H Phillip Koeffler

Cedars-Sinai Medical Center, Los Ángeles, California, United States

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Publications (790)5599.06 Total impact

  • Cancer Research 11/2015; 75(22 Supplement 1):A2-20-A2-20. DOI:10.1158/1538-7445.TRANSCAGEN-A2-20 · 9.33 Impact Factor
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    PLoS ONE 10/2015; 10(10):e0139915. DOI:10.1371/journal.pone.0139915 · 3.23 Impact Factor
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    ABSTRACT: Acute myeloid leukemia (AML) with a FLT3 internal tandem duplication (FLT3-ITD) mutation is an aggressive hematologic malignancy with a grave prognosis. To identify mutational spectrum associated with relapse, whole exome sequencing was performed on 13 matched diagnosis, relapse and remission trios followed by targeted sequencing of 299 genes in 67 FLT3-ITD patients. FLT3-ITD genome has an average of 13 mutations per sample, similar to other AML subtypes, which is a low mutation rate compared to solid tumors. Recurrent mutations occur in genes related to DNA-methylation, chromatin, histone-methylation, myeloid transcription factors, signaling, adhesion, cohesin-complex and spliceosome-complex. Their pattern of mutual exclusivity and cooperation among mutated genes suggests that these genes have a strong biologic relationship. In addition, we identify mutations in previously unappreciated genes such as MLL3, NSD1, FAT1, FAT4, and IDH3B. Mutations in nine genes are observed in the relapse specific phase. DNMT3A mutations are the most stable mutations and this DNMT3A transformed clone can be present even in morphological complete remissions. Of note, all matched trios AML samples share at least one genomic alteration at diagnosis and relapse, suggesting common ancestral clones. Two types of clonal evolution occur at relapse either: (a) the founder clone recurs or (b) a subclone of the founder clone escapes from the induction chemotherapy and expands at relapse by acquiring new mutations. Relapse-specific mutations display increase in transversions. Functional assays demonstrate both MLL3 and FAT1 exert tumor-suppressor activity in the FLT3-ITD subtype. An inhibitor of XPO1 synergized with standard AML induction chemotherapy to inhibit FLT3-ITD growth. This study clearly shows that FLT3-ITD AML requires additional driver genetic alterations in addition to FLT3-ITD alone.
    Blood 10/2015; DOI:10.1182/blood-2015-05-646240 · 10.45 Impact Factor
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    ABSTRACT: Sorafenib is a specific ATP-competitive RAF inhibitor used as a first-line treatment of advanced hepatocellular carcinoma (HCC). However, the responses are variable reflecting heterogeneity of the disease while the resistance mechanism remains poorly understood. Here, we report that sorafenib treatment can exacerbate disease progression in both patient-derived xenografts (PDX) and cell line derived xenografts (CDX), and the therapeutic effect of the drug inversely co-varies to the ratio of EpCAM positive cells, which may be tumor initiating cells (TIC) in HCC. The TSC2-AKT cascade mediates this sorafenib resistance. In response to sorafenib treatment, formation of the TSC1/2 complex is enhanced causing an increased phosphorylation of AKT, which contributes to up-regulation of "stemness"-related genes in EpCAM positive cells and enhancement of tumorigenicity. The expression of TSC2 negatively correlated with prognosis in clinical sorafenib therapy. Furthermore, all-trans retinoic acid (ATRA) decreased AKT activity, reduced the EpCAM positive cell population enriched by sorafenib and potentiated the therapeutic effect of sorafenib in the PDX model. Our findings suggest that a subtype of HCC is not suitable for sorafenib therapy. This resistance to sorafenib can be predicted by the status of TSC2, and agents inducing differentiation of TICs (e.g., ATRA) should improve the prognosis of this subtype of HCC. This article is protected by copyright. All rights reserved. © 2015 by the American Association for the Study of Liver Diseases.
    Hepatology 08/2015; DOI:10.1002/hep.28117 · 11.06 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):2868-2868. DOI:10.1158/1538-7445.AM2015-2868 · 9.33 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):138-138. DOI:10.1158/1538-7445.AM2015-138 · 9.33 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):LB-255-LB-255. DOI:10.1158/1538-7445.AM2015-LB-255 · 9.33 Impact Factor
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    ABSTRACT: 1,2,3-triazole-based heterocycles have previously been shown to possess significant anticancer activity in various tumor models. In the present study, we attached a 1,2,3-triazole moiety to the third position of a 1,2-benzisoxazole heterocycle via Copper (I)-catalyzed azide-alkyne cycloaddition (CuAAC) with various alkynes and established for the title compounds significant antiproliferative effect against human acute myeloid leukemia (AML) cells. Among the tested compounds, 3-(4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1- yl)benzo[d]isoxazole (PTB) was found to be the most potent antiproliferative agent with an IC50 of 2 µM against MV4-11 cells using MTT assay. Notably, PTB induced cytotoxicity in MOLM13, MOLM14 and MV4-11 cells with selectivity over normal bone marrow cells (C57BL/6). Furthermore, PTB was found to induce cytotoxicity by increasing apoptosis of AML cells (MOLM13, MOLM14 and MV4-11) as well as sub-G1 cell population and apoptotic cells at submicromolar concentrations, as shown by flow cytometry and Annexin-V staining, respectively. On the protein level we suggested histone deacetylases (HDACs) as the potential protein target of those compounds in silico, and the predicted target was next experimentally validated by measuring the variations in the levels of p21, cyclin D and acetylation of histone H3 and tubulin. Molecular docking analysis of the title compounds with the second deacetylase domain of HDAC6 displayed high degree of shape complementarity to the binding site of the enzyme, forming multiple molecular interactions in the hydrophobic region as well as a hydrogen bond to the phenol side-chain of Tyr-782. Thus, 1,2,3-triazole derivatives appear to represent a class of novel, biologically active ligands against histone deacetylases which deserve to be further evaluated in their applications in the cancer field.
    Bioorganic & medicinal chemistry 07/2015; 23(18). DOI:10.1016/j.bmc.2015.07.069 · 2.79 Impact Factor
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    Dhong Hyun Lee · Charles Forscher · Dolores Di Vizio · H Phillip Koeffler ·
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    ABSTRACT: Dedifferentiated liposarcoma (DDLPS) is a highly malignant subtype of human liposarcoma (LPS), whose genomic profile is characterized by chromosomal amplification at 12q13-q22. miR-26a-2 is one of the most frequently amplified genes in the region, and inhibition of its downstream target genes likely contributes to LPS tumorigenesis. Our previous study of LPS predicted homeobox protein A5 (HOXA5) as a target of miR-26a-2, and here we explored further the function of HOXA5, and its relationship with miR-26a-2 in DDLPS cells. Compared to normal human adipocytes, all LPS cell lines showed significant downregulation of HOXA5 (p = 0.046), and inhibition of miR-26a-2 using anti-miR-26a-2 substantially upregulated HOXA5 expression in these LPS cells. Interestingly, overexpression of HOXA5 alone induced very strong apoptotic response of LPS cells. HOXA5-induced apoptosis was p53-independent and caspase-dependent. Surprisingly, overexpression of HOXA5 induced nuclear translocation of RELA (p65), which was not associated with the transcriptional activity of RELA. Rather, nucleolar sequestration of RELA was observed. Overall, our study demonstrated for the first time that the downregulation of HOXA5 in LPS cells, partly by overexpression of miR-26a-2 in DDLPS, confers LPS cells resistance to apoptotic death. Further studies are required to understand the relationship of HOXA5 and the NFκB pathway in LPS cells.
    Scientific Reports 07/2015; 5:12580. DOI:10.1038/srep12580 · 5.58 Impact Factor
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    ABSTRACT: Studying mechanisms of malignant transformation of human pre-B cells, we found that acute activation of oncogenes induced immediate cell death in the vast majority of cells. Few surviving pre-B cell clones had acquired permissiveness to oncogenic signaling by strong activation of negative feedback regulation of Erk signaling. Studying negative feedback regulation of Erk in genetic experiments at three different levels, we found that Spry2, Dusp6, and Etv5 were essential for oncogenic transformation in mouse models for pre-B acute lymphoblastic leukemia (ALL). Interestingly, a small molecule inhibitor of DUSP6 selectively induced cell death in patient-derived pre-B ALL cells and overcame conventional mechanisms of drug-resistance. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cancer cell 06/2015; 28(1). DOI:10.1016/j.ccell.2015.05.008 · 23.52 Impact Factor
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    ABSTRACT: Molecular targeted therapy is an important approach for advanced hepatocellular carcinoma (HCC). Hepatitis B virus-related HCC (HBV-HCC) accounts for approximately 50% of all HCC cases. Bortezomib, a proteasome inhibitor, is used extensively for the treatment of hematologic malignancies, but its application in HCC, particularly in HBV-HCC, has not been fully explored. The effects of bortezomib on HCC tissues were evaluated by TUNEL assays. The growth inhibitory activity was measured using cell viability assays, and apoptosis was measured using flow cytometry. The levels of HBx, P-Raf/Raf and P-Erk/Erk expression were measured by Western blot. The ability of the MEK inhibitor PD98059 to enhance the cell killing activity of bortezomib was evaluated using ex vivo and in vivo methods. The potency of bortezomib varied among HCC samples and cell lines, and HBV/HBx expression was associated with resistance to bortezomib. Bortezomib increased the levels of P-Raf and P-Erk in HBV/HBx-positive cells but not in HBV/HBx-negative HCC cells or in breast cancer or glioblastoma multiform cells. HBx was also upregulated after exposure to bortezomib, which was associated with the inhibition of proteasome activity. P-Erk upregulation mediated by bortezomib was effectively suppressed by the addition of the MEK inhibitor PD98059. Moreover, bortezomib and PD98059 synergistically inhibited HCC cell proliferation, as measured using both ex vivo and in vivo models. Our studies demonstrate for the first time that HBx causes resistance to bortezomib in HCC, and this resistance can be antagonized by a MEK signaling inhibitor, providing a novel therapeutic approach. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 06/2015; 21(19). DOI:10.1158/1078-0432.CCR-14-2067 · 8.72 Impact Factor
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    ABSTRACT: Neutrophil-specific granule deficiency (SGD) is a rare autosomal recessive primary immunodeficiency characterized by neutrophil dysfunction, bilobed neutrophil nuclei and lack of neutrophil-specific granules. Defects in a myeloid-specific transcription factor, CCAAT/enhancer binding protein-ε (C/EBPε), have been identified in two cases in which homozygous frameshift mutations led to loss of the leucine zipper domain. In this study, we report a 55-y-old woman affected with SGD caused by a novel homozygous 2-aa deletion (ΔRS) in the leucine zipper domain of the C/EBPε gene. The patient showed characteristic neutrophil abnormalities and recurrent skin infections; however, there was no history of deep organ infections. Biochemical analysis revealed that, in contrast to the two frameshift mutations, the ΔRS mutant maintained normal cellular localization, DNA-binding activity, and dimerization, and all three mutants exhibited marked reduction in transcriptional activity. The ΔRS mutant was defective in its association with Gata1 and PU.1, as well as aberrant cooperative transcriptional activation of eosinophil major basic protein. Thus, the ΔRS likely impairs protein-protein interaction with other transcription factors, resulting in a loss of transcriptional activation. These results further support the importance of the leucine zipper domain of C/EBPε for its essential function, and indicate that multiple molecular mechanisms lead to SGD. Copyright © 2015 by The American Association of Immunologists, Inc.
    The Journal of Immunology 05/2015; 195(1). DOI:10.4049/jimmunol.1402222 · 4.92 Impact Factor
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    ABSTRACT: Next generation sequencing technologies have provided insights into the molecular heterogeneity of various myeloid neoplasms, revealing previously unknown somatic genetic events. In our cohort of 1444 cases analyzed by next generation sequencing, somatic mutations in the gene BRCA1-BRCA2-containing complex 3 (BRCC3) were identified in 28 cases (1.9%). BRCC3 is a member of the JAMM/MPN+ family of zinc metalloproteases capable of cleaving Lys-63 linked polyubiquitin chains, and is implicated in DNA repair. The mutations were located throughout its coding region. The average variant allelic frequency of BRCC3 mutations was 30.1%, and by a serial sample analysis at two different time points a BRCC3 mutation was already identified in the initial stage of a myelodysplastic syndrome. BRCC3 mutations commonly occurred in nonsense (n=12), frameshift (n=4), and splice site (n=5) configurations. Due to the marginal male dominance (odds ratio; 2.00, 0.84-4.73) of BRCC3 mutations, the majority of mutations (n=23; 82%) were hemizygous. Phenotypically, BRCC3 mutations were frequently observed in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms and associated with -Y abnormality (odds ratio; 3.70, 1.25-11.0). Clinically, BRCC3 mutations were also related to higher age (p=0.01), although prognosis was not affected. Knock-down of Brcc3 gene expression in murine bone marrow lineage negative, Sca1 positive, c-kit positive cells resulted in 2-fold more colony formation and modest differentiation defect. Thus, BRCC3 likely plays a role as tumor-associated gene in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. Copyright © 2015, Ferrata Storti Foundation.
    Haematologica 05/2015; 100(8). DOI:10.3324/haematol.2014.111989 · 5.81 Impact Factor
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    ABSTRACT: PARK2 (PARKIN) is an E3 ubiquitin ligase whose dysfunction has been associated with the progression of Parkinsonism and human malignancies, and its role in cancer remains to be explored. In this study, we report that PARK2 is frequently deleted and underexpressed in human glioma, and low PARK2 expression is associated with poor survival. Restoration of PARK2 significantly inhibited glioma cell growth both in vitro and in vivo, whereas depletion of PARK2 promoted cell proliferation. PARK2 attenuated both Wnt- and EGF-stimulated pathways through downregulating the intracellular level of beta-catenin and EGFR. Notably, PARK2 physically interacted with both beta-catenin and EGFR. We further found that PARK2 promoted the ubiquitination of these two proteins in an E3 ligase activity-dependent manner. Finally, inspired by these newly identified tumor-suppressive functions of PARK2, we tested and proved that combination of small-molecule inhibitors targeting both Wnt-beta-catenin and EGFR-AKT pathways synergistically impaired glioma cell viability. Together, our findings uncover novel cancer-associated functions of PARK2 and provide a potential therapeutic approach to treat glioma. Cancer Res; 75(9); 1-13. (c)2015 AACR.
    Cancer Research 04/2015; DOI:10.1158/0008-5472.CAN-14-1433 · 9.33 Impact Factor
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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 03/2015; DOI:10.1002/path.4482 · 7.43 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 02/2015; 230(2). DOI:10.1002/jcp.24729 · 3.84 Impact Factor
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    ABSTRACT: We utilized three tiers of screening to identify novel therapeutic agents for pancreatic cancers. First, we analyzed 14 pancreatic cancer cell lines against a panel of 66 small-molecule kinase inhibitors and dasatinib was the most potent. Second, we performed RNA expression analysis on 3 dasatinib-resistant and 3 dasatinib?sensitive pancreatic cancer cell lines to profile their gene expression. Third, gene profiling data was integrated with the connectivity map database to search for potential drugs. Thioridazine was one of the top ranking small molecules with highly negative enrichment. Thioridazine and its family members of phenothiazine including penfludidol caused pancreatic cancer cell death and affected protein expression levels of molecules involved in cell cycle regulation, apoptosis, and multiple kinase activities. This family of drugs causes activation of protein phosphatase 2 (PP2A). The drug FTY-720 (activator of PP2A) induced apoptosis of pancreatic cancer cells. Silencing catalytic unit of PP2A rendered pancreatic cancer cells resistant to penfluridol. Our observations suggest potential therapeutic use of penfluridol or similar agent associated with activation of PP2A in pancreatic cancers.
    Molecular Oncology 01/2015; DOI:10.1016/j.molonc.2015.01.002 · 5.33 Impact Factor
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    ABSTRACT: Somatic mutations in the spliceosome gene ZRSR2-located on the X chromosome-are associated with myelodysplastic syndrome (MDS). ZRSR2 is involved in the recognition of 3'-splice site during the early stages of spliceosome assembly; however, its precise role in RNA splicing has remained unclear. Here we characterize ZRSR2 as an essential component of the minor spliceosome (U12 dependent) assembly. shRNA-mediated knockdown of ZRSR2 leads to impaired splicing of the U12-type introns and RNA-sequencing of MDS bone marrow reveals that loss of ZRSR2 activity causes increased mis-splicing. These splicing defects involve retention of the U12-type introns, while splicing of the U2-type introns remain mostly unaffected. ZRSR2-deficient cells also exhibit reduced proliferation potential and distinct alterations in myeloid and erythroid differentiation in vitro. These data identify a specific role for ZRSR2 in RNA splicing and highlight dysregulated splicing of U12-type introns as a characteristic feature of ZRSR2 mutations in MDS.
    Nature Communications 01/2015; 6:6042. DOI:10.1038/ncomms7042 · 11.47 Impact Factor
  • Heyun Zhang · Wenbin Li · Pinbo Huang · Lehang Lin · Hua Ye · Dechen Lin · H Phillip Koeffler · Jie Wang · Dong Yin ·
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    ABSTRACT: Studies have reported that the CCN family of proteins plays an important role in stimulating tumorigenesis. However, the relationship between the CCN protein family members and the features of hepatocellular carcinoma (HCC) remains unclear. The objective of this study was to determine the relationship between the expression levels of CCN protein family members and the features of HCC. Expression levels of the CCN family of proteins in 80-paired primary HCC samples and 11 normal liver samples were determined by a quantitative real-time PCR assay. Enhanced expression of nephroblastoma overexpressed protein (NOV) and decreased expression of Wnt-induced secreted protein 1 (WISP1), cysteine-rich protein 61 (CYR61) and connective tissue growth factor (CTGF) were found in HCC samples when compared to levels in matched non-cancerous tissues. No significant difference in WISP2 was found between matched-pair samples; only a few samples showed WISP3 expression. Furthermore, the expression levels of NOV, WISP1 and CYR61 were closely correlated with certain clinical features, including venous invasion, cellular differentiation, pTNM stage, disease-free survival and overall survival. Our results suggest that HCC progression may be enhanced by NOV and suppressed by WISP1 and CYR61. Our statistical analysis suggests that these proteins may be valuable in determining the prognosis of this deadly disease and directs attention to modulating the levels of these proteins as a potential mode of therapy.
    Oncology Reports 01/2015; 33(3). DOI:10.3892/or.2015.3709 · 2.30 Impact Factor
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    Makoto Sudo · Seiichi Mori · Vikas Madan · Henry Yang · Geraldine Leong · H Phillip Koeffler ·
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    ABSTRACT: Somatic mutations of the epidermal growth factor receptor often cause resistance to therapy with tyrosine kinase inhibitor in non-small cell lung cancer (NSCLC). In this study, we aimed to identify partner drugs and pathways that can induce cell death in combination with gefitinib in NSCLC cells. We undertook a genome-wide RNAi screen to identify synthetic lethality with gefitinib in tyrosine kinase inhibitor resistant cells. The screening data were utilized in different approaches. Firstly, we identified PRKCSH as a candidate gene, silencing of which induces apoptosis of NSCLC cells treated with gefitinib. Next, in an in silico gene signature pathway analysis of shRNA library data, a strong correlation of genes involved in the CD27 signaling cascade was observed. We showed that the combination of dasatinib (NF-κB pathway inhibitor) with gefitinib synergistically inhibited the growth of NSCLC cells. Lastly, utilizing the Connectivity Map, thioridazine was identified as a top pharmaceutical perturbagen. In our experiments, it synergized with gefitinib to reduce p-Akt levels and to induce apoptosis in NSCLC cells. Taken together, a pooled short-hairpin library screen identified several potential pathways and drugs that can be therapeutic targets for gefitinib resistant NSCLC.
    Oncotarget 11/2014; 6(2). DOI:10.18632/oncotarget.2891 · 6.36 Impact Factor

Publication Stats

38k Citations
5,599.06 Total Impact Points

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  • 1991-2015
    • Cedars-Sinai Medical Center
      • • Cedars Sinai Medical Center
      • • Division of Hematology and Oncology
      • • Department of Medicine
      Los Ángeles, California, United States
  • 1980-2015
    • University of California, Los Angeles
      • • Division of Hematology and Medical Oncology
      • • Department of Medicine
      Los Ángeles, California, United States
  • 2014
    • National University of Singapore
      Tumasik, Singapore
    • National University (California)
      San Diego, California, United States
  • 2013
    • The University of Tokyo
      白山, Tōkyō, Japan
  • 1977-2013
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      • Department of Medicine
      Torrance, California, United States
  • 2012
    • National University Health System
    • Universitätsklinikum Münster
      Muenster, North Rhine-Westphalia, Germany
  • 2009-2011
    • Kochi University
      • Department of Hematology and Respiratory Medicine
      Kôti, Kōchi, Japan
    • Mayo Clinic - Rochester
      Рочестер, Minnesota, United States
  • 2005
    • IT University of Copenhagen
      København, Capital Region, Denmark
    • Kanazawa Medical University
      • Department of Hematology and Immunology
      Kanazawa, Ishikawa, Japan
  • 2004
    • Vanderbilt University
      • Department of Biochemistry
      Nashville, Michigan, United States
    • Institut Pasteur
      Lutetia Parisorum, Île-de-France, France
  • 1991-2004
    • Kochi Medical School
      Kôti, Kōchi, Japan
  • 2003
    • Kagawa University
      • Faculty of Medicine
      Takamatsu-shi, Kagawa-ken, Japan
    • Goethe-Universität Frankfurt am Main
      • Center for Internal Medicine
      Frankfurt, Hesse, Germany
  • 2000-2003
    • University of Münster
      • Department of Medicine, Hematology and Oncology
      Münster, North Rhine-Westphalia, Germany
  • 2002
    • Academia Sinica
      • Institute of Molecular Biology
      T’ai-pei, Taipei, Taiwan
    • Seoul National University Hospital
      • Department of Internal Medicine
      Seoul, Seoul, South Korea
  • 2001
    • Shinshu University
      • Department of Pediatrics
      Shonai, Nagano, Japan
  • 1999
    • Keck School of Medicine USC
      Los Angeles, California, United States
    • Hiroshima University
      • Medical Research Institute for Bio Functions
      Hiroshima-shi, Hiroshima-ken, Japan
  • 1998
    • University of Texas MD Anderson Cancer Center
      Houston, Texas, United States
  • 1997
    • Truman Medical Center
      Kansas City, Kansas, United States
  • 1995-1997
    • City of Hope National Medical Center
      Дуарте, California, United States
    • Nippon Medical School
      • Nippon Medical School Hospital
      Edo, Tōkyō, Japan
    • Memorial Sloan-Kettering Cancer Center
      New York, New York, United States
  • 1981-1997
    • Fred Hutchinson Cancer Research Center
      Seattle, Washington, United States
  • 1996
    • California State University
      • Department of Medicine
      Long Beach, California, United States
  • 1987-1990
    • University of California, Riverside
      • Department of Biochemistry
      Riverside, CA, United States
    • Emory University
      • Department of Pharmacology
      Atlanta, Georgia, United States
  • 1989
    • Baylor College of Medicine
      Houston, Texas, United States
  • 1988-1989
    • National Defense Medical College
      • Department of Internal Medicine
      Tokorozawa, Saitama, Japan
  • 1985-1989
    • Harbor-UCLA Medical Center
      Torrance, California, United States
  • 1986
    • CSU Mentor
      • Department of Medicine
      Long Beach, California, United States