H P Koeffler

National University of Singapore, Tumasik, Singapore

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Publications (746)5031.51 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Context: Anaplastic thyroid cancer (ATC) has no effective treatment, resulting in a high rate of mortality. We established cell lines from a primary ATC and its lymph node metastasis, and investigated the molecular factors and genomic changes associated with tumor growth. Objective: The aim of the study was to understand the molecular and genomic changes of highly aggressive ATC and its clonal evolution to develop rational therapies. Design: We established unique cell lines from primary (OGK-P) and metastatic (OGK-M) ATC specimen, as well as primagraft from the metastatic ATC, which was serially xeno-transplanted for more than 1 year in NSG mice were established. These cell lines and primagraft were used as tools to examine gene expression, copy number changes, and somatic mutations using RNA array, SNP Chip, and whole exome sequencing. Results: Mice carrying subcutaneous (OGK-P and OGK-M) tumors developed splenomegaly and neutrophilia with high expression of cytokines including CSF1, CSF2, CSF3, IL-1β, and IL-6. Levels of HIF-1α and its targeted genes were also elevated in these tumors. The treatment of tumor carrying mice with Bevacizumab effectively decreased tumor growth, macrophage infiltration, and peripheral WBCs. SNP chip analysis showed homozygous deletion of exons 3-22 of the PARD3 gene in the cells. Forced expression of PARD3 decreased cell proliferation, motility, and invasiveness, restores cell-cell contacts and enhanced cell adhesion. Next generation exome sequencing identified the somatic changes present in the primary, metastatic, and primagraft tumors demonstrating evolution of the mutational signature over the year of passage in vivo. Conclusion: To our knowledge, we established the first paired human primary and metastatic ATC cell lines offering unique possibilities for comparative functional investigations in vitro and in vivo. Our exome sequencing also identified novel mutations, as well as clonal evolution in both the metastasis and primagraft.
    The Journal of clinical endocrinology and metabolism. 11/2014;
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    ABSTRACT: We investigated the oncogenic role of SETDB1 focusing on non-small cell lung cancer (NSCLC) having high expression of this protein. A total of 387 lung cancer cases were examined by immunohistochemistry, 72% of NSCLC samples were positive for SETDB1 staining, compared to 46% samples of normal bronchial epithelium (106 cases) (p < 0.0001). Percent positive cells and intensity of staining increased significantly with increased grade of disease. Forced expression of SETDB1 in NSCLC cell lines enhanced their clonogenic growth in vitro and markedly increased tumor size in a murine xenograft model; while silencing (shRNA) SETDB1 in NSCLC cells slowed their proliferation. SETDB1 positively stimulated activity of the WNT/beta-catenin pathway and diminished P53 expression resulting in enhanced NSCLC growth in vitro and in vivo. Our finding suggests therapeutic targeting SETDB1 may benefit patients whose tumors express high levels of SETDB1.
    The Journal of Pathology 11/2014; · 7.59 Impact Factor
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    ABSTRACT: Bromodomain and extra terminal domain (BET) proteins are important epigenetic regulators facilitating the transcription of genes in chromatin areas linked to acetylated histones. JQ1, a BET protein inhibitor, has antiproliferative activity against many cancers, mainly through inhibition of c-MYC and upregulation of p21. In this research, we investigated the use of JQ1 for human osteosarcoma (OS) treatment. JQ1 significantly inhibited the proliferation and survival of OS cells inducing G1 cell cycle arrest, premature senescence, but little effect on apoptosis. Interestingly, c-MYC protein levels in JQ1-treated cells remained unchanged, whereas the upregulation of p21 protein was still observable. Although effective in vitro, JQ1 alone failed to reduce the size of the MNNG/HOS xenografts in immunocompromised mice. To overcome the resistance of OS cells to JQ1 treatment, we combined JQ1 with rapamycin, an mTOR inhibitor. JQ1 and rapamycin synergistically inhibited the growth and survival of OS cells in vitro and in vivo. We also identified that RUNX2 is a direct target of BRD4 inhibition by JQ1 in OS cells. Chromatin immunoprecipitation (ChIP) showed that enrichment of BRD4 protein around RUNX2 transcription start sites diminished with JQ1 treatment in MNNG/HOS cells. Overexpression of RUNX2 protected JQ1-sensitive OS cells from the effect of JQ1, and siRNA-mediated inhibition of RUNX2 sensitized the same cells to JQ1. In conclusion, our findings suggest that JQ1, in combination with rapamycin, is an effective chemotherapeutic option for OS treatment. We also show that inhibition of RUNX2 expression by JQ1 partly explains the antiproliferative activity of JQ1 in OS cells. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 10/2014; · 6.20 Impact Factor
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    ABSTRACT: Exportin-1 (XPO1, CRM1) mediates the nuclear export of several key growth regulatory and tumor suppressor proteins. Cancer cells often overexpress XPO1 resulting in cytoplasmic mislocalization and aberrant activity of its target proteins. Orally bioavailable selective inhibitors of nuclear export (SINE) that irreversibly bind to and inhibit the function of XPO1 have been recently developed. The aim of this study was to investigate the efficacy of the clinical staged, orally available, SINE compound, KPT-330 in hepatocellular carcinoma (HCC).
    Cancer Chemotherapy and Pharmacology 07/2014; · 2.80 Impact Factor
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    ABSTRACT: 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) and vitamin D receptor (VDR) have been reported to have an important role in the regulation of innate immunity. We earlier reported that the antimicrobial peptide cathelicidin is induced by 1,25(OH)2D3 in normal human bronchial epithelial cells with a resultant increase in antimicrobial activity against airway pathogens. In this study we demonstrate that C/EBP alpha (C/EBPα) is a potent enhancer of human cathelicidin antimicrobial peptide (CAMP) gene transcription in human lung epithelial cells. In addition we found that C/EBPα functionally cooperates with VDR in the regulation of CAMP transcription. A C/EBP binding site was identified at -627/-619 within the CAMP promoter, adjacent to the vitamin D response element (VDRE; -615/-600). Mutation of this site markedly attenuated the transcriptional response to C/EBPα as well as to 1,25(OH)2D3, further indicating cooperation between these two factors in the regulation of CAMP. ChIP analysis using 1,25(OH)2D3 treated human lung epithelial cells showed C/EBPα and VDR binding to the CAMP promoter. C/EBPα has previously been reported to cooperate with Brahma (Brm), an ATPase that is component of the SWI/SNF chromatin remodeling complex. We found that dominant negative Brm significantly inhibited C/EBPα as well as 1,25(OH)2D3 mediated induction of CAMP transcription, suggesting the functional involvement of Brm. These findings define novel mechanisms involving C/EBPα, SWI/SNF and 1,25(OH)2D3 in the regulation of CAMP in lung epithelial cells. These mechanisms of enhanced activation of the CAMP gene in lung epithelial cells suggest potential candidates for the development of modulators of innate immune responses for adjunct therapy in the treatment of airway infections. © 2014 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 07/2014; · 4.22 Impact Factor
  • Manoj Garg, Glenn Braunstein, Harold Phillip Koeffler
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    ABSTRACT: Cancer is the leading cause of morbidity and mortality in developed countries and the second major cause of death in developing countries. Laminins are crucial proteins in the basal lamina (one of the layers of the basement membrane), and these form a protein network that influences both normal and transformed cell differentiation, migration and adhesion, as well as phenotype and survival. The basement membranes act as a mechanical barrier to tumor growth, but these molecules, including laminins, are also important autocrine factors produced by cancers to promote tumorigenesis. Several studies in cancers have shown the importance of LAMC2, a laminin component. The elevated expression of LAMC2 on cancer cells appears to drive tumorigenesis through its interactions with several cell-surface receptors including α6β4 and α3β1 integrins and EGFRs. The accumulating evidence indicates that LAMC2-mediated signaling network plays an important role in the progression, migration and invasion of multiple types of cancer, suggesting that it might be a potential therapeutic anticancer target for inhibiting tumorigenesis. Furthermore, elevated serum levels of LAMC2 in cancer patients might be an attractive serum-based diagnostic biomarker.
    Expert opinion on therapeutic targets. 06/2014;
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    ABSTRACT: Nasopharyngeal carcinoma (NPC) has extremely skewed ethnic and geographic distributions, is poorly understood at the genetic level and is in need of effective therapeutic approaches. Here we determined the mutational landscape of 128 cases with NPC using whole-exome and targeted deep sequencing, as well as SNP array analysis. These approaches revealed a distinct mutational signature and nine significantly mutated genes, many of which have not been implicated previously in NPC. Notably, integrated analysis showed enrichment of genetic lesions affecting several important cellular processes and pathways, including chromatin modification, ERBB-PI3K signaling and autophagy machinery. Further functional studies suggested the biological relevance of these lesions to the NPC malignant phenotype. In addition, we uncovered a number of new druggable candidates because of their genomic alterations. Together our study provides a molecular basis for a comprehensive understanding of, and exploring new therapies for, NPC.
    Nature Genetics 06/2014; · 35.21 Impact Factor
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    ABSTRACT: Background:We investigated the biologic and pharmacologic activities of a chromosome region maintenance 1 (CRM1) inhibitor against human non-small cell lung cancer (NSCLC) cells both in vitro and in vivo.Methods:The in vitro and in vivo effects of a novel CRM1 inhibitor (KPT-330) for a large number of anticancer parameters were evaluated using a large panel of 11 NSCLC cell lines containing different key driver mutations. Mice bearing human NSCLC xenografts were treated with KPT-330, and tumour growth was assessed.Results:KPT-330 inhibited proliferation and induced cell cycle arrest and apoptosis-related proteins in 11 NSCLC cells lines. Moreover, the combination of KPT-330 with cisplatin synergistically enhanced the cell kill of the NSCLC cells in vitro. Human NSCLC tumours growing in immunodeficient mice were markedly inhibited by KPT-330. Also, KPT-330 was effective even against NSCLC cells with a transforming mutation of either exon 20 of EGFR, TP53, phosphatase and tensin homologue, RAS or PIK3CA, suggesting the drug might be effective against a variety of lung cancers irrespective of their driver mutation.Conclusions:Our results support clinical testing of KPT-330 as a novel therapeutic strategy for NSCLC.British Journal of Cancer advance online publication, 19 June 2014; doi:10.1038/bjc.2014.260 www.bjcancer.com.
    British Journal of Cancer 06/2014; · 5.08 Impact Factor
  • De-Chen Lin, Ming-Rong Wang, H Phillip Koeffler
    Cell cycle (Georgetown, Tex.) 06/2014; 13(13). · 5.24 Impact Factor
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    ABSTRACT: LNK (SH2B3) is an adaptor protein studied extensively in normal and malignant hematopoietic cells. In these cells, it downregulates activated tyrosine kinases at the cell surface resulting in an antiproliferative effect. To date, no studies have examined activities of LNK in solid tumors. In this study, we found by in silico analysis and staining tissue arrays that the levels of LNK expression were elevated in high-grade ovarian cancer. To test the functional importance of this observation, LNK was either overexpressed or silenced in several ovarian cancer cell lines. Remarkably, overexpression of LNK rendered the cells resistant to death induced by either serum starvation or nutrient deprivation, and generated larger tumors using a murine xenograft model. In contrast, silencing of LNK decreased ovarian cancer cell growth in vitro and in vivo. Western blot studies indicated that overexpression of LNK upregulated and extended the transduction of the mitogenic signal, whereas silencing of LNK produced the opposite effects. Furthermore, forced expression of LNK reduced cell size, inhibited cell migration and markedly enhanced cell adhesion. Liquid chromatography-mass spectroscopy identified 14-3-3 as one of the LNK-binding partners. Our results suggest that in contrast to the findings in hematologic malignancies, the adaptor protein LNK acts as a positive signal transduction modulator in ovarian cancers.Oncogene advance online publication, 7 April 2014; doi:10.1038/onc.2014.34.
    Oncogene 04/2014; · 8.56 Impact Factor
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    ABSTRACT: Esophageal squamous cell carcinoma (ESCC) is prevalent worldwide and particularly common in certain regions of Asia. Here we report the whole-exome or targeted deep sequencing of 139 paired ESCC cases, and analysis of somatic copy number variations (SCNV) of over 180 ESCCs. We identified previously uncharacterized mutated genes such as FAT1, FAT2, ZNF750 and KMT2D, in addition to those already known (TP53, PIK3CA and NOTCH1). Further SCNV evaluation, immunohistochemistry and biological analysis suggested their functional relevance in ESCC. Notably, RTK-MAPK-PI3K pathways, cell cycle and epigenetic regulation are frequently dysregulated by multiple molecular mechanisms in this cancer. Our approaches also uncovered many druggable candidates, and XPO1 was further explored as a therapeutic target because it showed both gene mutation and protein overexpression. Our integrated study unmasks a number of novel genetic lesions in ESCC and provides an important molecular foundation for understanding esophageal tumors and developing therapeutic targets.
    Nature Genetics 03/2014; · 35.21 Impact Factor
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    ABSTRACT: Lipocalin 2 (LCN2 or neutrophil gelatinase-associated lipocalin) is a secretory protein discovered from neutrophils, which accumulates in the blood and urine during acute kidney injury (AKI) and in the blood by bacterial infection. Little is known about the tissue source and molecular forms of this protein under normal and pathophysiologic conditions. By sandwich ELISA, serum and urinary LCN2 levels were measured in 36 patients with hematologic malignancies who transiently became neutropenic by stem cell transplantation (SCT). To evaluate contribution of neutrophil-derived LCN2 in the physiologic blood LCN2 concentrations, we examined CCAAT/enhancer-binding protein ε (C/EBPε) knockout mice, which lack mature neutrophils. In patients without AKI and bacterial infection, at 1 week after SCT, the median blood neutrophil counts became zero and serum LCN2 levels were decreased by 76 ± 6 % (p < 0.01), but urinary LCN2 levels were not altered. During neutropenic conditions, bacterial infection caused only a modest rise of serum LCN2 but AKI produced a marked rise of serum and urinary LCN2 levels. Serum LCN2 concentrations in C/EBPε knockout mice were reduced by 66 ± 11 % compared to wild-type mice (p < 0.05). Blood LCN2 existed predominantly in high molecular weight forms (>100 kDa), while urinary LCN2 was mainly in low molecular weight forms. Our findings suggest that neutrophils are the major source of circulating LCN2 in normal and infected conditions, whereas blood and urinary LCN2 mainly derive from the kidney during AKI, and that the molecular forms and regulation of blood and urinary LCN2 are clearly distinct.
    Clinical and Experimental Nephrology 03/2014; · 1.25 Impact Factor
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    ABSTRACT: The anti-apoptotic protein Bcl-2 is a well-known and attractive therapeutic target for cancer. In the present study the solution-phase T3P-DMSO mediated efficient synthesis of 2-amino-chromene-3-carbonitriles from alcohols, malanonitrile and phenols is reported. These novel 2-amino-chromene-3-carbonitriles showed cytotoxicity in human acute myeloid leukemia (AML) cell lines. Compound 4g was found to be the most bioactive, decreasing growth and increasing apoptosis of AML cells. Moreover, compound 4g (at a concentration of 5 µM) increased the G2/M and sub-G1 (apoptosis) phases of AML cells. The AML cells treated with compound 4g exhibited decreased levels of Bcl-2 and increased levels of caspase-9. In silico molecular interaction analysis showed that compound 4g shared a similar global binding motif with navitoclax (another small molecule that binds Bcl-2), however compound 4g occupies a smaller volume within the P2 hot spot of Bcl-2. The intermolecular π-stacking interaction, direct electrostatic interactions, and docking energy predicted for 4g in complex with Bcl-2 suggest a strong affinity of the complex, rendering 4g as a promising Bcl-2 inhibitor for evaluation as a new anticancer agent.
    PLoS ONE 01/2014; 9(9):e107118. · 3.53 Impact Factor
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    ABSTRACT: The CCAAT/enhancer binding proteins (C/EBPs) are transcription factors involved in hematopoietic cell development and induction of several inflammatory mediators. C/EBPε is expressed only in myeloid cells including monocytes/macrophages. Atherosclerosis is an inflammatory disorder of the vascular wall and circulating immune cells such as monocytes/macrophages. Mice deficient in the low density lipoprotein (LDL) receptor (Ldlr-/-) fed on a high cholesterol diet (HCD) show elevated blood cholesterol levels and are widely used as models to study human atherosclerosis. In this study, we generated Ldlr and Cebpe double-knockout (llee) mice and compared their atherogenic phenotypes to Ldlr single deficient (llEE) mice after HCD. Macrophages from llee mice have reduced lipid uptake by foam cells and impaired phagokinetic motility in vitro compared to macrophages from llEE mice. Also, compared to llEE mice, llee mice have alterations of lipid metabolism, and reduced atheroma and obesity, particularly the males. Peritoneal macrophages of llee male mice have reduced mRNA expression of FABP4, a fatty acid binding protein implicated in atherosclerosis. Overall, our study suggests that the myeloid specific factor C/EBPε is involved in systemic lipid metabolism and that silencing of C/EBPε could decrease the development of atherosclerosis.
    PLoS ONE 01/2014; 9(1):e85341. · 3.53 Impact Factor
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    ABSTRACT: Studies from our laboratory and others have shown that cysteine-rich 61 (Cyr61) may be involved in tumor proliferation and invasion. In earlier studies, we demonstrated increased insulin-like growth factor-I (IGF-1) is associated with breast tumor formation and poor clinical outcomes. In our current study we have investigated IGF-1 regulation of Cyr61 and whether targeting IGF-1 could inhibit Cyr61 induced tumor growth and proliferation.
    PLoS ONE 01/2014; 9(7):e103534. · 3.53 Impact Factor
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    Liang Xu, De-Chen Lin, Dong Yin, H Phillip Koeffler
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    ABSTRACT: PARK2 (PARKIN) is an E3 ubiquitin ligase involved in multiple signaling pathways and cellular processes. Activity of PARK2 is tightly regulated through inter- and intra-molecular interactions. Dysfunction of PARK2 is associated with the progression of parkinsonism. Notably, frequent PARK2 inactivation has been identified in various human cancers. Park2-deficient mice are more susceptible to tumorigenesis, indicating its crucial role as a tumor suppressor. However, biological studies also show that PARK2 possesses both pro-survival and growth suppressive functions. Here, we summarize the genetic lesions of PARK2 in human cancers and discuss the current knowledge of PARK2 in cancer progression. We further highlight future efforts for the study of PARK2 in cancer.
    Journal of Molecular Medicine 12/2013; · 4.77 Impact Factor
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    ABSTRACT: Proteasome inhibitors have been proven to be effective anticancer compounds in many tumor models, including glioblastoma multiforme (GBM). In this study, we found that the proteasome inhibitor Velcade (PS-341/bortezomib) caused GBM cell death while simultaneously activating the PI3K/Akt pathway. Therefore, we sought to investigate if the PI3K inhibitor ZSTK474 would enhance the effectiveness of Velcade in anticancer therapy. Two GBM cell lines were used to detect the effects of Velcade and ZSTK474 alone or in combination in vitro. The combination of Velcade and ZSTK474 synergistically inhibited the proliferation of GBM cell lines. Cell apoptosis was increased when exposed to Velcade and ZSTK474 in combination as shown by Annexin V analysis. Treatment with both drugs led to downregulation of the p-Akt, p-4EBP1 and p-mTOR proteins as determined by western blot analysis. The anticancer ability of Velcade for glioblastoma multiforme was, therefore, enhanced by combination with the PI3K pathway inhibitor ZSTK474 in glioblastoma multiforme.
    International Journal of Oncology 12/2013; · 2.66 Impact Factor
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    ABSTRACT: High-throughput DNA sequencing significantly contributed to diagnosis and prognostication in patients with myelodysplastic syndromes (MDS). We determined the biological and prognostic significance of genetic aberrations in MDS. 944 patients with various MDS subtypes were screened for known/putative mutations/deletions in 104 genes using targeted deep-sequencing and array-based genomic hybridization. 845/944 patients (89.5%) harbored at least one mutation (median, 3 per patient; range, 0-12). Forty-seven genes were significantly mutated with TET2, SF3B1, ASXL1, SRSF2, DNMT3A, and RUNX1 mutated in >10% of cases. Many mutations were associated with higher risk groups and/or blast elevation. Survival was investigated in 875 patients. By univariate analysis, 25/48 genes (resulting from 47 genes tested significantly plus PRPF8) affected survival (P<0.05). The status of 14 genes combined with conventional factors revealed a novel prognostic model ('Model-1') separating patients into four risk groups ('low', 'intermediate', 'high', 'very high risk') with 3-year survival of 95.2%, 69.3%, 32.8%, and 5.3% (P<0.001). Subsequently, a 'gene-only model' ('Model-2') was constructed based on 14 genes also yielding four significant risk groups (P<0.001). Both models were reproducible in the validation cohort (n=175 patients; P<0.001 each). Thus, large-scale genetic and molecular profiling of multiple target genes is invaluable for subclassification and prognostication in MDS patients.Leukemia accepted article preview online, 13 November 2013; doi:10.1038/leu.2013.336.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 11/2013; · 10.16 Impact Factor
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    ABSTRACT: Context:Anaplastic thyroid carcinoma (ATC) is an aggressive malignancy having no effective treatment. Laminin subunit gamma-2 (LAMC2) is an epithelial basement membrane protein involved in cell migration and tumour invasion and might represent an ideal target for the development of novel therapeutic approaches for ATC.Objective:Study the role of LAMC2 in ATC tumorigenesis.Design:LAMC2 expression was evaluated by RT-PCR, western blotting and immunohistochemistry in tumor specimens, adjacent non-cancerous tissues and cell lines. shRNA approach was used to investigate the effect of LAMC2 knockdown on tumorigenesis of ATC.Results:LAMC2 was highly expressed in ATC samples and cell lines compared to normal thyroid tissues. Silencing LAMC2 by shRNA in ATC cells moderately inhibited cell growth in liquid culture and dramatically decreased growth in soft agar and in xenografts growing in immunodeficient mice. Silencing LAMC2 caused cell cycle arrest and significantly suppressed migration, invasion and wound healing of ATC cells. Rescue experiments by overexpressing LAMC2 in LAMC2 knockdown cells, reversed the inhibitory effects as shown by increased cell proliferation and colony formation. Microarray data demonstrated that LAMC2 shRNA significantly altered expression of genes associated with migration, invasion, proliferation and survival. Immunoprecipitation studies showed that LAMC2 bound to EGFR in ATC cells. Silencing LAMC2 partially blocked EGF-mediated activation of EGFR and its downstream pathway. Interestingly, cetuximab (EGFR blocking antibody) or EGFR siRNA additively enhanced the anti-proliferative activity of the LAMC2 knockdown ATC cells compared to control cells.Conclusions:To our knowledge, this is the first report investigating the effect of LAMC2 on cell growth, cell cycle, migration, invasion and EGFR signaling in ATC cells, suggesting that LAMC2 may be a potential therapeutic target for treatment of ATC.
    The Journal of Clinical Endocrinology and Metabolism 10/2013; · 6.31 Impact Factor

Publication Stats

27k Citations
5,031.51 Total Impact Points

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Institutions

  • 2014
    • National University of Singapore
      Tumasik, Singapore
  • 1991–2014
    • Cedars-Sinai Medical Center
      • • Division of Hematology and Oncology
      • • Cedars Sinai Medical Center
      • • Department of Medicine
      Los Angeles, California, United States
    • University of Freiburg
      • Institute of Forensic Medicine
      Freiburg, Lower Saxony, Germany
  • 1980–2014
    • University of California, Los Angeles
      • • Division of Hematology and Medical Oncology
      • • Department of Obstetrics and Gynecology
      • • Department of Medicine
      • • Center for Culture and Health
      Los Angeles, California, United States
  • 2013
    • Peking University
      Peping, Beijing, China
    • Münchner Leukämie Labor GmbH
      München, Bavaria, Germany
  • 2012–2013
    • Sun Yat-Sen University
      Shengcheng, Guangdong, China
    • Universitätsklinikum Münster
      Muenster, North Rhine-Westphalia, Germany
  • 2010–2013
    • Charles R. Drew University of Medicine and Science
      • Department of Medicine
      Los Angeles, California, United States
    • University of the Free State
      Bloemfontein, Free State, South Africa
  • 2007–2013
    • The University of Tokyo
      • Faculty & Graduate School of Medicine
      Tōkyō, Japan
  • 2005–2013
    • University of California, San Francisco
      • Department of Laboratory Medicine
      San Francisco, CA, United States
  • 2011–2012
    • Shanghai Institutes for Biological Sciences
      Shanghai, Shanghai Shi, China
  • 2004–2011
    • Kochi University
      • • Department of Hematology and Respiratory Medicine
      • • Department of Medicine
      Kōchi-shi, Kochi-ken, Japan
    • Institut Pasteur
      Lutetia Parisorum, Île-de-France, France
    • Nagasaki University
      Nagasaki, Nagasaki, Japan
    • Showa University
      • Division of Hematology
      Shinagawa, Tōkyō, Japan
    • Vanderbilt University
      • Department of Biochemistry
      Nashville, Michigan, United States
  • 2001–2011
    • Goethe-Universität Frankfurt am Main
      • Center for Internal Medicine
      Frankfurt, Hesse, Germany
  • 1996–2011
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      Torrance, California, United States
    • Cincinnati Children's Hospital Medical Center
      Cincinnati, Ohio, United States
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, MA, United States
  • 1993–2011
    • Kochi Medical School
      Kôti, Kōchi, Japan
    • University of California, Irvine
      • Department of Pathology & Laboratory Medicine
      Irvine, CA, United States
  • 2009–2010
    • Kanazawa University
      • Department of Hematology
      Kanazawa, Ishikawa, Japan
    • Oregon State University
      • Department of Biochemistry and Biophysics
      Corvallis, OR, United States
  • 1982–2010
    • University of Southern California
      • • Norris Comprehensive Cancer Center
      • • Division of Hematology
      • • Department of Obstetrics and Gynecology
      • • Department of Medicine
      Los Angeles, CA, United States
  • 2005–2009
    • Charité Universitätsmedizin Berlin
      • • Department of Pediatrics, Division of Oncology and Hematology
      • • Medical Department, Division of Oncology and Hematology
      Berlin, Land Berlin, Germany
  • 2008
    • Roswell Park Cancer Institute
      • Department of Pharmacology and Therapeutics
      Buffalo, NY, United States
  • 2007–2008
    • Northeast Institute of Geography and Agroecology
      • Institute for Nutritional Sciences
      Beijing, Beijing Shi, China
  • 1992–2008
    • Universitätsklinikum Freiburg
      • Department of Internal Medicine
      Freiburg an der Elbe, Lower Saxony, Germany
  • 1977–2008
    • Children's Hospital Los Angeles
      • • Division of Hematology-Oncology
      • • Division of Hospital Medicine
      Los Angeles, California, United States
  • 1980–2007
    • CSU Mentor
      Long Beach, California, United States
  • 2002–2006
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany
  • 2000–2005
    • University of Birmingham
      • • School of Biosciences
      • • Group of Medical Science and Education
      Birmingham, England, United Kingdom
    • University of Michigan
      Ann Arbor, Michigan, United States
    • University of Illinois at Chicago
      • Department of Surgical Oncology (Chicago)
      Chicago, IL, United States
    • Seoul National University Hospital
      • Department of Internal Medicine
      Seoul, Seoul, South Korea
    • Simmons College
      Boston, Massachusetts, United States
  • 2003
    • Kagawa University
      • Faculty of Medicine
      Takamatsu-shi, Kagawa-ken, Japan
  • 2001–2003
    • University of Münster
      • Department of Medicine, Hematology and Oncology
      Münster, North Rhine-Westphalia, Germany
  • 1999–2003
    • Hiroshima University
      • • Department of Molecular Oncology
      • • Medical Research Institute for Bio Functions
      Hiroshima-shi, Hiroshima-ken, Japan
    • Keck School of Medicine USC
      Los Angeles, California, United States
  • 1997–2001
    • Shinshu University
      • Department of Pediatrics
      Shonai, Nagano, Japan
    • Wistar Institute
      Philadelphia, Pennsylvania, United States
    • Truman Medical Center
      Kansas City, Kansas, United States
  • 1993–1999
    • Keio University
      • • Department of Internal Medicine
      • • School of Medicine
      Tokyo, Tokyo-to, Japan
  • 1998
    • Nagasaki University Hospital
      Nagasaki, Nagasaki, Japan
    • University of Texas MD Anderson Cancer Center
      Houston, Texas, United States
  • 1994–1998
    • National Institute of Radiological Sciences
      Tiba, Chiba, Japan
    • Dong-Pusan College
      Tsau-liang-hai, Busan, South Korea
  • 1988–1991
    • University of California, Riverside
      • • Department of Biochemistry
      • • Division of Biomedical Sciences
      Riverside, CA, United States
  • 1988–1989
    • Harbor-UCLA Medical Center
      Torrance, California, United States