Peng Huang

Sun Yat-Sen University Cancer Center, Shengcheng, Guangdong, China

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Publications (115)846.2 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Oncogenic activation of the K-ras gene occurs in >90% of pancreatic ductal carcinoma and plays a critical role in the pathogenesis of this malignancy. Increase of reactive oxygen species (ROS) has also been observed in a wide spectrum of cancers. This study aimed to investigate the mechanistic association between K-ras-induced transformation and increased ROS stress and its therapeutic implications in pancreatic cancer. ROS level, NADPH oxidase (NOX) activity and expression, and cell invasion were examined in human pancreatic duct epithelial E6E7 cells transfected with K-ras (G12V) compared with parental E6E7 cells. The cytotoxic effect and antitumor effect of capsaicin, a NOX inhibitor, were also tested in vitro and in vivo. K-ras transfection caused activation of the membrane-associated redox enzyme NOX and elevated ROS generation through the phosphatidylinositol 3'-kinase (PI3K) pathway. Importantly, capsaicin preferentially inhibited the enzyme activity of NOX and induced severe ROS accumulation in K-ras-transformed cells compared with parental E6E7 cells. Furthermore, capsaicin effectively inhibited cell proliferation, prevented invasiveness of K-ras-transformed pancreatic cancer cells, and caused minimum toxicity to parental E6E7 cells. In vivo, capsaicin exhibited antitumor activity against pancreatic cancer and showed oxidative damage to the xenograft tumor cells. K-ras oncogenic signaling causes increased ROS stress through NOX, and abnormal ROS stress can selectively kill tumor cells by using NOX inhibitors. Our study provides a basis for developing a novel therapeutic strategy to effectively kill K-ras-transformed cells through a redox-mediated mechanism.
    Chinese journal of cancer 12/2015; 34(1). DOI:10.1186/s40880-015-0012-z
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    ABSTRACT: The oncogenic K-Ras can transform various mammalian cells and plays a critical role in development of pancreatic cancer. MicroRNAs (miRNA) have been shown to contribute to tumorigenic progression. However, the nature of miRNAs involved in K-Ras transformation remains to be investigated. Here, by using microarray we identified miR-155 as the most upregulated miRNA after both acute and prolonged activation of K-Ras in a doxycyline-inducible system. Pharmacological inhibition of MAPK and NF-κB pathway blocked the induction of miR-155 in response to K-Ras activation. Overexpression of miR-155 caused inhibition of Foxo3a, leading to decrease of major antioxidants including SOD2 and catalase, and enhanced pancreatic cell proliferation induced by ROS generation. Importantly, correlations of K-Ras, miR-155 and Foxo3a were also validated in human pancreatic cancer tissues. Therefore, we propose that miR-155 plays an important role in oncogenic K-Ras transformation mediated by cellular redox regulation.
    Oncotarget 05/2015; · 6.63 Impact Factor
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    ABSTRACT: Increase in aerobic glycolysis and mitochondrial dysfunction are important biochemical features observed in human cancers. Recent studies suggest oncogenic K-Ras can cause suppression of mitochondrial respiration and up-regulation of glycolytic activity through a yet unknown mechanism. Here we employed proteomic approach and used a K-RasG12V inducible cell system to investigate the impact of oncogenic K-Ras on mitochondria and cell metabolism. Mitochondria isolated from cells before and after K-Ras induction were subjected to protein analysis using stable isotope labeling with amino acids (SILAC) and liquid chromatography coupled with mass spectrometry (LC-MS). 70 mitochondrial proteins with significant expression alteration after K-Ras induction were identified. A majority of these proteins were involved in energy metabolism. Five proteins with significant decrease belong to mitochondrial respiratory chain complex I. NADH dehydrogenase 1 alpha subcomplex assembly factor 1 (NDUFAF1) showed most significant decrease by 50%. Such decrease was validated in primary human pancreatic cancer tissues. Knockdown of NDUFAF1 by siRNA caused mitochondrial respiration deficiency, accumulation of NADH and subsequent increase of glycolytic activity. Our study revealed that oncogenic K-Ras is able to induce significant alterations in mitochondrial protein expression, and identified NDUFAF1 as an important molecule whose low expression contributes to mitochondrial dysfunction induced by K-Ras.
    Oncotarget 01/2015; · 6.63 Impact Factor
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    ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) frequently develops therapeutic resistances, which can be divided into extrinsic and intrinsic resistance. The extrinsic resistance that arises from the surrounding dense tumor stromal is much better understood. However, the mechanisms of intrinsic resistance are not well understood. Here we report that ROS induced by gemcitabine treatment, a newly discovered cytotoxic activity, served as a probe in our study to reveal the mechanisms of the intrinsic therapeutic resistance. Our results showed that gemcitabine-induced ROS is generated by NOX and through the increase of p22-phox expression via NF-κB activation. As a feedback mechanism, nuclear translocation of Nrf2 stimulated the transcription of cytoprotective antioxidant genes, especially genes encoding enzymes that catalyze glutathione production to reduce elevated ROS as an intrinsic resistance counter measure. RNA interference-mediated depletion of Nrf2 or addition of b-phenylethyl isothiocyanate inhibited the ROS detoxification process by reducing glutathione levels; which, in turn, increased the efficacy of gemcitabine in vitro and in vivo. Thus, our study suggests that a redox-mediated pathway contributes to the intrinsic resistance of PDAC to gemcitabine and provides a basis for developing strategies to preferentially kill PDAC cells through ROS-mediated mechanism. The combination of gemcitabine and PEITC has a selective cytotoxic effect against pancreatic cancer cells in vivo and could thus prove valuable as a cancer treatment. Copyright © 2014, American Association for Cancer Research.
    Molecular Cancer Therapeutics 12/2014; 14(3). DOI:10.1158/1535-7163.MCT-14-0420 · 6.11 Impact Factor
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    ABSTRACT: Santacruzamate A, a recently discovered natural product from a Panamanian marine cyanobacterium Symploca sp., features a similar structure to the clinically used histone deacetylase (HDAC) inhibitor vorinostat (SAHA). We have synthesized the natural product and a small set of analogues for SAR studies. To our surprise, the synthetic natural product santacruzamate A (1a) and the analogues did not show an obvious inhibition even at 2 μM in HDAC enzyme assays while the IC50 value was 0.12 nM in the original report. However, a novel compound, 5, containing a terminal thiourea motif was found to inhibit the growth of malignant cells at submicromolar concentrations. Moreover, 5 was not cytotoxic to normal human colonic epithelial cells CCD841, suggesting that its cytotoxicity was specific to cancer cells. Further investigation indicated that the compound induced apoptosis, affected cell cycle progression and increased ROS production. We believe its mechanism of action is unrelated to HDAC inhibition and the original activity reported for santacruzamate needs to be reevaluated.
    RSC Advances 12/2014; 5(2). DOI:10.1039/C4RA13889A · 3.71 Impact Factor
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    ABSTRACT: Palladium(ii)-catalyzed dual C-H functionalization of indoles with cyclic diaryliodoniums was successfully achieved, providing a concise method to synthesize dibenzocarbazoles. In a single operation, two C-C bonds and one ring were formed. The reaction was ligand free and tolerated air and moisture conditions.
    Organic & Biomolecular Chemistry 10/2014; 12(48). DOI:10.1039/c4ob02170c · 3.49 Impact Factor
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    ABSTRACT: Linear iodoniums are widely used as arylating reagents. However, cyclic diaryl idodoniums are ignored despite their potential to initiate dual arylations, atom and step economically. In our current work, a three-component cascade reaction of cyclic diaryliodoniums, sodium azide, and alkynes has been successfully achieved under mild conditions, catalyzed by cheap copper species. The regioselectivity associated with unsymmetrical iodoniums was enhanced by installing two methyls ortho and para to the I(III) center. The reaction enables a rapid access to a variety of complex molecules, triazolophenanthridine derivatives.
    Organic Letters 10/2014; 16(21). DOI:10.1021/ol502654a · 6.32 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):LB-58-LB-58. DOI:10.1158/1538-7445.AM2014-LB-58 · 9.28 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):806-806. DOI:10.1158/1538-7445.AM2014-806 · 9.28 Impact Factor
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    ABSTRACT: IntroductionTriple-negative breast cancer (TNBC) is a subtype of highly malignant breast cancer with poor prognosis. TNBC is not amenable to endocrine therapy and often exhibit resistance to current chemotherapeutic agents, therefore, further understanding of the biological properties of these cancer cells and development of effective therapeutic approaches are urgently needed.Methods We first investigated the metabolic alterations in TNBC cells in comparison with other subtypes of breast cancer cells using molecular and metabolic analyses. We further demonstrated that targeting these alterations using specific inhibitors and siRNA approach could render TNBC cells more sensitive to cell death compared to other breast cancer subtypes.ResultsWe found that TNBC cells compared to estrogen receptor (ER) positive cells possess special metabolic characteristics manifested by high glucose uptake, increased lactate production, and low mitochondrial respiration which is correlated with attenuation of mTOR pathway and decreased expression of p70S6K. Re-expression of p70S6K in TNBC cells reverses their glycolytic phenotype to an active oxidative phosphorylation (OXPHOS) state, while knockdown of p70S6K in ER positive cells leads to suppression of mitochondrial OXPHOS. Furthermore, lower OXPHOS activity in TNBC cells renders them highly dependent on glycolysis and the inhibition of glycolysis is highly effective in targeting TNBC cells despite their resistance to other anticancer agents.Conclusions Our study shows that TNBC cells have profound metabolic alterations characterized by decreased mitochondrial respiration and increased glycolysis. Due to their impaired mitochondrial function, TNBC cells are highly sensitive to glycolytic inhibition, suggesting that such metabolic intervention may be an effective therapeutic strategy for this subtype of breast cancer cells.
    Breast cancer research: BCR 09/2014; 16(5):434. DOI:10.1186/s13058-014-0434-6 · 5.88 Impact Factor
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    ABSTRACT: Activation of K-ras and inactivation of p16 are the most frequently identified genetic alterations in human pancreatic epithelial adenocarcinoma (PDAC). Mouse models engineered with mutant K-ras and deleted p16 recapitulate key pathological features of PDAC. However, a human cell culture transformation model that recapitulates the human pancreatic molecular carcinogenesis is lacking. In this study, we investigated the role of p16 in hTERT-immortalized human pancreatic epithelial nestin-expressing (HPNE) cells expressing mutant K-ras (K-rasG12V). We found that expression of p16 was induced by oncogenic K-ras in these HPNE cells and that silencing of this induced p16 expression resulted in tumorigenic transformation and development of metastatic PDAC in an orthotopic xenograft mouse model. Our results revealed that PI3K/Akt, ERK1/2 pathways and TGFα signaling were activated by K-ras and involved in the malignant transformation of human pancreatic cells. Also, p38/MAPK pathway was involved in p16 up-regulation. Thus, our findings establish an experimental cell-based model for dissecting signaling pathways in the development of human PDAC. This model provides an important tool for studying the molecular basis of PDAC development and gaining insight into signaling mechanisms and potential new therapeutic targets for altered oncogenic signaling pathways in PDAC.
    PLoS ONE 07/2014; 9(7):e101452. DOI:10.1371/journal.pone.0101452 · 3.53 Impact Factor
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    ABSTRACT: Linear diaryliodonium salts are widely used as arylating reagents for C-C and C-X bond formation. Meanwhile, synthetic applications of cyclic iodoniums are relatively rare although they offer the opportunity to set up reaction cascades. We demonstrate an atom and step economical three-component reaction involving cyclic diphenyleneiodoniums, alkynes, and boronic acids, resulting in the construction of methylidenefluorenes in a single operation. Our route enables facile access to both symmetrical and unsymmetrical methylidenefluorene derivatives, compounds that have attracted interest due to their optical properties.
    Organic Letters 04/2014; 16(9). DOI:10.1021/ol5006714 · 6.32 Impact Factor
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    ABSTRACT: The purpose of this study is to identify miRNAs involved in the pathology of colorectal cancer (CRC) liver metastasis and investigate their underlying mechanisms. A total of 39 miRNAs were identified to be differentially expressed between 16 primary CRC tissues with liver metastases and 16 CRC tissues without liver metastases from 32 patients by Affymetric miRNA microarrays. A panel of 8 miRNAs were confirmed to be significantly and differentially expressed between CRC tissues with and without liver metastases through quantitative RT-PCR analysis in the 32 patients. In a validated cohort of 99 CRC patients (44 with and 55 without liver metastases), only miR-214 was validated to be significantly down-regulated in CRC with liver metastases, which was associated with an unfavorable prognosis. Ectopic expression of miR-214 suppressed proliferation, migration, and invasion in vitro, tumor growth and liver metastasis in an in vivo xenograft mouse model; whereas miR-214 knockdown promoted proliferation, migration, and invasion in CRC cell lines. Further studies indicated that fibroblast growth factor receptor 1 (FGFR1) was a potential target of miR-214. Restoring miR-214 expression in CRC cells decreased endogenous FGFR1 mRNA and protein levels. FGFR1 knockdown mimicked the tumor suppressive effect of miR-214 on CRC cells, while reintroduction of FGFR1 abolished the tumor suppressive effect of miR-214 on CRC cells. Moreover, miR-214 expression levels were inversely correlated with FGFR1 in CRC patients. Conclusion: Down-regulation of miR-214 expression was correlated with increased FGFR1 expression levels, which may contribute to increased CRC liver metastasis. miR-214 may serve as a potential marker to predict survival, and the miR-214-FGFR1 axis may be a therapeutic target in CRC patients. (Hepatology 2014;).
    Hepatology 03/2014; 60(2). DOI:10.1002/hep.27118 · 11.19 Impact Factor
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    ABSTRACT: Chronic lymphocytic leukemia (CLL) exhibits high remission rates after initial chemo-immunotherapy, but relapses to treatment-refractory disease is the most common outcome, especially in CLL with the deletion of chromosome 11q or 17p. In addressing the need of treatments for relapsed disease, we report the identification of an existing FDA-approved small molecule drug to repurpose for CLL treatment. Auranofin (AF) (Ridaura®) is approved for use in treating rheumatoid arthritis but it exhibited preclinical efficacy in CLL cells. By inhibiting thioredoxin reductase activity and increasing intracellular ROS levels, AF induced a lethal endoplasmic reticulum stress response in cultured and primary CLL cells. Additionally, AF displayed synergistic lethality with heme oxygenase-1 and glutamate-cysteine ligase inhibitors against CLL cells. AF overcame apoptosis resistance mediated by protective stromal cells, and it also killed primary CLL cells with deletion of chromosome 11q or 17p. In TCL-1 transgenic mice, an in vivo model of CLL, AF treatment markedly reduced tumor cell burden and improved mouse survival. Our results provide a rationale to reposition the approved drug Auranofin for clinical evaluation in the therapy of CLL.
    Cancer Research 03/2014; 74(9). DOI:10.1158/0008-5472.CAN-13-2033 · 9.28 Impact Factor
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    ABSTRACT: Solid tumors often become hypoxic, leading to activation of hypoxia-response genes. We investigated the effects of overexpression of the hypoxia response genes eIF5A2 in esophageal squamous cell carcinoma (ESCC). We used quantitative real-time PCR and immunohistochemistry analyses to compare expression of eIF5A2 between paired ESCC samples and non-tumor esophageal tissues, and fluorescence in situ hybridization to detect gene copy number alterations. Luciferase reporter and chromatin immunoprecipitation assays were used to study interactions between eIF5A2 and HIF1α. We determined the effects of eIF5A2 overexpression and knockdown in ESCC cell lines, and growth of ESCC xenograft tumors in nude mice. Levels of eIF5A2 mRNA and protein were increased in over 40% of ESCC samples, compared with matched non-tumor tissues, along with levels of HIF1α and VEGF. Increased levels of EIF5A2 were significantly associated with ESCC metastasis to lymph nodes (P<.001) and tissue invasion (P=.037), and shorter survival times of patients (P<.001). Amplification of eIF5A2 was detected in 35.14% of ESCC samples that overexpressed eIF5A2. Hypoxia increased expression of eIF5A2 4- to 8-fold in ESCC cell lines; we observed bidirectional regulation between eIF5A2 and HIF1α. Transient transfection of ESCC cell lines with eIF5A2 increased their migratory and invasive abilities and markers of the epithelial to mesenchymal transition, whereas eIF5A2 knockdown or HIF1α inhibition reduced these. In mice, xenograft tumors grown from ESCC cells that expressed eIF5A2 formed tumors more rapidly than cells that expressed only vector (controls); they also expressed higher levels of HIF1α and VEGF, and formed more microvessels than controls. Knockdown of eIF5A2 in ESCC cells with interfering RNAs reduced their growth as xenograft tumors in mice, particularly when mice were given docetaxel or cisplatin. eIF5A2 is overexpressed by gene amplification or hypoxia in ESCCs, and associated with upregulation of HIF1α, metastasis, and shorter survival times of patients. Increased expression of eIF5A2 increases matastasis and angiogenesis in ESCC via the HIF1α-mediated signaling pathway.
    Gastroenterology 02/2014; 146(7). DOI:10.1053/j.gastro.2014.02.029 · 13.93 Impact Factor
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    ABSTRACT: Carbazoles have attracted high interest among synthetic chemists due to their unique structural features and potential pharmacological activities. Compared to linear aryliodoniums, cyclic diphenyleneiodoniums are more inert and have not attracted much attention to their application as building blocks. Employing our synthetic strategy, diversified carbazoles can be efficiently obtained from a single cyclic diphenyleneiodonium under mild conditions. The reactions catalyzed by copper(II) acetate have provided a variety of carbazoles in modest to good yields with a broad range of amines including anilines, aliphatic amines and sulfonamides. Moreover, one of the obtained carbazoles has displayed an outstanding ability to protect HT-22 neuronal cells from the damage induced by neurotoxins glutamate and homocysteic acid.
    ChemInform 01/2014; 45(4). DOI:10.1002/chin.201404124
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    ABSTRACT: N-Acyl-N,O-acetals are present in a number of bioactive natural products, and this unusual functional group can act as a synthetic precursor to unstable reactive N-acylimines. In this paper, a variety of N-acyl-O-ethyl-N,O-acetals was concisely prepared under mild conditions mediated by titanium ethoxide (Ti(OEt)(4)). The method also offers a new strategy to make other O-alkyl-N,O-acetals. Furthermore, this strategy was extended to the synthesis of an analogue of the natural product turtschamide.
    Organic Letters 12/2013; 16(1). DOI:10.1021/ol4031155 · 6.32 Impact Factor
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    ABSTRACT: The circadian clock gene Bmal1 is involved in cancer cell proliferation and DNA damage sensitivity. The aim of this study was to explore the effect of Bmal1 on oxaliplatin sensitivity and to determine its clinical significance in colorectal cancer (CRC). Three CRC cell lines, HCT116, THC8307 and HT29, were used. The Bmal1-mediated control of CRC cell proliferation was tested in vitro and in vivo. MTT and colony formation assays were performed to determine the sensitivity of CRC cells to oxaliplatin. Flow cytometry was used to examine changes in the cell cycle distribution and apoptosis rate. Proteins expressed downstream of Bmal1 upon its overexpression were determined by Western blotting. Immunohistochemistry was used to analyze Bmal1 expression in 82 archived CRC tumors from patients treated with oxaliplatin-based regimens. Bmal1 overexpression inhibited CRC cell proliferation and increased CRC sensitivity to oxaliplatin in three CRC cell lines and HCT116 cells model in vivo. Furthermore, the overall survival of CRC patients with high Bmal1 levels in their primary tumors was significantly longer than that of patients with low Bmal1 levels (27 vs. 19 months; p=0.043). The progression free survival of patients with high Bmal1 expression was also significantly longer than that of patients with low Bmal1 expression (11 vs. 5 months; p=0.015). Mechanistically, the effect of Bmal1 was associated with its ability to regulate G2/M arrest by activating the ATM pathway. Bmal1 shows the potential as a novel prognostic biomarker and may represent a new therapeutic target in CRC.
    Clinical Cancer Research 11/2013; 20(4). DOI:10.1158/1078-0432.CCR-13-0171 · 8.19 Impact Factor
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    ABSTRACT: Elevated aerobic glycolysis in cancer cells (Warburg effect) has been observed in many tumor types including nasopharyngeal carcinoma (NPC), which can often be detected clinically using FDG-PET. However, the role of glycolysis in supporting the growth of NPC cells and its therapeutic implications still remain to be investigated. In the present study, we showed that the LDH inhibitor oxamate significantly suppressed NPC cell proliferation in vitro and tumor growth in vivo, yet exhibited minimum toxicity to normal nasopharyngeal epithelial cells in vitro and was well tolerated in mice. Moreover, oxamate exhibited cytotoxic effect in NPC cells under hypoxia. Mechanistic study showed that oxamate significantly inhibited LDH activity, leading to a substantial decrease in glucose uptake and lactate production. Combination of oxamate with a mitochondrial respiratory complex I inhibitor resulted in a significant depletion of cellular ATP and a synergistic killing of cancer cells. Our results suggest that inhibition of glycolysis by oxamate is an effective therapeutic strategy for treatment of NPC and that combination of this compound with mitochondrial-targeted agents may improve the therapeutic activity.
    International Journal of Oncology 08/2013; 43(5). DOI:10.3892/ijo.2013.2080 · 3.03 Impact Factor
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    ABSTRACT: Carbazole moiety is an important scaffold with a variety of biological applications, for example, anti-oxidative stress. Our previous synthesized carbazoles were screened for their neuroprotective properties against two individual oxidative stresses. Some of the new carbazole derivatives were observed with modest to good neuroprotective effects on neuronal cells HT22 against cell injury induced by glutamate or homocysteic acid (HCA). Substituents introduced to the carbazole ring system play crucial roles in their biological activities. In particular, a bulky group favors the neuroprotective activity of the compounds. One of the new compounds, 6, showed the best neuroprotective effects, which might result from its anti-oxidative activity with a GSH-independent mechanism. These findings might provide an alternative strategy for the development of novel carbazole derivatives for the treatment of CNS diseases such as Alzheimer's disease.
    European Journal of Medicinal Chemistry 08/2013; 68C:81-88. DOI:10.1016/j.ejmech.2013.07.029 · 3.43 Impact Factor

Publication Stats

8k Citations
846.20 Total Impact Points


  • 2012–2015
    • Sun Yat-Sen University Cancer Center
      Shengcheng, Guangdong, China
  • 2014
    • Sun Yat-Sen University of Medical Sciences
      • Cancer Institute
      Shengcheng, Guangdong, China
  • 2013–2014
    • Sun Yat-Sen University
      Shengcheng, Guangdong, China
  • 1995–2014
    • University of Texas MD Anderson Cancer Center
      • • Department of Molecular Pathology
      • • Department of Pathology
      • • Department of Experimental Therapeutics
      • • Department of Clinical Investigations
      Houston, Texas, United States
  • 2008
    • University of Texas Health Science Center at San Antonio
      • Cancer Therapy & Research Center
      San Antonio, TX, United States
  • 2002–2008
    • University of Houston
      Houston, Texas, United States
  • 2005
    • University of Iowa
      Iowa City, Iowa, United States
  • 2003
    • University of Texas Health Science Center at Houston
      • Graduate School of Biomedical Sciences
      Houston, Texas, United States