In Silico Drug Prescription for Targeting Cancer Patient Heterogeneity and Prediction of Clinical Outcome.

Cancers (Basel). 2019 Sep 13;11(9):

Authors: Piñeiro-Yáñez E, Jiménez-Santos MJ, Gómez-López G, Al-Shahrour F

Abstract
In silico drug prescription tools for precision cancer medicine can match molecular alterations with tailored candidate treatments. These methodologies require large and well-annotated datasets to systematically evaluate their performance, but this is currently constrained by the lack of complete patient clinicopathological data. Moreover, in silico drug prescription performance could be improved by integrating additional tumour information layers like intra-tumour heterogeneity (ITH) which has been related to drug response and tumour progression. PanDrugs is an in silico drug prescription method which prioritizes anticancer drugs combining both biological and clinical evidence. We have systematically evaluated PanDrugs in the Genomic Data Commons repository (GDC). Our results showed that PanDrugs is able to establish an a priori stratification of cancer patients treated with Epidermal Growth Factor Receptor (EGFR) inhibitors. Patients labelled as responders according to PanDrugs predictions showed a significantly increased overall survival (OS) compared to non-responders. PanDrugs was also able to suggest alternative tailored treatments for non-responder patients. Additionally, PanDrugs usefulness was assessed considering spatial and temporal ITH in cancer patients and showed that ITH can be approached therapeutically proposing drugs or combinations potentially capable of targeting the clonal diversity. In summary, this study is a proof of concept where PanDrugs predictions have been correlated to OS and can be useful to manage ITH in patients while increasing therapeutic options and demonstrating its clinical utility.

PMID: 31540260 [PubMed]

The Influence of Beta-2 Adrenergic Receptor Gene Polymorphisms on Albuterol Therapy for Patients With Asthma: Protocol for a Systematic Review and Meta-Analysis.

JMIR Res Protoc. 2019 Sep 16;8(9):e14759

Authors: Hikino K, Kobayashi S, Ota E, Mushiroda T, Kobayashi T

Abstract
BACKGROUND: Albuterol is one of the most frequently used medications in clinical practice and seeing varying responses to albuterol between individuals is not uncommon. Multiple studies have been conducted to investigate the associations of differing responses due to albuterol, particularly with regards to the two nonsynonymous single nucleotide polymorphisms (SNPs) at positions 16 (Arg16Gly: substitution of arginine to glycine at position 16; rs1042713) and 27 (Glu27Gln: substitution of glutamic acid to glutamine at position 27; rs1042714) on the β-2 adrenergic receptor (ADRB2) gene. However, the directions of the correlations are conflicting.
OBJECTIVE: The objective of this systematic review and meta-analysis is to assess the effect of the two SNPs on the ADRB2 gene, in terms of the responses that present in asthmatic patients shortly after albuterol inhalation.
METHODS: The primary outcome of this work is a detailed study of the associations of the two SNPs in the ADRB2 gene with treatment response and lung function testing shortly after administration of albuterol to asthmatic patients. A comprehensive literature search, using the OVID platform, MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials, will be conducted by a specialized librarian without language restrictions. We will include both prospective and retrospective original observational studies, and we will exclude nonhuman or in vitro studies. All abstracts will be reviewed by two authors who will also individually perform data extraction from each eligible study. Any arising disagreements will be resolved through discussion with a third party. Risk of bias for all included studies will be independently assessed using the quality of genetic association studies tool. We will report the systematic review and meta-analysis, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. A narrative synthesis of study results or meta-analyses will be undertaken when appropriate.
RESULTS: At the moment of writing, we have already started the preliminary literature search and piloting of the study selection process. The anticipated completion date is September 30, 2019.
CONCLUSIONS: Our systematic review and meta-analysis aims to clarify the current evidence of associations between the two nonsynonymous SNPs in the ADRB2 gene and the responses that present in asthmatic patients shortly after albuterol inhalation. If positive correlations are found, this knowledge may be used to improve personalized pharmacotherapy of albuterol use.
TRIAL REGISTRATION: PROSPERO CRD42019074554; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=74554.
INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/14759.

PMID: 31538939 [PubMed]

Dissection of DLBCL microenvironment provides a gene expression-based predictor of survival applicable to formalin-fixed paraffin-embedded tissue.

Ann Oncol. 2019 Sep 20;:

Authors: Ciavarella S, Vegliante MC, Fabbri M, De Summa S, Melle F, Motta G, De Iuliis V, Opinto G, Enjuanes A, Rega S, Gulino A, Agostinelli C, Scattone A, Tommasi S, Mangia A, Mele F, Simone G, Zito AF, Ingravallo G, Vitolo U, Chiappella A, Tarella C, Gianni AM, Rambaldi A, Zinzani PL, Casadei B, Derenzini E, Loseto G, Pileri A, Tabanelli V, Fiori S, Rivas-Delgado A, López-Guillermo A, Venesio T, Sapino A, Campo E, Tripodo C, Guarini A, Pileri SA

PMID: 31539020 [PubMed - as supplied by publisher]

The Pharmacogenomics of Inhaled Corticosteroids and Lung Function Decline in COPD.

Eur Respir J. 2019 Sep 19;:

Authors: Obeidat M, Faiz A, Li X, van den Berge M, Hansel NN, Joubert P, Hao K, Brandsma CA, Rafaels N, Mathias R, Ruczinski I, Beaty TH, Barnes KC, Paul Man SF, Paré PD, Sin DD

Abstract
Inhaled corticosteroids (ICS) are widely prescribed for patients with chronic obstructive pulmonary disease (COPD), yet with variable outcomes and adverse reactions which may be genetically determined. The primary aim of the study was to identify the genetic determinants for FEV1 changes related to ICS therapy. In the Lung Health Study 2 (LHS-2), 1116 COPD patients were randomised to the ICS, triamcinolone acetonide (n=559), or placebo (n=557) with spirometry performed every 6 months for 3 years. We performed a pharmacogenomic genome-wide association study (GWAS) for the genotype-by-ICS treatment effect on 3 years of forced expiratory volume in 1 s (FEV1) changes (estimated as slope) in 802 genotyped LHS-2 participants. Replication was performed in 199 COPD patients randomised to the ICS, fluticasone or placebo. A total of five loci showed genotype-by-ICS interaction at p<5×10-6; of these, SNP rs111720447 on chromosome 7 was replicated (discovery p=4.8×10-6, replication p=5.9×10-5) with the same direction of interaction effect. ENCODE data revealed that in glucocorticoid treated (dexamethasone) A549 alveolar cell line, glucocorticoid receptor binding sites were located near SNP rs111720447. In stratified analyses of LHS-2, genotype at SNP rs111720447 was significantly associated with rate of FEV1 decline in patients taking ICS (C allele beta=56.35 mL·year-1, 95% confidence interval (CI)=29.96, 82.76 mL·yr-1) and also in patients who were assigned to placebo, though the relationship was weaker and in the opposite direction than that in the ICS group (C allele beta=-27.57 mL·year-1, 95% CI=-53.27, -1.87 mL·yr-1). The study uncovered genetic factors associated with FEV1 changes related to ICS in COPD patients, which may provide new insight on the potential biology of steroid responsiveness in COPD.

PMID: 31537701 [PubMed - as supplied by publisher]

Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen.

J Am Soc Nephrol. 2019 Sep 19;:

Authors: Salem RM, Todd JN, Sandholm N, Cole JB, Chen WM, Andrews D, Pezzolesi MG, McKeigue PM, Hiraki LT, Qiu C, Nair V, Di Liao C, Cao JJ, Valo E, Onengut-Gumuscu S, Smiles AM, McGurnaghan SJ, Haukka JK, Harjutsalo V, Brennan EP, van Zuydam N, Ahlqvist E, Doyle R, Ahluwalia TS, Lajer M, Hughes MF, Park J, Skupien J, Spiliopoulou A, Liu A, Menon R, Boustany-Kari CM, Kang HM, Nelson RG, Klein R, Klein BE, Lee KE, Gao X, Mauer M, Maestroni S, Caramori ML, de Boer IH, Miller RG, Guo J, Boright AP, Tregouet D, Gyorgy B, Snell-Bergeon JK, Maahs DM, Bull SB, Canty AJ, Palmer CNA, Stechemesser L, Paulweber B, Weitgasser R, Sokolovska J, Rovīte V, Pīrāgs V, Prakapiene E, Radzeviciene L, Verkauskiene R, Panduru NM, Groop LC, McCarthy MI, Gu HF, Möllsten A, Falhammar H, Brismar K, Martin F, Rossing P, Costacou T, Zerbini G, Marre M, Hadjadj S, McKnight AJ, Forsblom C, McKay G, Godson C, Maxwell AP, Kretzler M, Susztak K, Colhoun HM, Krolewski A, Paterson AD, Groop PH, Rich SS, Hirschhorn JN, Florez JC, SUMMIT Consortium, DCCT/EDIC Research Group, GENIE Consortium

Abstract
BACKGROUND: Although diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown.
METHODS: To identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function.
RESULTS: Our GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition (BMP7) or renal biology (COLEC11 and DDR1).
CONCLUSIONS: The 16 diabetic kidney disease-associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.

PMID: 31537649 [PubMed - as supplied by publisher]

Efficacy and safety of TAS-116, an oral inhibitor of heat shock protein 90, in patients with metastatic or unresectable gastrointestinal stromal tumour refractory to imatinib, sunitinib and regorafenib: a phase II, single-arm trial.

Eur J Cancer. 2019 Sep 16;121:29-39

Authors: Doi T, Kurokawa Y, Sawaki A, Komatsu Y, Ozaka M, Takahashi T, Naito Y, Ohkubo S, Nishida T

Abstract
AIM: We evaluated the efficacy and safety of TAS-116, a novel class of an orally active selective inhibitor of heat shock protein 90, in patients with advanced gastrointestinal stromal tumour (GIST) after failure of three or more lines of standard treatment with imatinib, sunitinib and regorafenib.
METHODS: In this single-arm phase II study, patients received 160 mg/day oral TAS-116 for five consecutive days, followed by a 2-day rest. The primary end-point was centrally assessed progression-free survival (PFS). The secondary end-points were objective response rate, disease control rate, overall survival (OS), metabolic response rate, safety, pharmacokinetics and pharmacogenomics.
RESULTS: Forty-one patients were enrolled in Japan, and 40 patients underwent efficacy and safety evaluation. At the cut-off date, the median PFS was 4.4 months (95% confidence interval [CI], 2.8-6.0) and 12-week progression-free rate was 73.4% (95% CI, 58.1-88.7). Thirty-four patients (85.0%) had stable disease for ≥ 6 weeks. The median OS was 11.5 months (95% CI, 7.0-not reached). All patients experienced at least one treatment-related adverse event (AE), including diarrhoea (80.0%), decreased appetite (45.0%) and increase in blood creatinine level (42.5%). Grade ≥3 AEs and treatment-related grade ≥3 AEs occurred in 23 (57.5%) and 21 (52.5%) patients, respectively. All AEs resolved after dose modification, and no TAS-116-related AEs led to treatment discontinuation.
CONCLUSION: TAS-116 showed significant activity in advanced GIST refractory to standard treatment. Further development of TAS-116 is warranted.
TRIAL REGISTRATION: JapicCTI-163182.

PMID: 31536852 [PubMed - as supplied by publisher]

Interrogation of CYP2D6 structural variant alleles improves the correlation between CYP2D6 genotype and CYP2D6-mediated metabolic activity.

Clin Transl Sci. 2019 Sep 19;:

Authors: Dalton R, Lee SB, Claw KG, Prasad B, Phillips BR, Shen DD, Hong Wong L, Fade M, McDonald MG, Dunham MJ, Fowler DM, Rettie AE, Schuetz E, Thornton TA, Nickerson DA, Gaedigk A, Thummel KE, Woodahl EL

Abstract
The CYP2D6 gene locus is challenging to accurately genotype due to numerous single nucleotide variants and complex structural variation. Our goal was to determine whether the CYP2D6 genotype-phenotype correlation is improved when diplotype assignments incorporate structural variation, identified by the bioinformatics tool Stargazer, with next-generation sequencing data. Using CYP2D6 activity measured with substrates dextromethorphan and metoprolol, activity score explained 40% and 34% of variability in metabolite formation rates, respectively, when diplotype calls incorporated structural variation, increased from 36% and 31% variability explained by activity score when diplotype calls did not incorporate structural variation. We also investigated whether the revised Clinical Pharmacogenetics Implementation Consortium (CPIC) recommendations for translating genotype to phenotype improve CYP2D6 activity predictions over the current system. Although the revised recommendations do not improve the correlation between activity score and CYP2D6 activity, perhaps because of low frequency of the CYP2D6*10 allele, the correlation with metabolizer phenotype group was significantly improved for both substrates. We also measured the function of seven rare coding variants: one (A449D) exhibited decreased (44%) and another (R474Q) increased (127%) activity compared to reference CYP2D6.1 protein. Allele-specific analysis found that A449D is part of a novel CYP2D6*4 suballele, CYP2D6*4.028. The novel haplotype containing R474Q was designated CYP2D6*138 by PharmVar; another novel haplotype containing R365H was designated CYP2D6*139. Accuracy of CYP2D6 phenotype prediction is improved when the CYP2D6 gene locus is interrogated using next-generation sequencing coupled with structural variation analysis. Additionally, revised CPIC genotype to phenotype translation recommendations provide an improvement in assigning CYP2D6 activity.

PMID: 31536170 [PubMed - as supplied by publisher]

ON selectivity in Drosophila vision is a multisynaptic process involving both glutamatergic and GABAergic inhibition.

Elife. 2019 Sep 19;8:

Authors: Molina-Obando S, Vargas-Fique JF, Henning M, Gür B, Schladt TM, Akhtar J, Berger TK, Silies M

Abstract
Sensory systems sequentially extract increasingly complex features. ON and OFF pathways, for example, encode increases or decreases of a stimulus from a common input. This ON/OFF pathway split is thought to occur at individual synaptic connections through a sign-inverting synapse in one of the pathways. Here, we show that ON selectivity is a multisynaptic process in the Drosophila visual system. A pharmacogenetics approach demonstrates that both glutamatergic inhibition through GluClα and GABAergic inhibition through Rdl mediate ON responses. Although neurons postsynaptic to the glutamatergic ON pathway input L1 lose all responses in GluClα mutants, they are resistant to a cell-type-specific loss of GluClα. This shows that ON selectivity is distributed across multiple synapses, and raises the possibility that cell-type-specific manipulations might reveal similar strategies in other sensory systems. Thus, sensory coding is more distributed than predicted by simple circuit motifs, allowing for robust neural processing.

PMID: 31535971 [PubMed - as supplied by publisher]

CAV1 - GLUT3 signaling is important for cellular energy and can be targeted by Atorvastatin in Non-Small Cell Lung Cancer.

Theranostics. 2019;9(21):6157-6174

Authors: Ali A, Levantini E, Fhu CW, Teo JT, Clohessy JG, Goggi JL, Wu CS, Chen L, Chin TM, Tenen DG

Abstract
Background: The development of molecular targeted therapies, such as EGFR-TKIs, has positively impacted the management of EGFR mutated NSCLC. However, patients with innate and acquired resistance to EGFR-TKIs still face limited effective therapeutic options. Statins are the most frequently prescribed anti-cholesterol agents and have been reported to inhibit the progression of various malignancies, including in lung. However, the mechanism by which statin exerts its anti-cancer effects is unclear. This study is designed to investigate the anti-proliferative effects and identify the mechanism-of-action of statins in NSCLC. Methods: In this study, the anti-tumoral properties of Atorvastatin were investigated in NSCLC utilizing cell culture system and in vivo models. Results: We demonstrate a link between elevated cellular cholesterol and TKI-resistance in NSCLC, which is independent of EGFR mutation status. Atorvastatin suppresses growth by inhibiting Cav1 expression in tumors in cell culture system and in in vivo models. Subsequent interrogations demonstrate an oncogenic physical interaction between Cav1 and GLUT3, and glucose uptake found distinctly in TKI-resistant NSCLC and this may be due to changes in the physical properties of Cav1 favoring GLUT3 binding in which significantly stronger Cav1 and GLUT3 physical interactions were observed in TKI-resistant than in TKI-sensitive NSCLC cells. Further, the differential effects of atorvastatin observed between EGFR-TKI resistant and sensitive cells suggest that EGFR mutation status may influence its actions. Conclusions: This study reveals the inhibition of oncogenic role of Cav1 in GLUT3-mediated glucose uptake by statins and highlights its potential impact to overcome NSCLC with EGFR-TKI resistance.

PMID: 31534543 [PubMed - in process]

[BIOMARKERS FOR PREDICTING FUTURE EXACERBATIONS IN ADULT PATIENTS WITH ASTHMA].

Arerugi. 2019;68(8):942-947

Authors: Hirai K, Shirai T, Itoh K

PMID: 31534105 [PubMed - in process]

Feasibility of Integrating Panel-Based Pharmacogenomics Testing for Chemotherapy and Supportive Care in Patients With Colorectal Cancer.

Technol Cancer Res Treat. 2019 Jan 01;18:1533033819873924

Authors: Kasi PM, Koep T, Schnettler E, Shahjehan F, Kamatham V, Baldeo C, Hughes CL

Abstract
INTRODUCTION: Pharmacogenomics is about selecting the "right drug in the right amount for the right patient." In metastatic colorectal cancer, germline pharmacogenomics testing presents a unique opportunity to improve outcomes, since the genes dihydropyrimidine dehydrogenase and UDP-glucuronosyltransferase metabolizing the chemotherapy drugs, 5-fluorouracil, and irinotecan are already well known. In a retrospective analysis of the landmark TRIBE clinical trial [(TRIBE - TRIplet plus BEvacizumab multicenter, phase III trial by the Italian Cooperative GONO (Gruppo Oncologico Nord Ovest) group (NCT00719797)], the proportion of patients with serious adverse events was higher in those with dihydropyrimidine dehydrogenase/UDP-glucuronosyltransferase aberrations and was dose dependent. We aimed to report on the feasibility and the results of incorporating pharmacogenomics testing into clinical practice.
METHODS: As a quality improvement initiative and a center of individualized medicine grant, we integrated the use of OneOme RightMed comprehensive test, which reports on 27 genes related to pharmacogenomics and over 300 medications of interest. We limited initial testing to patients with colorectal cancer. Pharmacists provided dosage recommendations based on test results in real-time.
RESULTS: At our cancer center, 155 patients underwent pharmacogenomics testing from November 2017 to January 2019. Results were available within 3 to 5 days of testing for most patients and were integrated into treatment decision-making. Of 155 sampled participants, a total of 89 (57.4%) participants had an UGT1A1 variant genotype, NM_000463.2: c.-53_-52[8] *1/*28, n = 74 (47.7%); *28/*28, n = 15 (9.7%). Additionally, 4 (2.6%) participants were heterozygous for dihydropyrimidine dehydrogenase. Two (1.3%) individuals were heterozygous for both UDP-glucuronosyltransferase and dihydropyrimidine dehydrogenase genes. All (100%) the patients had at least 1 actionable aberration related to supportive care medications (CYP-family) of all the possible medications listed on their pharmacogenomics report.
CONCLUSION: Preemptive comprehensive pharmacogenomics testing can be integrated into clinical practice in real-time for patients with cancer given faster turnaround and low cost. Pharmacist-driven, patient-specific medication management consults add further value given the number of genes/drugs. This sets the stage for a prospective randomized clinical trial to demonstrate the amount of benefit this can result in these patients.

PMID: 31533552 [PubMed - in process]

Interactions Between Regulatory Variants in CYP7A1 (Cholesterol 7α-Hydroxylase) Promoter and Enhancer Regions Regulate CYP7A1 Expression.

Circ Genom Precis Med. 2018 10;11(10):e002082

Authors: Wang D, Hartmann K, Seweryn M, Sadee W

Abstract
BACKGROUND: CYP7A1 (cholesterol 7α-hydroxylase) catalyzes the rate-limiting step in bile acid biosynthesis from cholesterol-a main pathway for cholesterol removal from the body. CYP7A1 single-nucleotide polymorphisms (SNPs) are associated with total cholesterol and LDL (low-density lipoprotein) levels, risk of cardiovascular diseases, and other phenotypes; however, results are inconsistent, and causative variants remain uncertain, except for a frequent promoter SNP (rs3808607).
METHODS: We used chromatin conformation capture (4C assay), chromatin immunoprecipitation qPCR assay in hepatocytes, and CRISPR (clustered regularly interspaced short palindromic repeats)-mediated genome editing in hepatocellular carcinoma cell line cells to identify regulatory regions for CYP7A1. We then screened for SNPs located in regulatory regions, testing effects on reporter gene assays and on hepatic CYP7A1 expression by measuring allelic mRNA expression imbalance.
RESULTS: 4C assays showed several regions interacting with CYP7A1 promoter. CRISPR-mediated genome editing in hepatocellular carcinoma cell line cells revealed a novel CYP7A1 enhancer and a repressor region, located >10 kb downstream of the CYP7A1 promoter. SNP screening with an allelic mRNA expression imbalance in human livers and reporter gene assays identified a frequent functional SNP (rs9297994) located in the downstream CYP7A1 enhancer region. SNP rs9297994 is in high linkage disequilibrium with promoter SNP rs3808607 but has opposite effects on CYP7A1 mRNA expression. Their combined effects using a 2-SNP model robustly associate with hepatic CYP7A1 mRNA expression, ranging >2 orders of magnitude. Moreover, only the 2-SNP model, but not each SNP alone, is significantly associated with LDL levels, risk of coronary artery disease, statin response, and diabetes mellitus in several clinical cohorts, including CATHGEN (Catheterization Genetics) and Framingham.
CONCLUSIONS: Two interacting regulatory SNPs modulate CYP7A1 expression and are associated with risk of coronary artery disease and diabetes mellitus.

PMID: 30354296 [PubMed - indexed for MEDLINE]

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pharmacogenomics

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pharmacogenomics

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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 and drug metabolism. Historical perspective and appraisal.

Xenobiotica. 2019 Sep 16;:1-22

Authors: Smith RL, Mitchell SC

Abstract
The events leading up to the discovery of genetically-controlled polymorphic metabolism of xenobiotics and pharmaceutical chemicals are briefly summarised with the salient historical features being emphasised. Especial attention has been given to seminal works in the then emerging field. The evolving knowledge of such polymorphic metabolism and its role in the quest for personalised medicine and the individualisation of patient drug therapy are appraised. Opinion is offered as to whether or not the full potential has been exploited and if the practical application of this information may be regarded as a success or failure within the present clinical arena.

PMID: 31524553 [PubMed - as supplied by publisher]

Derivation and applications of human hepatocyte-like cells.

World J Stem Cells. 2019 Aug 26;11(8):535-547

Authors: Li S, Huang SQ, Zhao YX, Ding YJ, Ma DJ, Ding QR

Abstract
Human hepatocyte-like cells (HLCs) derived from human pluripotent stem cells (hPSCs) promise a valuable source of cells with human genetic background, physiologically relevant liver functions, and unlimited supply. With over 10 years' efforts in this field, great achievements have been made. HLCs have been successfully derived and applied in disease modeling, toxicity testing and drug discovery. Large cohorts of induced pluripotent stem cells-derived HLCs have been recently applied in studying population genetics and functional outputs of common genetic variants in vitro. This has offered a new paradigm for genome-wide association studies and possibly in vitro pharmacogenomics in the nearly future. However, HLCs have not yet been successfully applied in bioartificial liver devices and have only displayed limited success in cell transplantation. HLCs still have an immature hepatocyte phenotype and exist as a population with great heterogeneity, and HLCs derived from different hPSC lines display variable differentiation efficiency. Therefore, continuous improvement to the quality of HLCs, deeper investigation of relevant biological processes, and proper adaptation of recent advances in cell culture platforms, genome editing technology, and bioengineering systems are required before HLCs can fulfill the needs in basic and translational research. In this review, we summarize the discoveries, achievements, and challenges in the derivation and applications of HLCs.

PMID: 31523372 [PubMed]

Cancers in Taiwan: Practical insight from epidemiology, treatments, biomarkers, and cost.

J Formos Med Assoc. 2019 Sep 12;:

Authors: Kuo CN, Liao YM, Kuo LN, Tsai HJ, Chang WC, Yen Y

Abstract
Cancer is the leading cause of death in Taiwan, and the overall incidence rate has gradually increased. The four most common cancers in Taiwan are colorectal, lung, breast and liver cancers. With the rise in incidence, the clinical use and costs of all anticancer drugs have steadily increased. The costs of novel therapeutics, such as targeted therapies and immunotherapy were accounted almost two-third of all antineoplastic agents in Taiwan. Moving forward, it will be necessary to discuss the economic impacts to clinical use of new therapeutics, while continuing to monitor and improve the quality of cancer therapy. In this review, we describe the epidemiology, disease screening policies and medication treatment policies for colorectal, lung, breast and liver cancer. We focus on the recent developments in cancer therapeutics, discuss the use of biomarkers, and finally consider the costs and the recent advances of anticancer medications in Taiwan.

PMID: 31522970 [PubMed - as supplied by publisher]

Integration of complementary biomarkers in patients with first episode psychosis: research protocol of a prospective follow up study.

Psychiatr Danub. 2019 Jun;31(2):162-171

Authors: Rojnic Kuzman M, Makaric P, Bosnjak Kuharic D, Kekin I, Rossini Gajsak L, Boban M, Bozina N, Bozina T, Celic Ruzic M, Darmopil S, Filipcic I, Ganoci L, Hladnik A, Madzarac Z, Malojcic B, Mihaljevic Peles A, Mueller DJ, Ostojic D, Petanjek Z, Petrovic R, Vogrinc Z, Savic A, Silic A, Sagud M, Zivkovic M, Bajic Z

Abstract
In this project, we recruited a sample of 150 patients with first episode of psychosis with schizophrenia features (FEP) and 100 healthy controls. We assessed the differences between these two groups, as well as the changes between the acute phase of illness and subsequent remission among patients over 18-month longitudinal follow-up. The assessments were divided into four work packages (WP): WP1- psychopathological status, neurocognitive functioning and emotional recognition; WP2- stress response measured by saliva cortisol during a stress paradigm; cerebral blood perfusion in the resting state (with single photon emission computed tomography (SPECT) and during activation paradigm (with Transcranial Ultrasonography Doppler (TCD); WP3-post mortem analysis in histologically prepared human cortical tissue of post mortem samples of subjects with schizophrenia in the region that synaptic alteration was suggested by WP1 and WP2; WP4- pharmacogenetic analysis (single gene polymorphisms and genome wide association study (GWAS). We expect that the analysis of these data will identify a set of markers that differentiate healthy controls from patients with FEP, and serve as an additional diagnostic tool in the first episode of psychosis, and prediction tool which can be then used to help tailoring individualized treatment options. In this paper, we describe the project protocol including aims and methods and provide a brief description of planned post mortem studies and pharmacogenetic analysis.

PMID: 31291220 [PubMed - indexed for MEDLINE]

Precision Medicine: Functional Advancements.

Annu Rev Med. 2018 01 29;69:1-18

Authors: Caskey T

Abstract
Precision medicine was conceptualized on the strength of genomic sequence analysis. High-throughput functional metrics have enhanced sequence interpretation and clinical precision. These technologies include metabolomics, magnetic resonance imaging, and I rhythm (cardiac monitoring), among others. These technologies are discussed and placed in clinical context for the medical specialties of internal medicine, pediatrics, obstetrics, and gynecology. Publications in these fields support the concept of a higher level of precision in identifying disease risk. Precise disease risk identification has the potential to enable intervention with greater specificity, resulting in disease prevention-an important goal of precision medicine.

PMID: 29261360 [PubMed - indexed for MEDLINE]

Effects of aripiprazole on circadian prolactin secretion related to pharmacogenetics in healthy volunteers.

Basic Clin Pharmacol Toxicol. 2019 Sep 14;:

Authors: Koller D, Belmonte C, Saiz-Rodríguez M, Zubiaur P, Román M, Ochoa D, Abad-Santos F

Abstract
Aripiprazole treatment in schizophrenic patients was previously associated to lower or normalized prolactin levels. Genetic variants in cytochrome P450 (CYP) (CYP2D6), dopamine receptor (DRD2, DRD3) and serotonin receptor (HTR2A, HTR2C) genes were previously associated to antipsychotic-induced hyperprolactinaemia. Our aim was to evaluate if aripiprazole affects prolactin secretion and its relationship with pharmacogenetics. Thirty-one healthy volunteers receiving a 10-mg single oral dose of aripiprazole were genotyped for 12 polymorphisms in CYP2D6, DRD2, DRD3, HTR2A and HTR2C genes by qPCR. Aripiprazole and dehydro-aripiprazole plasma concentrations were measured by HPLC-MS/MS. Prolactin concentrations of the 31 subjects taking aripiprazole and 12 subjects receiving ibuprofen were determined by ELISA. Prolactin concentrations after ibuprofen intake were considered as control, since it is known to cause no effect. Prolactin concentrations were slightly higher in the aripiprazole group compared to the ibuprofen group. All prolactin pharmacokinetic parameters were higher in females than in males. CYP2D6 poor and intermediate metabolizers had notably higher prolactin Cmax and AUC0-12 than normal and ultrarapid metabolizers. The DRD3 rs6280 polymorphism affected prolactin levels: volunteers carrying Ser/Ser genotype had significantly lower prolactin levels than volunteers carrying the Gly allele. Furthermore, HTR2C rs3813929 C/C homozygotes had significantly lower prolactin levels than T allele carriers. Nevertheless, aripiprazole did increase prolactin levels compared to ibuprofen.

PMID: 31520576 [PubMed - as supplied by publisher]