Pharmacogenomics of Cisplatin-Induced Ototoxicity: Successes, Shortcomings and Future Avenues of Research.

Clin Pharmacol Ther. 2019 Apr 23;:

Authors: Drögemöller BI, Wright GEB, Lo C, Le T, Brooks B, Bhavsar AP, Rassekh SR, Ross CJD, Carleton BC

Abstract
Cisplatin is a highly effective chemotherapeutic. Unfortunately, its use is limited by cisplatin-induced ototoxicity (CIO). Substantial research has been performed to uncover the genetic variants associated with CIO, however, there has been a lack of consistency in the results that have been reported. This article aims to provide an overview of the current state of CIO genomics research, delving into the shortcomings of past research and providing recommendations for future avenues of study. This article is protected by copyright. All rights reserved.

PMID: 31012503 [PubMed - as supplied by publisher]

Pharmacogenomics-Driven Prediction of Antidepressant Treatment Outcomes: A Machine Learning Approach with Multi-Trial Replication.

Clin Pharmacol Ther. 2019 Apr 23;:

Authors: Athreya AP, Neavin D, Carrillo-Roa T, Skime M, Biernacka J, Frye MA, Rush AJ, Wang L, Binder EB, Iyer RK, Weinshilboum RM, Bobo WV

Abstract
We set out to determine whether machine learning-based algorithms that included functionally validated pharmacogenomic biomarkers joined with clinical measures could predict selective serotonin reuptake inhibitor (SSRI) remission/response in patients with major depressive disorder (MDD). We studied 1,030 Caucasian MDD outpatients treated with citalopram/escitalopram in the PGRN-AMPS (n = 398), STAR*D (n = 467), and ISPC (n = 165) trials. GWAS for PGRN-AMPS plasma metabolites associated with SSRI response (serotonin) and baseline MDD severity (kynurenine) identified SNPs in DEFB1, ERICH3, AHR, and TSPAN5 that we tested as predictors. Supervised machine learning methods trained using SNPs and total baseline depression scores predicted remission and response at 8 weeks with AUC > 0.7 (p<0.04) in PGRN-AMPS patients, with comparable prediction accuracies >69% (p<0.05) in STAR*D and ISPC. These results demonstrate that machine learning can achieve accurate and, importantly, replicable prediction of SSRI therapy response using total baseline depression severity combined with pharmacogenomic biomarkers. This article is protected by copyright. All rights reserved.

PMID: 31012492 [PubMed - as supplied by publisher]

Diabetes: Is there a future for Pharmacogenomics guided treatment?

Clin Pharmacol Ther. 2019 Apr 23;:

Authors: Pearson ER

Abstract
Diabetes is a disease defined on the basis of hyperglycaemia. There are monogenic forms of diabetes where defining the genetic cause has a dramatic impact on treatment - with patients being able to transition from insulin to sulphonylureas. However, the majority of diabetes is type 2 diabetes. This review outlines the robust evidence accrued to date for pharmacogenetics of metformin, sulphonylureas, thiazolidinediones and DPP4 inhibitors, but highlights that these variants will only be of clinical utility when the genotype is already known at the point of prescribing. The future of pharmacogenetics in diabetes and other common complex disease relies on a paradigm shift - that of pre-emptive panel genotyping and use of clinical decision support tools to assimilate this genetic information with other clinical phenotypic data and to present this information simply to the prescriber. Given the recent dramatic fall in genotyping costs, this future is not far off. This article is protected by copyright. All rights reserved.

PMID: 31012484 [PubMed - as supplied by publisher]

Community pharmacists' educational needs for implementing clinical pharmacogenomic services.

J Am Pharm Assoc (2003). 2019 Apr 19;:

Authors: Berenbrok LA, Hart KM, McGrath SH, Coley KC, Somma McGivney MA, Empey PE

Abstract
OBJECTIVES: Pharmacist leadership and knowledge of pharmacogenomics is critical to the acceleration and enhancement of clinical pharmacogenomic services. This study aims for a qualitative description of community pharmacists' pharmacogenomic educational needs when implementing clinical pharmacogenomic services at community pharmacies.
METHODS: Pharmacists practicing at Rite Aid Pharmacy locations in the Greater Pittsburgh Area were recruited to participate in this qualitative analysis. Pharmacists from pharmacy locations offering pharmacogenomic testing and robust patient care services were eligible to participate in a semistructured, audio-recorded interview. The semistructured interview covered 4 domains crafted by the investigative team: (1) previous knowledge of pharmacogenomics; (2) implementation resources; (3) workflow adaptation; and (4) learning preferences. Interviews were transcribed verbatim and independently coded by 2 researchers. A thematic analysis by the investigative team followed. Supporting quotes were selected to illustrate each theme.
RESULTS: Eleven pharmacists from 9 unique pharmacy locations participated in this study. The average length of practice as a community pharmacist was 12 years (range, 1.5-31 years). Pharmacist's pharmacogenomic educational needs were categorized into 5 key themes: (1) enriched pharmacogenomic education and training; (2) active learning to build confidence in using pharmacogenomic data in practice; (3) robust and reputable clinical resources to effectively implement pharmacogenomic services; (4) team-based approach throughout implementation; (5) readily accessible network of pharmacogenomic experts.
CONCLUSION: This study describes the educational needs and preferences of community pharmacists for the successful provision of clinical pharmacogenomic services in community pharmacies. Pharmacists recognized their needs for enriched knowledge and instruction, practice applying pharmacogenomic principles with team-based approaches, robust clinical resources, and access to pharmacogenomic experts. This deeper understanding of pharmacist needs for pharmacogenomic education could help to accelerate and enhance the clinical implementation of pharmacogenomic services led by community pharmacists.

PMID: 31010787 [PubMed - as supplied by publisher]

Knowledge and Opinions Among Canadian Academic Physicians Regarding Genetic Screening to Prevent Severe Cutaneous Adverse Drug Reactions.

J Am Acad Dermatol. 2019 Apr 19;:

Authors: Chan FL, Shear NH, Maharaj A, Olteanu C, Hashimoto R, Ziv M, Dodiuk-Gad RP

PMID: 31009670 [PubMed - as supplied by publisher]

Pharmacogenomics guidelines: current status and future development.

Clin Exp Pharmacol Physiol. 2019 Apr 22;:

Authors: Guo C, Xie X, Li J, Huang L, Chen S, Li X, Yi X, Wu Q, Yang G, Zhou H, Liu J, Chen X

Abstract
Genetic polymorphisms impact biological responses to drugs. Current pharmacogenomics guidelines formulated by different countries, such as CPIC, DPWG, CPNDS, and RNPGx, play important roles in clinical practices. However, the drafting standards for these guidelines vary, resulting in differences in recommendations. The present review discusses these differences by head-to-head comparison of the existing pharmacogenomics guidelines and proposes new strategies for their future development. This article is protected by copyright. All rights reserved.

PMID: 31009088 [PubMed - as supplied by publisher]

Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen.

Expert Rev Clin Pharmacol. 2019 Apr 22;:

Authors: Sanchez-Spitman AB, Swen JJ, Dezentje VO, Moes DJAR, Gelderblom H, Guchelaar HJ

Abstract
INTRODUCTION: Tamoxifen dominates the anti-estrogenic therapy in the early and metastatic breast cancer setting. Tamoxifen has a complex metabolism, being mainly metabolized by CYP2D6 into its 30-100 times more potent metabolite, endoxifen. Recently, a phase I study in which endoxifen as an orally z-endoxifen hydrochloride, has been successfully evaluated. Areas covered: the principal pharmacogenetic and non-genetic differences in the pharmacology of tamoxifen and endoxifen are evaluated. To this end, references from PubMed, Embase or Web of Science, among others, were reviewed As non-genetic factors, important differences and similarities such age, gender, or adherence to tamoxifen therapy are comprehensively illustrated. Additionally, since CYP2D6 genotypes is considered the main limitation of tamoxifen, many studies have investigated the association between the worsened clinical outcomes in patients with non-functional CYP2D6 genotypes. In this review, an overview of the research on this field is presented. Also, a summary describing the literature about individualizing tamoxifen therapy with endoxifen concentrations and its limitations is listed. Expert opinion: z-endoxifen hydrochloride is only investigated in the metastatic setting, still more research is required before its place in therapeutics is known. Similarly, monitoring tamoxifen efficacy based on endoxifen concentrations might not be overall recommended due to the limited evidence available.

PMID: 31008668 [PubMed - as supplied by publisher]

Glutathione S-transferase theta genotypes and environmental exposures in the risk of canine transitional cell carcinoma.

J Vet Intern Med. 2019 Apr 22;:

Authors: Luethcke KR, Ekena J, Chun R, Trepanier LA

Abstract
INTRODUCTION: Transitional cell carcinoma (TCC) in humans is associated with environmental exposures and variants in glutathione S-transferase (GST) genes. Scottish Terriers have a high breed risk for TCC, but the relationship between genetic and environmental risk in dogs is not fully understood.
HYPOTHESES: Scottish Terriers have a higher frequency of GST-theta variants compared to lower risk breeds. Dogs with TCC of any breed have a higher frequency of GST-theta variants along with higher environmental exposures, compared to controls.
ANIMALS: One hundred and five Scottish Terriers and 68 controls from lower risk breeds; 69 dogs of various breeds with TCC, and 72 breed- and sex-matched unaffected geriatric dogs.
METHODS: In this prospective case-control study, dogs were genotyped for 3 canine GST-theta variants: GSTT1 I2+28 G>A, a GSTT1 3'UTR haplotype, and GSTT5 Asp129_Gln130del. Owners of dogs with TCC and unaffected geriatric controls completed a household environmental questionnaire.
RESULTS: The GSTT1 3'UTR haplotype and GSTT5 Asp129_Gln130del variants were significantly underrepresented in Scottish Terriers (minor allele frequency [MAF] = 0.000 for both), compared to dogs from lower risk breeds (MAF = 0.108 and 0.100; P ≤ .0002). Dogs with TCC did not differ from unaffected geriatric controls across the 3 investigated loci. Transitional cell carcinoma was associated with household insecticide use (odds ratio [OR] = 4.28, 95% confidence interval [CI] = 1.44-12.33, P = .02), and was negatively associated with proximity to a farm (OR = 0.49, 95% CI = 0.25-0.99, P = .04).
CONCLUSIONS AND CLINICAL IMPORTANCE: Low-activity GST-theta loci are unlikely contributors to TCC risk in dogs. Increased risk is associated with household insecticide use, and possibly with less rural households.

PMID: 31008543 [PubMed - as supplied by publisher]

Association of CYP2C19 Polymorphisms With Clopidogrel Reactivity and Clinical Outcomes in Chronic Ischemic Stroke.

Circ J. 2019 Apr 19;:

Authors: Tanaka T, Yamagami H, Ihara M, Miyata T, Miyata S, Hamasaki T, Amano S, Fukuma K, Yamamoto H, Nakagawara J, Furui E, Uchiyama S, Hyun B, Yamamoto Y, Manabe Y, Ito Y, Fukunaga R, Abumiya T, Yasaka M, Kitagawa K, Toyoda K, Nagatsuka K

Abstract
BACKGROUND: CYP2C19variants are associated with the antiplatelet effects of clopidogrel against recurrent cardiovascular events. However, it remains unknown whether the elapsed time from stroke onset affects the relationship between the genetic variants and such events. To address this, we conducted a prospective cohort study to determine the effect ofCYP2C19variants on clinical outcomes in the chronic phase.Methods and Results:In total, 518 Japanese non-acute stroke patients treated with clopidogrel were registered at 14 institutions. Patients were classified into 3 clopidogrel-metabolizing groups according toCYP2C19genotype: extensive metabolizer (EM:*1/*1), intermediate metabolizer (IM:*1/*2or*1/*3), and poor metabolizer (PM:*2/*2,*2/*3, or*3/*3). Antiplatelet effects of clopidogrel were assessed by adenosine diphosphate (ADP)-induced platelet aggregation and vasodilator-stimulated phosphoprotein (VASP) phosphorylation. The endpoint was composite cerebrocardiovascular events (CVEs). In 501 successfully followed-up patients, the median time from index stroke to enrollment was 181 days. There were 28 cardiovascular and 2 major bleeding events. There were no significant differences in the rates of cardiovascular events among the groups.
CONCLUSIONS: Despite associations betweenCYP2C19variants and on-clopidogrel platelet reactivity, there was no significant difference in rates of CVEs in the chronic stroke phase among the 3 clopidogrel-metabolizing groups ofCYP2C19variants.

PMID: 31006731 [PubMed - as supplied by publisher]

Insufficient harmonization of antibiotics assays - Polish experience with an external quality assessment program in the years 2011-2018.

Clin Biochem. 2019 Apr;66:91-94

Authors: Kowalski R, Ćwiklińska A, Lizakowski M, Kortas-Stempak B, Bednarczuk G, Fijałkowska A, Pikul P, Lewandowski K

Abstract
INTRODUCTION: Treatment with vancomycin and gentamycin requires strict monitoring of its serum concentration for proper dosage optimization. This study aimed to assess the quality and the harmonization of antibiotics assays in Polish laboratories.
MATERIALS AND METHODS: 413 results of vancomycin and 148 results of gentamycin assays obtained from Polish laboratories in 30 international external quality assessment (EQA) surveys carried out from March 2011 to May 2018 were analyzed.
RESULTS: Interlaboratory robust coefficients of variation (rCVs) in particular surveys comprised between 1.3 and 47.2% for vancomycin, and between 1.8 and 34.2% for gentamycin. The percentage of the results with the difference above acceptable limit ±10% from the target value established for own method group was 25.7% for vancomycin and 25.6% for gentamycin. When the difference was established according to target value for all methods, the percentage of results outside the acceptable limit was 2-fold higher on average (54.8% for vancomycin and 43.2% for gentamycin). The comparison of target values for methods revealed statistically significant differences between analytical systems used (p < .0001). The highest difference was 40% for vancomycin and 12% for gentamycin.
CONCLUSIONS: The present analysis revealed high dispersion of the antibiotics assays results in Polish laboratories. Moreover, vancomycin and gentamycin results differed significantly in a way dependent on the analytical system used. There appear to be an urgent need for harmonization of methods used for vancomycin and gentamycin measurement.

PMID: 30731069 [PubMed - indexed for MEDLINE]

Anticancer effects of alloxanthoxyletin and fatty acids esters - In vitro study on cancer HTB-140 and A549 cells.

Biomed Pharmacother. 2019 Feb;110:618-630

Authors: Jóźwiak M, Struga M, Roszkowski P, Filipek A, Nowicka G, Olejarz W

Abstract
Alloxanthoxyletin, a natural occurring pyranocoumarin isolated from a number of plant sources, such as family of Rutaceae, and its synthetic derivatives show cytotoxic and antitumor activities. In the present study new eleven esters of alloxanthoxyletin and fatty acids were synthesized and evaluated for their anticancer toxicity. The structures of the compounds were confirmed by Proton Nuclear Magnetic Resonance (1H NMR), Carbon-13 Nuclear Magnetic Resonance (13C NMR) and High Resolution Mass Spectrometry (HRMS) analyses. For all compounds 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay was used to determine the cytotoxic effect on human melanoma cells (HTB-140), human epithelial lung carcinoma cells (A549) and human keratinocyte line (HaCaT). For the most active compounds (8-11) lactate dehydrogenase (LDH) assay to assess the level of cell damage as well as migration inhibition assay were performed. To explain the basic mechanism of cell death induction, the effect of derivatives 8-11 on early and late apoptosis in Annexin V-FITC/7-AAD flow cytometry analysis was investigated. The results indicate that human melanoma cells (HTB-140) and human epithelial lung carcinoma cells (A549) were more sensitive to new alloxanthoxyletin derivatives exposure compared to human keratinocytes (HaCaT). Both, the cytotoxicity and the migration tests showed a concentration-dependent inhibition of cell growth, although with a different degree of efficacy. Tested compounds induced apoptosis in cancer cells, however, derivatives 8, 9, 10 and 11 were found to be much more potent inducers of early apoptosis in HTB-140 cells than in A549 and HaCaT cells. To establish the potent mechanism of action of alloxanthoxyletin derivatives 8, 9, 10 and 11 on HaCaT, A549 and HTB-140 cells, the level of IL-6 was measured. Our results indicate, that tested compounds significantly decrease the release of IL-6 for all cancer cell lines.

PMID: 30544062 [PubMed - indexed for MEDLINE]

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2B6 and Efavirenz-containing Antiretroviral Therapy.

Clin Pharmacol Ther. 2019 Apr 21;:

Authors: Desta Z, Gammal RS, Gong L, Whirl-Carrillo M, Gaur AH, Sukasem C, Hockings J, Myers A, Swart M, Tyndale R, Masimirembwa C, Iwuchukwu OF, Chirwa S, Lennox J, Gaedigk A, Klein T, Haas DW

Abstract
The human immunodeficiency virus (HIV) type-1 non-nucleoside reverse transcriptase inhibitor, efavirenz, is widely used to treat HIV-1 infection. Efavirenz is predominantly metabolized into inactive metabolites by CYP2B6, and patients with certain CYP2B6 genetic variants may be at increased risk for adverse effects, particularly central nervous system toxicity and treatment discontinuation. We summarize the evidence from the literature and provide therapeutic recommendations for efavirenz prescribing based on CYP2B6 genotypes. This article is protected by copyright. All rights reserved.

PMID: 31006110 [PubMed - as supplied by publisher]

A Genome-Wide Association Study of Bisphosphonate-Associated Atypical Femoral Fracture.

Calcif Tissue Int. 2019 Apr 20;:

Authors: Kharazmi M, Michaëlsson K, Schilcher J, Eriksson N, Melhus H, Wadelius M, Hallberg P

Abstract
Atypical femoral fracture is a well-documented adverse reaction to bisphosphonates. It is strongly related to duration of bisphosphonate use, and the risk declines rapidly after drug withdrawal. The mechanism behind bisphosphonate-associated atypical femoral fracture is unclear, but a genetic predisposition has been suggested. With the aim to identify common genetic variants that could be used for preemptive genetic testing, we performed a genome-wide association study. Cases were recruited mainly through reports of adverse drug reactions sent to the Swedish Medical Products Agency on a nation-wide basis. We compared atypical femoral fracture cases (n = 51) with population-based controls (n = 4891), and to reduce the possibility of confounding by indication, we also compared with bisphosphonate-treated controls without a current diagnosis of cancer (n = 324). The total number of single-nucleotide polymorphisms after imputation was 7,585,874. A genome-wide significance threshold of p < 5 × 10-8 was used to correct for multiple testing. In addition, we performed candidate gene analyses for a panel of 29 genes previously implicated in atypical femoral fractures (significance threshold of p < 5.7 × 10-6). Compared with population controls, bisphosphonate-associated atypical femoral fracture was associated with four isolated, uncommon single-nucleotide polymorphisms. When cases were compared with bisphosphonate-treated controls, no statistically significant genome-wide association remained. We conclude that the detected associations were either false positives or related to the underlying disease, i.e., treatment indication. Furthermore, there was no significant association with single-nucleotide polymorphisms in the 29 candidate genes. In conclusion, this study found no evidence of a common genetic predisposition for bisphosphonate-associated atypical femoral fracture. Further studies of larger sample size to identify possible weakly associated genetic traits, as well as whole exome or whole-genome sequencing studies to identify possible rare genetic variation conferring a risk are warranted.

PMID: 31006051 [PubMed - as supplied by publisher]

Comprehensive study of thiopurine methyltransferase genotype, phenotype, and genotype-phenotype discrepancies in Sweden.

Biochem Pharmacol. 2019 Apr 18;:

Authors: Zimdahl Kahlin A, Helander S, Skoglund K, Söderkvist P, Mårtensson LG, Lindqvist Appell M

Abstract
Thiopurines are widely used in the treatment of leukemia and inflammatory bowel diseases. Thiopurine metabolism varies among individuals because of differences in the polymorphic enzyme thiopurine methyltransferase (TPMT, EC 2.1.1.67), and to avoid severe adverse reactions caused by incorrect dosing it is recommended that the patient's TPMT status be determined before the start of thiopurine treatment. This study describes the concordance between genotyping for common TPMT alleles and phenotyping in a Swedish cohort of 12,663 patients sampled before or during thiopurine treatment. The concordance between TPMT genotype and enzyme activity was 94.5%. Compared to the genotype, the first measurement of TPMT enzyme activity was lower than expected for 4.6% of the patients. Sequencing of all coding regions of the TPMT gene in genotype/phenotype discrepant individuals led to the identification of rare and novel TPMT alleles. Fifteen individuals (0.1%) with rare or novel genotypes were identified, and three TPMT alleles (TPMT*42, *43, and *44) are characterized here for the first time. These 15 patients would not have been detected as carrying a deviating TPMT genotype if only genotyping of the most common TPMT variants had been performed. This study highlights the benefit of combining TPMT genotype and phenotype determination in routine testing. More accurate dose recommendations can be made, which might decrease the number of adverse reactions and treatment failures during thiopurine treatment.

PMID: 31005613 [PubMed - as supplied by publisher]

An integrin-based nanoparticle that targets activated hepatic stellate cells and alleviates liver fibrosis.

J Control Release. 2019 Apr 17;:

Authors: Li Y, Pu S, Liu Q, Li R, Zhang J, Wu T, Chen L, Li H, Yang X, Zou M, Xiao J, Xie W, He J

Abstract
Activation of hepatic stellate cells (HSCs) contributes to the development of liver fibrosis. Because of a relatively small population of HSCs in the liver and the lack of specific membrane targeting proteins, HSC-targeted therapy remains a major clinical challenge. Here we first showed that a hallmark of activated HSC (aHSC) is their increased expression of integrin αvβ3. Thus we established sterically stable liposomes that contain the cyclic peptides (cRGDyK) with a high affinity to αvβ3 to achieve aHSC-specific delivery. Our results showed that the cRGDyK-guided liposomes were preferentially internalized by activated HSCs in vitro and in vivo, and the internalization was abolished by excess free cRGDyK or knockdown of αvβ3. In contrast, quiescent HSCs, hepatocytes, Kupffer cells, sinusoidal endothelial cells, or biliary cells showed minimal uptake of the cRGDyK-guided liposomes. When loaded with the hedgehog inhibitor vismodegib, the cRGDyK-guided liposomes inhibited hedgehog pathway signaling specifically in activated HSCs. Moreover, treatment of mice with vismodegib-loaded cRGDyK-liposomes markedly inhibited the fibrogenic phenotype in bile duct ligation- or thioacetamide-treated mice. We conclude that the cRGDyK-guided liposomes can specifically target the activated HSCs, but not quiescent HSCs. This nanoparticle system showed great promise to deliver therapeutic agents to aHSC to treat liver fibrosis.

PMID: 31004666 [PubMed - as supplied by publisher]

Come Dance With Me: Transformative Changes in the Science and Practice of Drug-Drug Interactions.

Clin Pharmacol Ther. 2019 Apr 20;:

Authors: Venkatakrishnan K, Rostami-Hodjegan A

Abstract
The past 2 decades have witnessed transformative changes in our approach to drug-drug interactions (DDIs) from scientific research to clinical practice. Collaborative cooperation across the sectors of academia, pharmaceutical industry, providers of translational research tools and services, global regulatory agencies, and healthcare providers has created and galvanized a science-informed and patient-centered approach. Multidisciplinary innovations in mechanistic assessment of absorption, distribution, metabolism, and excretion (ADME), population pharmacology and pharmacogenetics, physiologically based modeling, and regulatory science have enabled a profound shift in mindset from risk aversion to informative prescribing guidance for optimal risk management. Foundational to this transformation is a commitment to maximizing the value of innovative therapeutics for all patients and across clinical contexts of use through rational knowledge management and translation based on the totality of best available evidence, thereby removing the void that can lead to arbitrary decisions in clinical therapeutics.

PMID: 31004453 [PubMed - as supplied by publisher]

Navigating the Labyrinth of Pharmacogenetic Testing: A Guide to Test Selection.

Clin Pharmacol Ther. 2019 Apr 20;:

Authors: Bousman CA, Zierhut H, Müller DJ

PMID: 31004441 [PubMed - as supplied by publisher]

9za plays cytotoxic and proapoptotic roles and induces cytoprotective autophagy through the PDK1/Akt/mTOR axis in non-small-cell lung cancer.

J Cell Physiol. 2019 Apr 19;:

Authors: Liu R, Chen Z, Yi X, Huang F, Hu G, Liu D, Li X, Zhou H, Liu Z

Abstract
Non-small-cell lung cancer (NSCLC) is an aggressive subtype of pulmonary carcinomas with high mortality. However, chemotherapy drug resistance and high recurrence rates hinder the curative effect of platinum-based first-line chemotherapy, which makes it urgent to develop new antitumor drugs for NSCLC. 9za, a new candidate drug synthesized by our research group, has been verified with potent antilung cancer activity in preliminary experiments. However, the underlying molecular mechanism of 9za remains largely vague. This work revealed that 9za could play important cytotoxic and proapoptotic roles in NSCLC cells. Moreover, 9za could induce autophagy and promote autophagy flux. Interestingly, the cytotoxic and proapoptotic roles were significantly dependent on 9za-induced cytoprotective autophagy. That is, the coadministration of 9za with an autophagy inhibitor such as chloroquine or 3-methyladenine exhibited increased cytotoxic and proapoptotic effects compared with 9za treatment alone. In addition, 9za exposure suppressed the phosphorylation of phosphoinositide-dependent protein kinase 1 (PDK1), protein kinase B (Akt), mammalian targets of rapamycin (mTOR), p70 S6 kinase, and 4E binding protein 1 by a dose-dependent way, manifesting that the Akt/mTOR axis was implicated in 9za-induced autophagy. In addition, the overexpression of PDK1 resulted in increased phosphorylation of PDK1 and Akt and blocking of 9za-mediated autophagy. These data showed that the PDK1/Akt/mTOR pathway was involved in 9za-induced autophagy. Hence, this work provides a theoretical basis for exploiting 9za as a new antilung cancer candidate drug and hints that the combination of 9za with an autophagy inhibitor is a feasible alternative approach for the therapy of NSCLC.

PMID: 31004362 [PubMed - as supplied by publisher]

Orthogonal joint sparse NMF for microarray data analysis.

J Math Biol. 2019 Apr 19;:

Authors: Esposito F, Gillis N, Del Buono N

Abstract
The 3D microarrays, generally known as gene-sample-time microarrays, couple the information on different time points collected by 2D microarrays that measure gene expression levels among different samples. Their analysis is useful in several biomedical applications, like monitoring dose or drug treatment responses of patients over time in pharmacogenomics studies. Many statistical and data analysis tools have been used to extract useful information. In particular, nonnegative matrix factorization (NMF), with its natural nonnegativity constraints, has demonstrated its ability to extract from 2D microarrays relevant information on specific genes involved in the particular biological process. In this paper, we propose a new NMF model, namely Orthogonal Joint Sparse NMF, to extract relevant information from 3D microarrays containing the time evolution of a 2D microarray, by adding additional constraints to enforce important biological proprieties useful for further biological analysis. We develop multiplicative updates rules that decrease the objective function monotonically, and compare our approach to state-of-the-art NMF algorithms on both synthetic and real data sets.

PMID: 31004215 [PubMed - as supplied by publisher]

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