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1.
PLoS One ; 17(5): e0267027, 2022.
Article in English | MEDLINE | ID: mdl-35503762

ABSTRACT

ErbB3 (HER3), a member of the HER family, is overexpressed in various cancers and plays an important role in cell proliferation and survival. Certain HER3 mutations have also been identified as oncogenic drivers, making them potential therapeutic targets. In the current study, antitumor activity of patritumab deruxtecan (HER3-DXd), a HER3 directed antibody drug conjugate, was evaluated in tumor models with clinically reported HER3 mutations. MDA-MB-231, a HER3-negative human triple-negative breast cancer cell line, was transduced with lentiviral vectors encoding HER3 wild type (HER3WT), one of 11 HER3 mutations, or HER3 empty vector (HER3EV), in the presence/absence of HER2 overexpression. Targeted delivery of HER3-DXd was assessed using cell-surface binding, lysosomal trafficking, and cell-growth inhibition assays. HER3-DXd bound to the surface of HER3WT and mutant cells in a similar, concentration-dependent manner but not to HER3EV. HER3-DXd was translocated to the lysosome, where time- and concentration-dependent signals were observed in the HER3 mutant and HER3WT cells. HER3-DXd inhibited the growth of HER3WT and HER3 mutant cells. HER3-DXd activity was observed in the presence and absence of HER2 overexpression. These data suggest that HER3-DXd may have activity against tumors expressing wild type HER3 or clinically observed HER3 mutations, supporting further clinical evaluation.


Subject(s)
Breast Neoplasms , Immunoconjugates , Triple Negative Breast Neoplasms , Antibodies, Monoclonal, Humanized , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Camptothecin/analogs & derivatives , Cell Line, Tumor , Female , Humans , Immunoconjugates/therapeutic use , Mutation , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Receptor, ErbB-3/metabolism , Trastuzumab/genetics , Trastuzumab/pharmacology , Triple Negative Breast Neoplasms/drug therapy
2.
Clin Cancer Res ; 26(18): 4785-4794, 2020 09 15.
Article in English | MEDLINE | ID: mdl-32591465

ABSTRACT

PURPOSE: Taletrectinib (DS-6051b/AB-106) is an oral, tyrosine kinase inhibitor of ROS1 and NTRK with potent preclinical activity against ROS1 G2032R solvent-front mutation among others. We report the first-in-human U.S. phase I results of taletrectinib. PATIENTS AND METHODS: Patients ≥18 years old with neuroendocrine tumors, with tumor-induced pain, or tumors harboring ROS1/NTRK rearrangements were eligible. Accelerated titration followed by modified continuous reassessment method and escalation with overdose control was used (50-1,200 mg once daily or 400 mg twice daily). Primary objectives were safety/tolerability, and MTD determination. Secondary objectives were food-effect pharmacokinetics and antitumor activity. RESULTS: A total of 46 patients were enrolled. Steady-state peak concentration (C max) and exposure (AUC0-8) increased dose dependently from 50-mg to 800-mg once-daily doses. The ratio of the geometric mean of AUC0-24 between low-fat-diet-fed/fasted state was 123% (90% confidence interval, 104%-149%). Dose-limiting toxicities (grade 3 transaminases increase) occurred in two patients (1,200-mg once-daily dose). MTD was 800 mg once daily. Most common treatment-related adverse events were nausea (47.8%), diarrhea (43.5%), and vomiting (32.6%). Pain score reductions were observed in the 800-mg once-daily dose cohort. Confirmed objective response rate was 33.3% among the six patients with RECIST-evaluable crizotinib-refractory ROS1+ NSCLC. One patient with TPM3-NTRK1 differentiated thyroid cancer achieving a confirmed partial response of 27 months at data cutoff. We identified a cabozantinib-sensitive ROS1 L2086F as an acquired taletrectinib-resistance mutation. CONCLUSIONS: Taletrectinib has manageable toxicities at the MTD of 800 mg daily. Preliminary efficacy was observed in patients with crizotinib-refractory ROS1+ NSCLC.


Subject(s)
Food-Drug Interactions , Imidazoles/adverse effects , Neoplasms/drug therapy , Protein Kinase Inhibitors/adverse effects , Pyridazines/adverse effects , Adult , Aged , Female , Humans , Imidazoles/administration & dosage , Imidazoles/pharmacokinetics , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Staging , Neoplasms/diagnosis , Neoplasms/pathology , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacokinetics , Protein-Tyrosine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Pyridazines/administration & dosage , Pyridazines/pharmacokinetics , Receptor, trkA/antagonists & inhibitors , Response Evaluation Criteria in Solid Tumors , Young Adult
3.
Oncotarget ; 9(34): 23729-23737, 2018 May 04.
Article in English | MEDLINE | ID: mdl-29805770

ABSTRACT

Oncogenic ROS1 and NTRK fusions were reported in solid tumors, including non-small cell lung cancer (NSCLC). DS-6051b is an oral, potent selective small molecule tyrosine kinase inhibitor. We report the safety, tolerability, efficacy, and pharmacokinetics of DS-6051b in 15 Japanese patients with NSCLC harboring ROS1 fusions. Patients received DS-6051b once daily (400 mg n = 6; 600 mg n = 6; or 800 mg n = 3) for cycles of 3 weeks. Safety, tolerability, maximum-tolerated dose, pharmacokinetics, and recommended dose for phase II were determined. Common treatment-related adverse events were increased: aspartate aminotransferase and alanine aminotransferase (80.0% each), diarrhea (53.3%), and nausea (46.7%). Dose-limiting toxicities (two grade-3 alanine aminotransferase increases) were seen in the 800 mg cohort. The maximum-tolerated dose and recommended phase II dose was 600 mg once daily. Plasma concentrations of free DS-6051b and DS-6051a increased with dose. Compared with a US phase I study, AUC0-24 h on day 15 was higher but narrowed after body weight correction. Objective response rate was 58.3% in patients with target lesions (n = 12) and 66.7% in crizotinib-naïve patients (n = 9). Disease control rate was 100%. DS-6051b is well tolerated and effective in Japanese patients with NSCLC harboring ROS1 fusions and might be a targeted therapy for advanced NSCLC.

4.
Cancer Res ; 78(10): 2721-2731, 2018 05 15.
Article in English | MEDLINE | ID: mdl-29490944

ABSTRACT

Early clinical trials using murine double minute 2 (MDM2) inhibitors demonstrated proof-of-concept of p53-induced apoptosis by MDM2 inhibition in cancer cells; however, not all wild-type TP53 tumors are sensitive to MDM2 inhibition. Therefore, more potent inhibitors and biomarkers predictive of tumor sensitivity are needed. The novel MDM2 inhibitor DS-3032b is 10-fold more potent than the first-generation inhibitor nutlin-3a. TP53 mutations were predictive of resistance to DS-3032b, and allele frequencies of TP53 mutations were negatively correlated with sensitivity to DS-3032b. However, sensitivity to DS-3032b of TP53 wild-type tumors varied greatly. We thus used two methods to create predictive gene signatures. First, by comparing sensitivity to MDM2 inhibition with basal mRNA expression profiles in 240 cancer cell lines, a 175-gene signature was defined and validated in patient-derived tumor xenograft models and ex vivo human acute myeloid leukemia (AML) cells. Second, an AML-specific 1,532-gene signature was defined by performing random forest analysis with cross-validation using gene expression profiles of 41 primary AML samples. The combination of TP53 mutation status with the two gene signatures provided the best positive predictive values (81% and 82%, compared with 62% for TP53 mutation status alone). In addition, the top-ranked 50 genes selected from the AML-specific 1,532-gene signature conserved high predictive performance, suggesting that a more feasible size of gene signature can be generated through this method for clinical implementation. Our model is being tested in ongoing clinical trials of MDM2 inhibitors.Significance: This study demonstrates that gene expression profiling combined with TP53 mutational status predicts antitumor effects of MDM2 inhibitors in vitro and in vivoCancer Res; 78(10); 2721-31. ©2018 AACR.


Subject(s)
Antineoplastic Agents/pharmacology , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Tumor Suppressor Protein p53/genetics , Animals , Apoptosis/genetics , Cell Line, Tumor , Cyclohexanes/pharmacology , Female , Gene Expression Profiling , Humans , Imidazoles/pharmacology , Leukemia, Myeloid, Acute/pathology , Mice , Mice, Nude , Piperazines/pharmacology , Proto-Oncogene Proteins c-mdm2/metabolism
5.
Biomark Insights ; 12: 1177271917699850, 2017.
Article in English | MEDLINE | ID: mdl-28469400

ABSTRACT

In preclinical studies, heregulin (HRG) expression was shown to be the most relevant predictive biomarker for response to patritumab, a fully human anti-epidermal growth factor receptor 3 monoclonal antibody. In support of a phase 2 study of erlotinib ± patritumab in non-small cell lung cancer (NSCLC), a reverse-transcription quantitative polymerase chain reaction (RT-qPCR) assay for relative quantification of HRG expression from formalin-fixed paraffin-embedded (FFPE) NSCLC tissue samples was developed and validated and described herein. Test specimens included matched FFPE normal lung and NSCLC and frozen NSCLC tissue, and HRG-positive and HRG-negative cell lines. Formalin-fixed paraffin-embedded tissue was examined for functional performance. Heregulin distribution was also analyzed across 200 NSCLC commercial samples. Applied Biosystems TaqMan Gene Expression Assays were run on the Bio-Rad CFX96 real-time PCR platform. Heregulin RT-qPCR assay specificity, PCR efficiency, PCR linearity, and reproducibility were demonstrated. The final assay parameters included the Qiagen FFPE RNA Extraction Kit for RNA extraction from FFPE NSCLC tissue, 50 ng of RNA input, and 3 reference (housekeeping) genes (HMBS, IPO8, and EIF2B1), which had expression levels similar to HRG expression levels and were stable among FFPE NSCLC samples. Using the validated assay, unimodal HRG distribution was confirmed across 185 evaluable FFPE NSCLC commercial samples. Feasibility of an RT-qPCR assay for the quantification of HRG expression in FFPE NSCLC specimens was demonstrated.

6.
J Pathol ; 240(3): 282-290, 2016 11.
Article in English | MEDLINE | ID: mdl-27477320

ABSTRACT

Oncogenic fusions in TRK family receptor tyrosine kinases have been identified in several cancers and can serve as therapeutic targets. We identified ETV6-NTRK3, MYO5A-NTRK3 and MYH9-NTRK3 fusions in Spitz tumours, and demonstrated that NTRK3 fusions constitutively activate the mitogen-activated protein kinase, phosphoinositide 3-kinase and phospholipase Cγ1 pathways in melanocytes. This signalling was inhibited by DS-6051a, a small-molecule inhibitor of NTRK1/2/3 and ROS1. NTRK3 fusions expand the range of oncogenic kinase fusions in melanocytic neoplasms and offer targets for a small subset of melanomas for which no targeted options currently exist. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Subject(s)
Discoidin Domain Receptor 2/genetics , Molecular Motor Proteins/genetics , Myosin Heavy Chains/genetics , Myosin Type V/genetics , Nevus, Epithelioid and Spindle Cell/enzymology , Proto-Oncogene Proteins c-ets/genetics , Repressor Proteins/genetics , Skin Neoplasms/enzymology , Adolescent , Adult , Aged , Child , Child, Preschool , Comparative Genomic Hybridization , Discoidin Domain Receptor 2/metabolism , Female , Humans , Male , Melanoma/enzymology , Melanoma/genetics , Melanoma/pathology , Mitogen-Activated Protein Kinases/genetics , Mitogen-Activated Protein Kinases/metabolism , Molecular Motor Proteins/metabolism , Myosin Heavy Chains/metabolism , Myosin Type V/metabolism , Nevus, Epithelioid and Spindle Cell/genetics , Nevus, Epithelioid and Spindle Cell/pathology , Oncogene Fusion , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-ets/metabolism , Repressor Proteins/metabolism , Sequence Analysis, DNA , Sequence Analysis, RNA , Skin Neoplasms/genetics , Skin Neoplasms/pathology , ETS Translocation Variant 6 Protein
7.
EBioMedicine ; 2(3): 264-71, 2015 Mar.
Article in English | MEDLINE | ID: mdl-26137564

ABSTRACT

BACKGROUND: During early clinical development, prospective identification of a predictive biomarker and validation of an assay method may not always be feasible. Dichotomizing a continuous biomarker measure to classify responders also leads to challenges. We present a case study of a prospective-retrospective approach for a continuous biomarker identified after patient enrollment but defined prospectively before the unblinding of data. An analysis of the strengths and weaknesses of this approach and the challenges encountered in its practical application are also provided. METHODS: HERALD (NCT02134015) was a double-blind, phase 2 study in patients with non-small cell lung cancer (NSCLC) randomized to erlotinib with placebo or with high or low doses of patritumab, a monoclonal antibody targeted against human epidermal growth factor receptor 3 (HER3). While the primary objective was to assess safety and progression-free survival (PFS), a secondary objective was to determine a single predictive biomarker hypothesis to identify subjects most likely to benefit from the addition of patritumab. Although not identified as the primary biomarker in the study protocol, on the basis of preclinical results from 2 independent laboratories, expression levels of the HER3 ligand heregulin (HRG) were prospectively declared the predictive biomarker before data unblinding but after subject enrollment. An assay to measure HRG mRNA was developed and validated. Other biomarkers, such as epidermal growth factor receptor (EGFR) mutation status, were also evaluated in an exploratory fashion. The cutoff value for high vs. low HRG mRNA levels was set at the median delta threshold cycle. A maximum likelihood analysis was performed to evaluate the provisional cutoff. The relationship of HRG values to PFS hazard ratios (HRs) was assessed as a measure of internal validation. Additional NSCLC samples were analyzed to characterize HRG mRNA distribution. RESULTS: The subgroup of patients with high HRG mRNA levels ("HRG-high") demonstrated clinical benefit from patritumab treatment with HRs of 0.37 (P = 0.0283) and 0.29 (P = 0.0027) in the high- and low-dose patritumab arms, respectively. However, only 102 of the 215 randomized patients (47.4%) had sufficient tumor samples for HRG mRNA measurement. Maximum likelihood analysis showed that the provisional cutoff was within the optimal range. In the placebo arm, the HRG-high subgroup demonstrated worse prognosis compared with HRG-low. A continuous relationship was observed between increased HRG mRNA levels and lower HR. Additional NSCLC samples (N = 300) demonstrated a similar unimodal distribution to that observed in this study, suggesting that the defined cutoff may be applicable to future NSCLC studies. CONCLUSIONS: The prospective-retrospective approach was successful in clinically validating a probable predictive biomarker. Post hoc in vitro studies and statistical analyses permitted further testing of the underlying assumptions. However, limitations of this analysis include the incomplete collection of adequate tumor tissue and a lack of stratification. In a phase 3 study, findings are being confirmed, and the HRG cutoff value is being further refined. CLINICALTRIALSGOV NUMBER: NCT02134015.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Neuregulin-1/genetics , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Humanized , Antibodies, Neutralizing/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/blood , Biomarkers, Tumor/genetics , Broadly Neutralizing Antibodies , Carcinoma, Non-Small-Cell Lung/mortality , Disease-Free Survival , Double-Blind Method , ErbB Receptors/genetics , Erlotinib Hydrochloride/administration & dosage , Erlotinib Hydrochloride/therapeutic use , Female , Humans , Lung Neoplasms/mortality , Male , Middle Aged , Neuregulin-1/blood , Prospective Studies , Receptor, ErbB-3/blood , Receptor, ErbB-3/immunology , Retrospective Studies , Translational Research, Biomedical , Treatment Outcome
8.
Biochem Biophys Res Commun ; 393(1): 55-60, 2010 Feb 26.
Article in English | MEDLINE | ID: mdl-20100464

ABSTRACT

Although various management methods have been developed for heart failure, it is necessary to investigate the diagnostic or therapeutic targets of heart failure. Accordingly, we have developed different approaches for managing heart failure by using conventional microarray analyses. We analyzed gene expression profiles of myocardial samples from 12 patients with heart failure and constructed datasets of heart failure-associated genes using clinical parameters such as pulmonary artery pressure (PAP) and ejection fraction (EF). From these 12 genes, we selected four genes with high expression levels in the heart, and examined their novelty by performing a literature-based search. In addition, we included four G-protein-coupled receptor (GPCR)-encoding genes, three enzyme-encoding genes, and one ion-channel protein-encoding gene to identify a drug target for heart failure using in silico microarray database. After the in vitro functional screening using adenovirus transfections of 12 genes into rat cardiomyocytes, we generated gene-targeting mice of five candidate genes, namely, MYLK3, GPR37L1, GPR35, MMP23, and NBC1. The results revealed that systolic blood pressure differed significantly between GPR35-KO and GPR35-WT mice as well as between GPR37L1-Tg and GPR37L1-KO mice. Further, the heart weight/body weight ratio between MYLK3-Tg and MYLK3-WT mice and between GPR37L1-Tg and GPR37L1-KO mice differed significantly. Hence, microarray analysis combined with clinical parameters can be an effective method to identify novel therapeutic targets for the prevention or management of heart failure.


Subject(s)
Gene Expression Profiling , Heart Failure/genetics , Myocardium/metabolism , Adenoviridae , Aged , Animals , Cells, Cultured , Female , Heart Failure/pathology , Humans , Male , Mice , Mice, Knockout , Mice, Transgenic , Middle Aged , Myocardium/pathology , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Rats
9.
J Card Fail ; 14(5): 426-30, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18514936

ABSTRACT

BACKGROUND: Because plasma levels of adenosine are increased in patients with chronic heart failure (CHF), we examined adenosine concentrations in the plasma and heart and assessed the activity of ecto-5'-nucleotidase in the plasma and ventricular myocardium in patients with CHF. METHODS AND RESULTS: We studied 36 patients with CHF (New York Heart Association Class I/II/III/IV, 9/8/12/7). Twenty-five subjects without CHF were used as controls. Both plasma adenosine levels and ecto-5'-nucleotidase activity were significantly higher in patients with CHF (219 +/- 28 nmol/L and 0.72 +/- 0.03 nmoL/mg protein/min, respectively) than in control subjects (71 +/- 8 nmol/L and 0.54 +/- 0.02 nmoL/mg protein/min, respectively). Plasma adenosine levels sampled from the coronary sinus were significantly higher than from the aorta in patients with CHF, but these differences were not observed in control subjects. Ecto-5'-nucleotidase protein levels were markedly increased in the ventricular myocardium in patients with CHF. CONCLUSIONS: These increases in ecto-5'-nucleotidase in the plasma and myocardium may contribute to increased plasma and cardiac adenosine levels. The increased ecto-5'-nucleotidase activity and adenosine levels in blood may become an index of the presence or severity of CHF.


Subject(s)
5'-Nucleotidase/blood , Heart Failure/enzymology , Myocardium/enzymology , 5'-Nucleotidase/metabolism , Adenosine/blood , Adenosine/metabolism , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Case-Control Studies , Female , Gene Expression , Heart Failure/blood , Heart Failure/physiopathology , Heart Ventricles/enzymology , Humans , Male , Middle Aged , Severity of Illness Index , Stroke Volume
10.
Hypertens Res ; 30(9): 781-7, 2007 Sep.
Article in English | MEDLINE | ID: mdl-18037770

ABSTRACT

Adenosine is well known to be a cardioprotective substance in ischemic heart disease. However, the modulation of adenosine receptors and the production and degradation of endogenous adenosine in chronic heart failure (CHF) are not fully understood. We analyzed the gene expression patterns of adenosine-related genes in human failing and nonfailing myocardium using DNA microarray analysis and quantitative real time-polymerase chain reaction (RT-PCR). DNA microarray analysis revealed that the gene expression of adenosine A2a, A2b, and A3 receptors (A2aR, A2bR, and A3R) as well as that of adenosine deaminase (ADA) decreased in failing myocardium. The down-regulation of these genes was verified by quantitative RT-PCR. We also measured the activities of these adenosine metabolism-related enzymes in failing myocardium and cardiac adenosine levels in patients with CHF. In CHF patients, we observed the decreased enzyme activity of ADA and the elevation of cardiac adenosine levels in CHF patients. To enhance the signaling of adenosine receptors, we increased plasma adenosine levels using dipyridamole, which decreased the severity of CHF. The gene expression of A2aR, A2bR, A3R, and ADA was decreased in the failing hearts, and this decrease may impair adenosine-related signal transduction. The activities of adenosine-related enzymes were altered, thus increasing the myocardial adenosine levels; this increase may compensate for the impairment of adenosine-related signal transduction in patients with CHF. The impairment of adenosine-related signal transmission contributes to the pathophysiology of CHF.


Subject(s)
Adenosine/metabolism , Heart Failure/metabolism , Myocardium/metabolism , Receptors, Purinergic P1/metabolism , Adult , Aged , Chronic Disease , Dipyridamole/therapeutic use , Female , Gene Expression , Gene Expression Profiling , Heart Failure/drug therapy , Heart Failure/physiopathology , Humans , Male , Middle Aged , Oligonucleotide Array Sequence Analysis , Phosphodiesterase Inhibitors/therapeutic use , Reverse Transcriptase Polymerase Chain Reaction
11.
J Clin Invest ; 117(10): 2812-24, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17885681

ABSTRACT

Marked sarcomere disorganization is a well-documented characteristic of cardiomyocytes in the failing human myocardium. Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (MLC2v), which is involved in the development of human cardiomyopathy, is an important structural protein that affects physiologic cardiac sarcomere formation and heart development. Integrated cDNA expression analysis of failing human myocardia uncovered a novel protein kinase, cardiac-specific myosin light chain kinase (cardiac-MLCK), which acts on MLC2v. Expression levels of cardiac-MLCK were well correlated with the pulmonary arterial pressure of patients with heart failure. In cultured cardiomyocytes, knockdown of cardiac-MLCK by specific siRNAs decreased MLC2v phosphorylation and impaired epinephrine-induced activation of sarcomere reassembly. To further clarify the physiologic roles of cardiac-MLCK in vivo, we cloned the zebrafish ortholog z-cardiac-MLCK. Knockdown of z-cardiac-MLCK expression using morpholino antisense oligonucleotides resulted in dilated cardiac ventricles and immature sarcomere structures. These results suggest a significant role for cardiac-MLCK in cardiogenesis.


Subject(s)
Cardiac Output, Low/enzymology , Heart/embryology , Myocardium/ultrastructure , Myosin-Light-Chain Kinase/metabolism , Myosin-Light-Chain Kinase/physiology , Organogenesis , Sarcomeres/metabolism , Zebrafish Proteins/physiology , Adult , Aged , Amino Acid Sequence , Animals , Cardiac Myosins/metabolism , Cardiac Output, Low/genetics , Cardiac Output, Low/pathology , Cells, Cultured , Cloning, Molecular , Embryo, Nonmammalian/metabolism , Female , Humans , Male , Middle Aged , Molecular Sequence Data , Myocardium/enzymology , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/ultrastructure , Myosin Light Chains/metabolism , Myosin-Light-Chain Kinase/antagonists & inhibitors , Myosin-Light-Chain Kinase/genetics , Oligonucleotide Array Sequence Analysis , Oligoribonucleotides, Antisense/pharmacology , Organogenesis/genetics , Rats , Up-Regulation , Zebrafish/embryology , Zebrafish/genetics , Zebrafish/metabolism , Zebrafish Proteins/antagonists & inhibitors , Zebrafish Proteins/genetics
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