Ronald A Lubet

National Cancer Institute (USA), 베서스다, Maryland, United States

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Publications (435)2146.2 Total impact

  • Cancer Research 08/2015; 75(15 Supplement):896-896. DOI:10.1158/1538-7445.AM2015-896 · 9.28 Impact Factor
  • Cancer Research 05/2015; 75(9 Supplement):P5-11-01-P5-11-01. DOI:10.1158/1538-7445.SABCS14-P5-11-01 · 9.28 Impact Factor
  • AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA; 04/2015
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    ABSTRACT: The COX inhibitors (NSAID/Coxibs) are a major focus for the chemoprevention of cancer. The COX-2-specific inhibitors have progressed to clinical trials and have shown preventive efficacy in colon and skin cancers. However, they have significant adverse cardiovascular effects. Certain NSAIDs (e.g., naproxen) have a good cardiac profile, but can cause gastric toxicity. The present study examined protocols to reduce this toxicity of naproxen. Female Fischer-344 rats were treated weekly with the urinary bladder-specific carcinogen hydroxybutyl(butyl)nitrosamine (OH-BBN) for 8 weeks. Rats were dosed daily with NPX (40 mg/kg body weight/day, gavage) or with the proton pump inhibitor omeprazole (4.0 mg/kg body weight/day) either singly or in combination beginning 2 weeks after the final OH-BBN. OH-BBN-treated rats, 96% developed urinary bladder cancers. While omeprazole alone was ineffective (97% cancers), naproxen alone or combined with omeprazole-prevented cancers, yielding 27 and 35% cancers, respectively. In a separate study, OH-BBN -: treated rats were administered naproxen: (A) daily, (B) 1 week daily naproxen/1week vehicle, (C) 3 weeks daily naproxen/3 week vehicle, or (D) daily vehicle beginning 2 weeks after last OH-BBN treatment. In the intermittent dosing study, protocol A, B, C, and D resulted in palpable cancers in 27%, 22%, 19%, and 96% of rats (P < 0.01). Short-term naproxen treatment increased apoptosis, but did not alter proliferation in the urinary bladder cancers. Two different protocols that should decrease the gastric toxicity of NSAIDs in humans did not alter chemopreventive efficacy. This should encourage the use of NSAIDs (e.g., naproxen) in clinical prevention trials. Cancer Prev Res; 1-7. ©2015 AACR. ©2015 American Association for Cancer Research.
    Cancer Prevention Research 03/2015; 8(4). DOI:10.1158/1940-6207.CAPR-14-0347 · 5.27 Impact Factor
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    ABSTRACT: Epidemiologic studies have shown that diabetics receiving the biguanide metformin, as compared with sulfonylureas or insulin, have a lower incidence of breast cancer. Metformin increases levels of activated AMPK (AMP-activated protein kinase) and decreases circulating IGF-1; encouraging its potential use in both cancer prevention and therapeutic settings. In anticipation of clinical trials in nondiabetic women, the efficacy of metformin in nondiabetic rat and mouse mammary cancer models was evaluated. Metformin was administered by gavage or in the diet, at a human equivalent dose, in standard mammary cancer models: (i) methylnitrosourea (MNU)-induced estrogen receptor-positive (ER(+)) mammary cancers in rats, and (ii) MMTV-Neu/p53KO ER(-) (estrogen receptor-negative) mammary cancers in mice. In the MNU rat model, metformin dosing (150 or 50 mg/kg BW/d, by gavage) was ineffective in decreasing mammary cancer multiplicity, latency, or weight. Pharmacokinetic studies of metformin (150 mg/kg BW/d, by gavage) yielded plasma levels (Cmax and AUC) higher than humans taking 1.5 g/d. In rats bearing small palpable mammary cancers, short-term metformin (150 mg/kg BW/d) treatment increased levels of phospho-AMPK and phospho-p53 (Ser20), but failed to reduce Ki67 labeling or expression of proliferation-related genes. In the mouse model, dietary metformin (1,500 mg/kg diet) did not alter final cancer incidence, multiplicity, or weight. Metformin did not prevent mammary carcinogenesis in two mammary cancer models, raising questions about metformin efficacy in breast cancer in nondiabetic populations. Cancer Prev Res; 1-9. ©2014 AACR. ©2014 American Association for Cancer Research.
    Cancer Prevention Research 02/2015; 8(3). DOI:10.1158/1940-6207.CAPR-14-0181-T · 5.27 Impact Factor
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    ABSTRACT: 3-Bromopyruvate (3-BrPA) is an alkylating agent and a well-known inhibitor of energy metabolism. Rapamycin is an inhibitor of the Serine/Threonine protein kinase "mammalian target of rapamycin (mTOR). Both 3-BrPA and rapamycin show chemopreventive efficacy in mouse models of lung cancer. Aerosol delivery of therapeutic drugs for lung cancer has been reported to be an effective route of delivery with little systemic distribution in humans. In this study, 3-BrPA and rapamycin were evaluated in combination for their preventive effects against lung cancer in mice by aerosol treatment, revealing a synergistic ability as measured by tumor multiplicity and tumor load compared treatment with either single agent alone. No evidence of liver toxicity was detected by monitoring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzymes. To understand the mechanism in vitro experiments were performed using human non-small cell lung cancer (NSCLC) cell lines. 3-Bromopyruvate and rapamycin also synergistically inhibited cell proliferation. Rapamycin alone blocked the mTOR signaling pathway, whereas 3- bromopyruvate did not potentiate this effect. Given the known role of 3-BrPA as an inhibitor of glycolysis, we investigated mitochondrial bioenergetics changes in vitro in 3-BrPA treated NSCLC cells. 3-BrPA significantly decreased glycolytic activity, which may be due to adenosine triphosphate (ATP) depletion and decreased expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Our results demonstrate that rapamycin enhanced the antitumor efficacy of 3-bromopyruvate, and that dual inhibition of mTOR signaling and glycolysis may be an effective therapeutic strategy for lung cancer chemoprevention. Copyright © 2015, American Association for Cancer Research.
    Cancer Prevention Research 02/2015; 8(4). DOI:10.1158/1940-6207.CAPR-14-0142 · 5.27 Impact Factor
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    ABSTRACT: The ability of the retinoid X receptors (RXRs) specific agonists (targretin [TRG] and UAB30) to alter rat liver gene and protein expression was determined using Affymetrix Exon arrays and high-performance liquid chromatography – tandem mass spectrometry (LC-MS/MS). TRG profoundly increases triglycerides levels while UAB30 does not. The expression patterns of transcripts or proteins from rat liver treated with TRG or UAB-30 were different from controls and each other. There were six times more gene transcripts identified than proteins. Differentially expressed RNAs or proteins were mapped into known gene ontology (GO) categories and GeneGo Metacore (KEGG) pathway maps. The GO categories which were highly overrepresented with differentially expressed RNAs (P < 10−16) were also overrepresented at the protein level. This high concordance of GO Terms was achieved despite the fact that typically ≤1/3 of the elements identified by gene expression were identified by proteomics. Within these GO categories, the magnitude of alterations induced by RXR agonists at the transcript and protein levels were correlated. When GO categories with moderate overrepresentation (10−5 < P < 10−9) were examined, there was greater discordance between the transcript and protein data. Examination of KEGG pathway maps with highly significant changes at both the protein and the RNA levels showed that the individual proteins/genes altered were often the same and changes were of similar magnitude; while KEGG pathways showed limited statistical significance and exhibited minimal overlap. Finally, metabolomics analysis of liver and serum identified altered expression of metabolites related to fatty acid oxidation and bile acid metabolism that were consistent with transcript/protein changes. We observed significant concordance between genomics and proteomics implying either can identify pathways modulated and can indirectly predict resulting physiologic effects.
    12/2014; 2(6). DOI:10.1002/prp2.74
  • European Journal of Cancer 11/2014; 50. DOI:10.1016/S0959-8049(14)70351-X · 4.82 Impact Factor
  • European Journal of Cancer 11/2014; 50. DOI:10.1016/S0959-8049(14)70348-X · 4.82 Impact Factor
  • V. E. Steele · C. Grubbs · C. V. Rao · R.A. Lubet
    European Journal of Cancer 11/2014; 50. DOI:10.1016/S0959-8049(14)70352-1 · 4.82 Impact Factor
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    ABSTRACT: 9-cis-UAB30 (UAB30) and Targretin are well-known retinoid X receptor (RXR) agonists. They were highly effective in decreasing the incidence of methylnitrosourea (MNU)-induced mammary cancers. However, whether the anti-mammary cancer effects of UAB30 or Targretin originate from the activation of RXR is unclear. In the present study, we hypothesized that UAB30 and Targretin not only affect RXR, but likely influence one or more off-target proteins. Virtual screening results suggest that Src is a potential target for UAB30 and Targretin that regulates extracellular matrix (ECM) molecules and cell motility and invasiveness. In vitro kinase assay data revealed that UAB30 or Targretin interacted with Src and attenuated its kinase activity. We found that UAB30 or Targretin substantially inhibited invasiveness and migration of MCF-7 and SK-BR-3 human breast cancer cells. We examined the effects of UAB30 and Targretin on the expression of matrix metalloproteinases (MMP)-9, which are known to play an essential role in tumor invasion. We show that activity and expression of MMP-9 were decreased by UAB30 or Targretin. Western blot data showed that UAB30 or Targretin decreased AKT and its substrate molecule p70s6k, which are downstream of Src in MCF-7 and SK-BR-3 cells. Moreover, knocking down the expression of Src effectively reduced the sensitivity of SK-BR-3 cells to the inhibitory effects of UAB30 and Targretin on invasiveness. Taken together, our results demonstrate that UAB30 and Targretin each inhibit invasion and migration by targeting Src in human breast cancer cells. © 2014 Wiley Periodicals, Inc.
    Molecular Carcinogenesis 10/2014; DOI:10.1002/mc.22232 · 4.77 Impact Factor
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    ABSTRACT: Honokiol is an important bioactive compound found in the bark of Magnolia tree. It is a non-adipogenic PPARγ agonist, and capable of inhibiting the growth of a variety of tumor types both in vitro and in xenograft models. However, to fully appreciate the potential chemopreventive activity of honokiol, a less artificial model system is required. To that end, this study examined the chemopreventive efficacy of honokiol in an initiation model of squamous cell lung cancer (SCC). This model system uses the carcinogen N-nitroso-trischloroethylurea (NTCU) which is applied topically, reliably triggering the development of SCC within 24-26 weeks. Administration of honokiol significantly reduced the percentage of bronchial that exhibit abnormal lung SCC histology from 24.4% bronchial in control to 11.0% bronchial in honokiol treated group (p= 0.01) while protecting normal bronchial histology (present in 20.5% of bronchial in control group and 38.5% of bronchial in honokiol treated group (p= 0.004)). P63 staining at the SCC site confirmed the lung SCCs phenotype. In vitro studies revealed that honokiol inhibited lung SCC cells proliferation, arrested cells at the G1/S cell cycle checkpoint, while also leading to increased apoptosis. Our study showed that interfering with mitochondrial respiration is a novel mechanism by which honokiol increased generation of reactive oxygen species (ROS) in the mitochondria, triggered apoptosis, and finally leads to the inhibition of lung SCC. This novel mechanism of targeting mitochondrial suggests honokiol as a potential lung SCC chemopreventive agent.
    Cancer Prevention Research 09/2014; 7(11). DOI:10.1158/1940-6207.CAPR-14-0091 · 5.27 Impact Factor
  • Qi Zhang · Jing Pan · Ronald A. Lubet · Yian Wang · Ming You
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    ABSTRACT: Insulin-like growth factor-1 receptor (IGF-1R) is a transmembrane heterotetramer that is activated by Insulin-like growth factor 1 and is crucial for tumor transformation and survival of malignant cells. Importantly, IGF-1R overexpression has been reported in many different cancers, implicating this receptor as a potential target for anticancer therapy. Picropodophyllin (PPP) is a potent inhibitor of IGF-1R and has antitumor efficacy in several cancer types. However, the chemopreventive effect of PPP in lung tumorigenesis has not been investigated. In this study, we investigated the chemopreventive activity of PPP in a mouse lung tumor model. Benzo(a)pyrene was used to induce lung tumors, and PPP was given by nasal inhalation to female A/J mice. Lung tumorigenesis was assessed by tumor multiplicity and tumor load. PPP significantly decreased tumor multiplicity and tumor load. Tumor multiplicity and load were decreased by 52% and 78% respectively by 4 mg/ml aerosolized PPP. Pharmacokinetics analysis showed good bioavailability of PPP in lung and plasma. Treatment with PPP increased staining for cleaved caspase-3 and decreased Ki-67 in lung tumors, suggesting that the lung tumor inhibitory effects of PPP were partially through inhibition of proliferation and induction of apoptosis. In human lung cancer cell lines, PPP inhibited cell proliferation, and also inhibited phosphorylation of IGF-1R downstream targets, AKT and MAPK, ultimately resulting in increased apoptosis. PPP also reduced cell invasion in lung cancer cell lines. In view of our data, PPP merits further investigation as a promising chemopreventive agent for human lung cancer. © 2014 Wiley Periodicals, Inc.
    Molecular Carcinogenesis 08/2014; 54(S1). DOI:10.1002/mc.22206 · 4.77 Impact Factor
  • Cancer Prevention Research 01/2014; 5(11_Supplement):B110-B110. DOI:10.1158/1940-6207.PREV-12-B110 · 5.27 Impact Factor
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    ABSTRACT: Green tea is a promising chemopreventive agent for lung cancer. Multiple signaling events have been reported, however, the relative importance of these mechanisms in mediating the chemopreventive function of green tea is unclear. In the present study, to examine the involvement of AP-1 in green tea polyphenols induced tumor inhibition, human NSCLC cell line H1299 and mouse SPON 10 cells were identified as AP-1 dependent, as these two lines exhibit high constitutive AP-1 activity, and when TAM67 expression was induced with doxycycline, cell growth was inhibited and correlated with suppressed AP-1 activity. RNA-seq was used to determine the global transcriptional effects of AP-1 inhibition and also uncover the possible involvement of AP-1 in tea polyphenols induced chemoprevention. TAM67 mediated changes in gene expression were identified, and within down-regulated genes, AP-1 was identified as a key transcription regulator. RNA-seq analysis revealed that Polyphenon E-treated cells shared 293 commonly down-regulated genes within TAM67 expressing H1299 cells, and by analysis of limited Chip-seq data, over 10% of the down-regulated genes contain a direct AP-1 binding site, indicating that Polyphenon E elicits chemopreventive activity by regulating AP-1 target genes. Conditional TAM67 expressing transgenic mice and NSCLC cell lines were used to further confirm that the chemopreventive activity of green tea is AP-1 dependent. Polyphenon E lost its chempreventive function both in vitro and in vivo when AP-1 was inhibited, indicating that AP-1 inhibition is a major pathway through which green tea exhibits chemopreventive effects. © 2013 Wiley Periodicals, Inc.
    Molecular Carcinogenesis 01/2014; 53(1):19-29. DOI:10.1002/mc.21941 · 4.77 Impact Factor
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    ABSTRACT: Urinary bladder cancer prevention studies were performed with the nonsteroidal anti-inflammatory drugs (NSAIDs) naproxen (standard NSAID with a good cardiovascular profile), sulindac, and their nitric oxide (NO) derivatives. Additionally, the effects of the ornithine decarboxylase inhibitor, difluoromethylornithine (DFMO), alone or combined with a suboptimal dose of naproxen or sulindac was examined. Agents were evaluated at their human equivalent doses (HEDs), as well as at lower doses. In the hydroxybutyl(butyl)nitrosamine (OH-BBN) model of urinary bladder cancer, naproxen (400 or 75 ppm) and sulindac (400 ppm) reduced the incidence of large bladder cancers by 82, 68 and 44%, respectively, when the agents were initially given 3 months after the final dose of the carcinogen; microscopic cancers already existed. NO-naproxen was highly effective, while NO-sulindac was inactive. To further compare naproxen and NO-naproxen, we examined their effects on gene expression in rat livers following a 7 day exposure. Limited, but similar, gene expression changes in the liver were induced by both agents, implying that the primary effects of both are mediated by the parent NSAID. When agents were initiated 2 weeks after the last administration of OH-BBN, DFMO at 1000 ppm had limited activity, a low dose of naproxen (75 ppm) and sulindac (150 ppm) were highly and marginally effective. Combining DFMO with suboptimal doses of naproxen had minimal effects whereas the combination of DMFO and sulindac was more active than either agent alone. Thus, naproxen and NO-naproxen were highly effective, while sulindac was moderately effective in the OH-BBN model at their HEDs.
    Cancer Prevention Research 12/2013; 7(2). DOI:10.1158/1940-6207.CAPR-13-0164 · 5.27 Impact Factor
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    ABSTRACT: Naproxen ((S)-6-methoxy-α-methyl-2-naphthaleneacetic acid) is a potent nonsteroidal anti-inflammatory drug that inhibits both COX-1 and COX-2 and is widely used as an over-the-counter medication. Naproxen exhibits analgesic, anti-pyretic, and anti-inflammatory activities. Naproxen, as well as other NSAIDS, has been reported to be effective in the prevention of urinary bladder cancer in rodents. However, potential targets other than the COX isozymes have not been reported. We examined potential additional targets in urinary bladder cancer cells and in rat bladder cancers. Computer kinase profiling results suggested that phosphatidylinositol 3-kinase (PI3-K) is a potential target for naproxen. In vitro kinase assay data revealed that naproxen interacts with PI3-K and inhibits its kinase activity. Pull-down binding assay data confirmed that PI3-K directly binds with naproxen in vitro and ex vivo. Western blot data showed that naproxen decreased phosphorylation of Akt, and subsequently decreased Akt signaling in UM-UC-5 and UMUC-14 urinary bladder cancer cells. Furthermore, naproxen suppressed anchorage-independent cell growth and decreased cell viability by targeting PI3-K in both cell lines. Naproxen caused an accumulation of cells at the G1 phase mediated through CDK4, cyclin D1 and p21. Moreover, naproxen induced significant apoptosis, accompanied with increased levels of cleaved caspase 3, caspase 7, and poly (ADP-ribose) polymerase (PARP) in both cell types. Naproxen-induced cell death was mainly due to apoptosis in which a prominent down-regulation of Bcl-2 and up-regulation of Bax were involved. Naproxen also caused apoptosis and inhibited Akt phosphorylation in rat urinary bladder cancers induced by N-butyl-N-(4-hydroxybutyl)-nitrosamine (OH-BBN).
    Cancer Prevention Research 12/2013; 7(2). DOI:10.1158/1940-6207.CAPR-13-0288 · 5.27 Impact Factor
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    ABSTRACT: Recent clinical trials raised concerns regarding the cardiovascular toxicity of selective cyclooxygenase-2 (COX-2) inhibitors and COX-1 is now being reconsidered as a target for chemoprevention. Our aims were to determine whether selective COX-1 inhibition could delay or prevent cancer development and also clarify the underlying mechanisms. Data clearly showed that COX-1 was required for maintenance of malignant characteristics of colon cancer cells or tumor promoter-induced transformation of pre-neoplastic cells. We also successfully applied a ligand docking computational method to identify a novel selective COX-1 inhibitor, 6-C-(E-phenylethenyl)-naringenin (designated herein as 6CEPN). 6CEPN could bind to COX-1 and specifically inhibited its activity both in vitro and ex vivo. In colorectal cancer cells, it potently suppressed anchorage-independent growth by inhibiting COX-1 activity. 6CEPN also effectively suppressed tumor growth in a 28-day colon cancer xenograft model without any obvious systemic toxicity. Taken together, COX-1 plays a critical role in human colorectal carcinogenesis, and this specific COX-1 inhibitor merits further investigation as a potential preventive agent against colorectal cancer.
    Cancer Research 11/2013; 74(1). DOI:10.1158/0008-5472.CAN-13-2245 · 9.28 Impact Factor
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    ABSTRACT: A multi-antigen multi-peptide vaccine, targeting proteins expressed in pre-invasive breast lesions, can stimulate Type I CD4+ T-cells which have been shown to be deficient in both breast cancer patients and mice that develop mammary tumors. Transgenic mice (TgMMTV-neu) were immunized with a multi-antigen peptide vaccine specific for neu, IGFBP-2 and IGF-IR at a time when some of the animals already had pre-invasive lesions (18 weeks of age). While immunization with each individual antigen was partially effective in inhibiting tumor growth, immunization with the multi-antigen vaccine was highly effective, blocking development of palpable lesions in 65% of mice and slowing tumor growth in the infrequent palpable tumors which did arise. Protection was mediated by CD4+ T-cells and the few slow-growing tumors that did develop demonstrated a significant increase in intratumoral CD8+ T-cells as compared to controls (p=0.0007). We also combined the vaccine with agents that were, by themselves, partially effective inhibitors of tumor progression in this model; lapatinib and the RXR agonist bexarotene. While the combination of lapatinib and vaccination performed similarly to vaccination alone (p=0.735), bexarotene and vaccination significantly enhanced disease free survival (p<0.0001) and approximately 90% of mice showed no pathologic evidence of carcinomas at 1 year. The vaccine also demonstrated significant clinical efficacy in an additional transgenic model of breast cancer (TgC3(I)-Tag). Chemo-immunoprevention combinations may be an effective approach to breast cancer prevention even when the vaccine is administered in the presence of subclinical disease.
    Cancer Prevention Research 10/2013; 6(12). DOI:10.1158/1940-6207.CAPR-13-0182 · 5.27 Impact Factor
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    ABSTRACT: Recent clinical trials raised concerns regarding the cardiovascular toxicity of selective cyclooxygenase-2 (COX-2) inhibitors. Many active dietary factors are reported to suppress carcinogenesis by targeting COX-2. A major question was accordingly raised: why has the lifelong use of phytochemicals that likely inhibit COX-2 presumably not been associated with adverse cardiovascular side effects. To answer this question, we selected a library of dietary-derived phytochemicals and evaluated their potential cardiovascular toxicity in human umbilical vein endothelial cells. Our data indicated that the possibility of cardiovascular toxicity of these dietary phytochemicals was low. Further mechanistic studies revealed that the actions of these phytochemicals were similar to aspirin in that they mainly inhibited COX-1 rather than COX-2, especially at low doses.
    PLoS ONE 10/2013; 8(10):e76452. DOI:10.1371/journal.pone.0076452 · 3.23 Impact Factor

Publication Stats

11k Citations
2,146.20 Total Impact Points

Institutions

  • 1990–2015
    • National Cancer Institute (USA)
      • • Division of Cancer Prevention
      • • Cancer Etiology Branch (CEB)
      베서스다, Maryland, United States
    • Johns Hopkins University
      • Department of Medicine
      Baltimore, Maryland, United States
  • 1992–2014
    • NCI-Frederick
      Фредерик, Maryland, United States
    • National Institute of Child Health and Human Development
      베서스다, Maryland, United States
  • 1993–2013
    • National Institutes of Health
      • • Group of Chemopreventive Agent Development Research
      • • Division of Cancer Prevention
      베서스다, Maryland, United States
  • 2012
    • University of Minnesota Duluth
      Duluth, Minnesota, United States
    • University of North Carolina at Chapel Hill
      • Department of Epidemiology
      North Carolina, United States
  • 2001–2007
    • University of Alabama at Birmingham
      • • Department of Surgery
      • • Department of Pathology
      Birmingham, Alabama, United States
  • 1995–2007
    • Medical University of Ohio at Toledo
      • Department of Biochemistry and Cancer Biology
      Toledo, Ohio, United States
  • 2004–2006
    • Washington University in St. Louis
      • Department of Surgery
      San Luis, Missouri, United States
  • 2004–2005
    • Università degli Studi di Genova
      • Dipartimento di Scienze della salute (DISSAL)
      Genova, Liguria, Italy
  • 2002
    • The Ohio State University
      • Division of Human Genetics
      Columbus, OH, United States
  • 2000–2001
    • University of Wisconsin–Madison
      Madison, Wisconsin, United States
    • Yale University
      • Department of Chemistry
      New Haven, Connecticut, United States
  • 1996–2000
    • University of Illinois at Chicago
      • • Department of Surgical Oncology (Chicago)
      • • Center for Pharmaceutical Biotechnology
      Chicago, Illinois, United States
  • 1998
    • National Eye Institute
      Maryland, United States
  • 1994
    • IIT Research Institute (IITRI)
      Chicago, Illinois, United States
  • 1991
    • Leidos Biomedical Research
      Фредерик, Maryland, United States
  • 1988
    • Argonne National Laboratory
      Lemont, Illinois, United States
  • 1979
    • University of Texas Health Science Center at Tyler
      Tyler, Texas, United States
  • 1971
    • The University of Tennessee Medical Center at Knoxville
      Knoxville, Tennessee, United States