marrow blood whole exome sequencing demonstrated that several novel somatic mutations were identified in all three trios comply or against the trendy of tumor size variation. Of note, six recurrent mutations in bromodomain PHD finger transcription factor (BPTF) were identified in nine NB patients under the continuous monitoring. The mutation rates variation was positively correlated to tumor size (CC = 0.428, P = 0.021), and patients with BPTF mutation may have a worse prognosis compared with wild type. Meanwhile, CGREF1, CUX2, GP1BA, SLC45A1 and TRA2A were mutated with the trendy oppose as therapeutic effects. The baseline research in three NB patients demonstrated that mutation rate of BPTF, TMCO3, GPRIN2 and C20orf96 in plasma cfDNA were in positive correlation with bone marrow genomic DNA (P = 0.001).
Conclusions: Our study showed that BPTF along with other mutations may function as a biomarker for evaluating to effects of chemotherapy to this refractory tumor, and patients with BPTF mutation might have a worse prognosis.

PMID: 29467591 [PubMed]

The exomic landscape of t(14;18)-negative diffuse follicular lymphoma with 1p36 deletion.

Br J Haematol. 2018 02;180(3):391-394

Authors: Zamò A, Pischimarov J, Horn H, Ott G, Rosenwald A, Leich E

Abstract
Predominantly diffuse t(14;18) negative follicular lymphoma (FL) with 1p36 deletion shows distinctive clinical, morphological and molecular features that distinguish it from classical FL. In order to investigate whether it possesses a unique mutation profile, we performed whole exome sequencing of six well-characterised cases. Our analysis showed that the mutational landscape of this subtype is largely distinct from classical FL. It appears to harbour several recurrent mutations, affecting STAT6, CREBBP and basal membrane protein genes with high frequency. Our data support the view that this FL subtype should be considered a separate entity from classical FL.

PMID: 29193015 [PubMed - indexed for MEDLINE]

Whole-exome sequencing identified mutational profiles of high-grade colon adenomas.

Oncotarget. 2017 Jan 24;8(4):6579-6588

Authors: Lee SH, Jung SH, Kim TM, Rhee JK, Park HC, Kim MS, Kim SS, An CH, Lee SH, Chung YJ

Abstract
Although gene-to-gene analyses identified genetic alterations such as APC, KRAS and TP53 mutations in colon adenomas, it is largely unknown whether there are any others in them. Mutational profiling of high-grade colon adenoma (HGCA) that just precedes colon carcinoma might identify not only novel adenoma-specific genes but also critical genes for its progression to carcinoma. For this, we performed whole-exome sequencing (WES) of 12 HGCAs and identified 11 non-hypermutated and one hypermutated (POLE-mutated) cases. We identified 22 genes including APC, KRAS, TP53, GNAS, NRAS, SMAD4, ARID2, and PIK3CA with non-silent mutations in the cancer Census Genes. Bi-allelic and mono-allelic APC alterations were found in nine and one HGCAs, respectively, while the other two harbored wild-type APC. Five HGCAs harbored either mono-allelic (four HGCAs) or bi-allelic (one HGCA) SMAD4 mutation or 18q loss that had been known as early carcinoma-specific changes. We identified MTOR, ACVR1B, GNAQ, ATM, CNOT1, EP300, ARID2, RET and MAP2K4 mutations for the first time in colon adenomas. Our WES data is largely matched with the earlier 'adenoma-carcinoma model' (APC, KRAS, NRAS and GNAS mutations), but there are newly identified SMAD4, MTOR, ACVR1B, GNAQ, ATM, CNOT1, EP300, ARID2, RET and MAP2K4 mutations in this study. Our findings provide resource for understanding colon premalignant lesions and for identifying genomic clues for differential diagnosis and therapy options for colon adenomas and carcinomas.

PMID: 28179590 [PubMed - indexed for MEDLINE]

Recurrent genetic defects on chromosome 5q in myeloid neoplasms.

Oncotarget. 2017 Jan 24;8(4):6483-6495

Authors: Hosono N, Makishima H, Mahfouz R, Przychodzen B, Yoshida K, Jerez A, LaFramboise T, Polprasert C, Clemente MJ, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Sanada M, Cui E, Verma AK, McDevitt MA, List AF, Saunthararajah Y, Sekeres MA, Boultwood J, Ogawa S, Maciejewski JP

Abstract
BACKGROUND: Deletion of chromosome 5q (del(5q)) is the most common karyotypic abnormality in myeloid neoplasms.
MATERIALS AND METHODS: To define the pathogenic molecular features associated with del(5q), next-generation sequencing was applied to 133 patients with myeloid neoplasms (MDS; N = 69, MDS/MPN; N = 5, sAML; N = 29, pAML; N = 30) with del(5q) as a sole abnormally or a part of complex karyotype and results were compared to molecular features of patients diploid for chr5.
FINDINGS: A number of 5q genes with haploinsufficient expression and/or recurrent somatic mutations were identified; for these genes, CSNK1A1 and G3BP1 within the commonly deleted 5q region and DDX41 within a commonly retained region were most commonly affected by somatic mutations. These genes showed consistent haploinsufficiency in deleted cases; low expression/mutations of G3BP1 or DDX41 were associated with poor survival, likely due to decreased cellular function. The most common mutations on other chromosomes in patients with del(5q) included TP53, and mutations of FLT3 (ITD or TKD), NPM1 or TET2 and were mutually exclusive. Serial sequencing allowed for definition of clonal architecture and dynamics, in patients with exome sequencing allelic imbalance for informative SNPs facilitated simultaneous approximation of clonal size of del(5q) and clonal burden for somatic mutations.
INTERPRETATION: Our results illuminate the spectrum of molecular defects characteristic of del(5q), their clinical impact and succession of stepwise evolution.

PMID: 28031539 [PubMed - indexed for MEDLINE]

Intratumoral heterogeneity and chemoresistance in nonseminomatous germ cell tumor of the testis.

Oncotarget. 2016 Dec 27;7(52):86280-86289

Authors: Bilen MA, Hess KR, Campbell MT, Wang J, Broaddus RR, Karam JA, Ward JF, Wood CG, Choi SL, Rao P, Zhang M, Naing A, General R, Cauley DH, Lin SH, Logothetis CJ, Pisters LL, Tu SM

Abstract
BACKGROUND: Nonseminomatous germ cell tumor of the testis (NSGCT) is largely curable. However, a small group of patients develop refractory disease. We investigated the hypothesis that intratumoral heterogeneity contributes to the emergence of chemoresistance and the development of refractory tumor subtypes.
RESULTS: Our institution's records for January 2000 through December 2010 included 275 patients whose primary tumor showed pure embryonal carcinoma (pure E); mixed embryonal carcinoma, yolk sac tumor, and teratoma (EYT); or mixed embryonal carcinoma, yolk sac tumor, seminoma, and teratoma (EYST). Patients with EYST had the highest cancer-specific mortality rate (P = .001). They tended to undergo somatic transformation (P = .0007). Two of 5 patients with clinical stage I EYST who had developed recurrence during active surveillance died of their disease.
MATERIALS AND METHODS: In this retrospective study, we evaluated consecutive patients who had been diagnosed with the three most common histological phenotypes of NSGCT. Chemoresistance was defined as the presence of teratoma, viable germ cell tumor, or somatic transformation in the residual tumor or the development of progressive or relapsed disease after chemotherapy. In a separate prospective study, we performed next-generation sequencing on tumor samples from 39 patients to identify any actionable genetic mutations.
CONCLUSIONS: Our data suggest that patients with EYST in their primary tumor may harbor a potentially refractory NSGCT phenotype and are at increased risk of dying from disease. Despite intratumoral heterogeneity, improved patient selection and personalized care of distinct tumor subtypes may optimize the clinical outcome of patients with NSGCT.

PMID: 27861143 [PubMed - indexed for MEDLINE]

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

"systems biology"

These pubmed results were generated on 2018/02/22

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.

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

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2018/02/22

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.

Repurposing anticancer drugs for targeting necroptosis.

Cell Cycle. 2018 Feb 21;:1-8

Authors: Fulda S

Abstract
Necroptosis represents a form of programmed cell death that can be engaged by various upstream signals, for example by ligation of death receptors, by viral sensors or by pattern recognition receptors. It depends on several key signaling proteins, including the kinases Receptor-Interacting Protein (RIP)1 and RIP3 and the pseudokinase mixed-lineage kinase domain-like protein (MLKL). Necroptosis has been implicated in a number of physiological and pathophysiological conditions and is disturbed in many human diseases. Thus, targeted interference with necroptosis signaling may offer new opportunities for the treatment of human diseases. Besides structure-based drug design, in recent years drug repositioning has emerged as a promising alternative to develop drug-like compounds. There is accumulating evidence showing that multi-targeting kinase inhibitors, for example Dabrafenib, Vemurafenib, Sorafenib, Pazopanib and Ponatinib, used for the treatment of cancer also display anti-necroptotic activity. This review summarizes recent evidence indicating that some anticancer kinase inhibitors also negatively affect necroptosis signaling. This implies that some cancer therapeutics may be repurposed for other pathologies, e.g. ischemic or inflammatory diseases.

PMID: 29464983 [PubMed - as supplied by publisher]

Pediatric Pulmonology year in review 2016: Part 1.

Pediatr Pulmonol. 2017 Sep;52(9):1226-1233

Authors: Birnkrant DJ, Black JB, Tapia IE, Nicolai T, Gower WA, Noah TL

Abstract
Pediatric Pulmonology continues to publish research and clinical topics related to the entire range of children's respiratory disorders. As we have done annually in recent years, we here summarize the past year's publications in our major topic areas, as well as selected literature in these areas from other core journals relevant to our discipline. This review (Part 1) covers selected articles on sleep, diagnostic testing/endoscopy, respiratory complications of neuromuscular disorders, and rare lung diseases.

PMID: 28440921 [PubMed - indexed for MEDLINE]

A rare case of renal thrombotic microangiopathy associated with Castleman's disease.

BMC Nephrol. 2017 Feb 10;18(1):57

Authors: Mutneja A, Cossey LN, Liapis H, Chen YM

Abstract
BACKGROUND: Castleman's disease (CD) is an uncommon, heterogeneous lympho-proliferative disorder leading to high circulating levels of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF). Renal involvement has been only described in a limited number of small studies. Herein, we report a rare case of renal thrombotic microangiopathy (TMA) associated with CD and investigate the podocyte expression of VEGF in the renal biopsy prior to initiation of treatment.
CASE PRESENTATION: An 18-year-old male presented with fever, diarrhea, diffuse lymphadenopathy, ascites and acute kidney injury. Laboratory tests for hemolytic uremic syndrome and thrombotic thrombocytopenic purpura were negative. The kidney biopsy showed TMA. An excisional lymph node biopsy was consistent with CD, plasma cell variant. Immunofluorescence staining showed suppressed podocyte VEGF expression. Chemotherapy that inhibits production of inflammatory mediators including IL-6 and VEGF led to complete recovery of renal function.
CONCLUSIONS: Our case illustrates a rare renal histological feature of CD. IL-6 and VEGF are postulated to suppress glomerular VEGF expression, thereby causing renal TMA. Therapy directed against these inflammatory mediators may have important therapeutic implications.

PMID: 28183278 [PubMed - indexed for MEDLINE]

[To reimburse or not? Evaluating expensive drugs differently].

Ned Tijdschr Geneeskd. 2016;160(0):D1022

Authors: Stolk J

Abstract
Health insurance organisations grant reimbursement for drug treatment on the basis of results of placebo-controlled randomised clinical trials showing a clinically meaningful and statistically significant effect over placebo. This often proves problematic in rare diseases as well as in many chronic diseases that are difficult to treat. Clinical scientists may address the issue by testing the drug on surrogate outcome parameters and ask for post-marketing studies conducted by expert reference centres as expediency research, using budgets provided by the government to show that the drug really works in terms of real-life patient experience. In the past 5 years, the pharmaceutical industry has released an increasing number of expensive drugs for rare diseases; this jeopardises the solidarity of health insurance cover for all EU citizens. To facilitate drug development, a new model might benefit all key players involved. The foundation Fair Medicine recently called for coalitions that jointly develop medicines based on contribution and complementarity, sharing responsibilities, risks and rewards.

PMID: 27879186 [PubMed - indexed for MEDLINE]

[Kleine Levin Syndrome: more than just periodic hypersomnia].

Ned Tijdschr Geneeskd. 2016;160:D238

Authors: Pillen S, Vandenbussche NL, Fronczek R, van Duijn J, Lammers GJ, Overeem S

Abstract
BACKGROUND: Kleine Levin Syndrome (KLS) is a rare disease with periodic hypersomnia as its main feature. Hyperphagia and hypersexuality are also described as classical symptoms, although quite recently it has become clear that the full triad is absent in the majority of patients.
CASE DESCRIPTION: A 14-year-old boy developed KLS after a period of flu-like symptoms. Over the course of three years he suffered from seven one-week episodes of extreme hypersomnia (sleeping 18 hours a day), depersonalisation, apathy, anxiety, paranoia, confusion, hallucinations and uninhibited sexual behaviour. He ate little. Ancillary investigations did not reveal any abnormalities. In between these episodes he had no symptoms.
CONCLUSION: From this case description and a summary of the symptoms of twelve other patients with KLS, it appears that neuropsychiatric symptoms are much more prominent than hyperphagia and hypersexuality. It is important that the typical KLS phenotype be reappraised, so that the condition can be recognised early and patients managed appropriately.

PMID: 27484420 [PubMed - indexed for MEDLINE]

An Advanced IoT-based System for Intelligent Energy Management in Buildings.

Sensors (Basel). 2018 Feb 16;18(2):

Authors: Marinakis V, Doukas H

Abstract
The energy sector is closely interconnected with the building sector and integrated Information and Communication Technologies (ICT) solutions for effective energy management supporting decision-making at building, district and city level are key fundamental elements for making a city Smart. The available systems are designed and intended exclusively for a predefined number of cases and systems without allowing for expansion and interoperability with other applications that is partially due to the lack of semantics. This paper presents an advanced Internet of Things (IoT) based system for intelligent energy management in buildings. A semantic framework is introduced aiming at the unified and standardised modelling of the entities that constitute the building environment. Suitable rules are formed, aiming at the intelligent energy management and the general modus operandi of Smart Building. In this context, an IoT-based system was implemented, which enhances the interactivity of the buildings' energy management systems. The results from its pilot application are presented and discussed. The proposed system extends existing approaches and integrates cross-domain data, such as the building's data (e.g., energy management systems), energy production, energy prices, weather data and end-users' behaviour, in order to produce daily and weekly action plans for the energy end-users with actionable personalised information.

PMID: 29462957 [PubMed - in process]

[MODERN VIEWS ON THE PHARMACOGENETICS OF PAIN.]

Anesteziol Reanimatol. 2017 Sep;61:219-223

Authors: Makharin OA, Zhenilo VM, Patyuchenko OY

Abstract
Quality anesthesia during surgery and in the postoperative period remains a topical problem of modern anesthesiology. The study of genetic characteristics of a patient is a goal that may be allow us to develop a personalized approach to solve this problem. The purpose of the review is a synthesis of literature data about the influence of genetic factors on pain perception and its treatment. The review included information obtained from SCOPUS, MedLine, EMBASE. The search keywords were: pain, pharmacogenetics, polymorphism, analgesics.Describe the effect ofgene polymorphisms of OPRM, 5HTRIA, 5HTR2A, COMT GCHI, SCN9A, KCNSI, CACNA2D3, CACNG2, PTGSI, PTGS2, MDRJ/ABCB] on the perception of pain, and CYP2D6, CYP2C9, CYP3A4 on the pharmacokinetics and pharmacodynamics of medi- cations used in the treatment of pain.

PMID: 29465208 [PubMed - in process]

Pharmacogenetic Testing May Improve Drug Treatments and Shorten Disability Leaves.

Benefits Q. 2017;33(1):43-49

Authors: Lefaivre A, Litinski V, Vandenhurk M

Abstract
This article describes how methods of personalized medicine-specifically, pharmacogenetic (PGx) testing-can benefit private health plans, benefits managers, care providers and consumers alike. The authors cover pharmacogenomics as a science and also introduce an innovative way to optimize drug treatments. The article touches on some important clinical outcomes drawn from a recent study in community pharmacy and reviews the application and return on investment of PGx testing in disability and medication management.

PMID: 29465186 [PubMed - in process]

Genetic variations in genes of the stress response pathway are associated with prolonged abstinence from heroin.

Pharmacogenomics. 2018 Feb 21;:

Authors: Levran O, Peles E, Randesi M, Correa da Rosa J, Shen PH, Rotrosen J, Adelson M, Kreek MJ

Abstract
AIM: This study assesses whether genetic variants in stress-related genes are associated with prolonged abstinence from heroin in subjects that are not in long-term methadone treatment.
METHODS: Frequencies of 117 polymorphisms in 30 genes were compared between subjects with history of heroin addiction, either without agonist treatment (n = 129) or in methadone maintenance treatment (n = 923).
RESULTS: SNP rs1500 downstream of CRHBP and an interaction of SNPs rs10482672 (NR3C1) and rs4234955 (NPY1R/NPY5R) were significantly associated with prolonged abstinence without agonist treatment.
CONCLUSION: This study suggests that variability in stress-related genes may contribute to the ability of certain subjects to remain in prolonged abstinence from heroin, possibly due to higher resilience to stress.

PMID: 29465008 [PubMed - as supplied by publisher]

Implications of KRAS mutations in acquired resistance to treatment in NSCLC.

Oncotarget. 2018 Jan 19;9(5):6630-6643

Authors: Re MD, Rofi E, Restante G, Crucitta S, Arrigoni E, Fogli S, Maio MD, Petrini I, Danesi R

Abstract
Rationale: KRAS is the most common and, simultaneously, the most ambiguous oncogene implicated in human cancer. Despite KRAS mutations were identified in Non Small Cell Lung Cancers (NSCLCs) more than 20 years ago, selective and specific inhibitors aimed at directly abrogating KRAS activity are not yet available. Nevertheless, many therapeutic approaches have been developed potentially useful to treat NSCLC patients mutated for KRAS and refractory to both standard chemotherapy and targeted therapies.The focus of this review will be to provide an overview of the network related to the intricate molecular KRAS pathways, stressing on preclinical and clinical studies that investigate the predictive value of KRAS mutations in NSCLC patients.
Materials and Methods: A bibliographic search of the Medline database was conducted for articles published in English, with the keywords KRAS, KRAS mutations in non-small cell lung cancer, KRAS and tumorigenesis, KRAS and TKIs, KRAS and chemotherapy, KRAS and monoclonal antibody, KRAS and immunotherapy, KRAS and drugs, KRAS and drug resistance.

PMID: 29464099 [PubMed]

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]