Timothy C Kennedy

University of Colorado, Denver, CO, United States

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Publications (36)131.34 Total impact

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    ABSTRACT: Lung cancers express lower levels of prostacyclin than normal lung tissues. Prostacyclin prevents lung cancer in a variety of mouse models. A randomized phase II trial comparing oral iloprost (a prostacyclin analogue) to placebo in high-risk subjects demonstrated improvement in bronchial histology in former, but not current, smokers. This placebo-controlled study offered the opportunity for investigation of other potential intermediate endpoint and predictive biomarkers to incorporate into chemoprevention trials. Matched bronchial biopsies were obtained at baseline (BL) and at 6 months follow-up (FU) from 125 high-risk individuals who completed the trial: 31/29 and 37/28 current/former smokers in the iloprost and placebo arm, respectively. We analyzed the expression of 14 selected miRNAs by qRT-PCR in 496 biopsies. The expression of seven miRNAs was significantly correlated with histology at BL. The expression of miR-34c was inversely correlated with histology at BL (p<0.0001) and with change in histology at FU (p=0.0003), independent of treatment or smoking status. Several miRNAs were also found to be differentially expressed in current smokers as compared with former smokers. In current smokers, miR-375 was up-regulated at BL (p<0.0001) and down-regulated after treatment with iloprost (p=0.0023). No miRNA at baseline reliably predicted a response to iloprost. No biomarker predictive of response to iloprost was found. MiR-34c was inversely correlated with BL histology and with histology changes. Mir-34c changes at FU could be used as a quantitative biomarker which parallels histologic response in formalin-fixed bronchial biopsies in future lung cancer chemoprevention studies.
    Cancer Prevention Research 12/2012; · 4.89 Impact Factor
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    ABSTRACT: INTRODUCTION:: The search for non-invasive diagnostic methods of lung cancer (LC) has led to new avenues of research, including the exploration of the exhaled breath. Previous studies have shown that LC can, in principle, be detected through exhaled-breath analysis. This study evaluated the potential of exhaled-breath analysis for the distinction of benign and malignant pulmonary nodules (PNs). METHODS:: Breath samples were taken from 72 patients with PNs in a prospective trial. Profiles of volatile organic compounds were determined by (1) gas chromatography/mass spectrometry (GC-MS) combined with solid-phase microextraction and (2) a chemical nanoarray. RESULTS:: Fifty-three PNs were malignant and 19 were benign with similar smoking histories and comorbidities. Nodule size (mean ± SD) was 2.7 ± 1.7 versus 1.6 ± 1.3 cm (p = 0.004), respectively. Within the malignant group, 47 were non-small-cell lung cancer and six were small-cell lung cancer. Thirty patients had early-stage disease and 23 had advanced disease. Gas chromatography/mass spectrometry analysis identified a significantly higher concentration of 1-octene in the breath of LC, and the nanoarray distinguished significantly between benign versus malignant PNs (p < 0.0001; accuracy 88 ± 3%), between adeno- and squamous-cell carcinomas [LINE SEPARATOR](p < 0.0001; 88 ± 3%) and between early stage and advanced disease (p < 0.0001; 88 ± 2%). CONCLUSIONS:: In this pilot study, breath analysis discriminated benign from malignant PNs in a high-risk cohort based on LC-related volatile organic compound profiles. Furthermore, it discriminated adeno- and squamous-cell carcinoma and between early versus advanced disease. Further studies are required to validate this noninvasive approach, using a larger cohort of patients with PNs detected by computed tomography.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 08/2012; 7(10):1528-1533. · 4.55 Impact Factor
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    ABSTRACT: To evaluate the methylation state of 31 genes in sputum as biomarkers in an expanded nested, case-control study from the Colorado cohort, and to assess the replication of results from the most promising genes in an independent case-control study of asymptomatic patients with stage I lung cancer from New Mexico. Cases and controls from Colorado and New Mexico were interrogated for methylation of up to 31 genes using nested, methylation-specific PCR. Individual genes and methylation indices were used to assess the association between methylation and lung cancer with logistic regression modeling. Seventeen genes with ORs of 1.4 to 3.6 were identified and selected for replication in the New Mexico study. Overall, the direction of effects seen in New Mexico was similar to Colorado with the largest increase in case discrimination (ORs, 3.2-4.2) seen for the PAX5α, GATA5, and SULF2 genes. Receiver operating characteristic (ROC) curves generated from seven-gene panels from Colorado and New Mexico studies showed prediction accuracy of 71% and 77%, respectively. A 22-fold increase in lung cancer risk was seen for a subset of New Mexico cases with five or more genes methylated. Sequence variants associated with lung cancer did not improve the accuracy of this gene methylation panel. These studies have identified and replicated a panel of methylated genes whose integration with other promising biomarkers could initially identify the highest risk smokers for computed tomographic screening for early detection of lung cancer.
    Clinical Cancer Research 04/2012; 18(12):3387-95. · 7.84 Impact Factor
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    ABSTRACT: There are no established chemopreventive agents for lung cancer, the leading cause of cancer death in the United States. Prostacyclin levels are low in lung cancer and supplementation prevents lung cancer in preclinical models. We carried out a multicenter double-blind, randomized, phase II placebo-controlled trial of oral iloprost in current or former smokers with sputum cytologic atypia or endobronchial dysplasia. Bronchoscopy was performed at study entry and after completion of six months of therapy. Within each subject, the results were calculated by using the average score of all biopsies (Avg), the worst biopsy score (Max), and the dysplasia index (DI). Change in Avg was the primary end point, evaluated in all subjects, as well as in current and former smokers. The accrual goal of 152 subjects was reached and 125 completed both bronchoscopies (60/75 iloprost, 65/77 placebo). Treatment groups were well matched for age, tobacco exposure, and baseline histology. Baseline histology was significantly worse for current smokers (Avg 3.0) than former smokers (Avg 2.1). When compared with placebo, former smokers receiving oral iloprost exhibited a significantly greater improvement in Avg (0.41 units better, P = 0.010), in Max (1.10 units better, P = 0.002), and in DI (12.45%, P = 0.006). No histologic improvement occurred in current smokers. Oral iloprost significantly improves endobronchial histology in former smokers and deserves further study to determine if it can prevent the development of lung cancer.
    Cancer Prevention Research 06/2011; 4(6):793-802. · 4.89 Impact Factor
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    ABSTRACT: Lung cancer usually is disseminated (advanced) and has a poor prognosis at diagnosis. Current and former smokers are at a high risk for lung cancer and are candidates for prevention and early detection strategies. Sputum is a potential source of biomarkers that might determine either lung cancer risk or the presence of early lung cancer, but no current sputum test is sufficiently sensitive and specific for effective screening. We used fluorescence in situ hybridization (FISH) to measure chromosomal aneusomy (CA) in sputum samples collected prospectively from 100 incident lung cancer cases and 96 controls (matched on age, gender, and date of collection) nested within an ongoing high-risk cohort. The CA-FISH assay was aimed at four DNA targets: epidermal growth factor receptor, MYC, 5p15, and CEP 6. The sensitivity of a positive CA-FISH assay (abnormal for two or more of the four markers) for lung cancer was substantially higher for samples collected within 18 months (76% sensitivity) than for samples collected more than 18 months (31%) before lung cancer diagnosis. Sensitivity was higher for squamous cell cancers (94%) than for other histologic types (69%). CA-FISH specificity based on samples collected within 18 months before diagnosis was 88%. The adjusted odds ratio (OR) of lung cancer for specimens collected within 18 months before a cancer diagnosis was higher for the CA-FISH assay [OR, 29.9; 95% confidence interval (95% CI), 9.5-94.1] than for previously studied ORs of cytologic atypia (OR, 1.8; 95% CI, 1.3-2.6) and gene promoter methylation (OR, 6.5; 95% CI, 1.2-35.5). Whether CA-FISH is an indicator of extreme risk for incident lung cancer or detects exfoliated cancer cells is unknown. The apparent promise of CA-FISH in sputum for assessing lung cancer risk and/or for lung cancer early detection now needs to be validated in a clinical screening trial.
    Cancer Prevention Research 03/2010; 3(4):447-53. · 4.89 Impact Factor
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    ABSTRACT: No chemoprevention strategies have been proven effective for lung cancer. We evaluated the effect of 13-cis retinoic acid (13-cis RA), with or without alpha tocopherol, as a lung cancer chemoprevention agent in a phase II randomized controlled clinical trial of adult subjects at high risk for lung cancer as defined by the presence of sputum atypia, history of smoking, and airflow obstruction, or a prior surgically cured nonsmall cell lung cancer (disease free, >3 years). Subjects were randomly assigned to receive either 13-cis RA, 13-cis RA plus alpha tocopherol (13-cis RA/alpha toco) or observation for 12 months. Outcome measures are derived from histologic evaluation of bronchial biopsy specimens obtained by bronchoscopy at baseline and follow-up. The primary outcome measure is treatment "failure" defined as histologic progression (any increase in the maximum histologic score) or failure to return for follow-up bronchoscopy. Seventy-five subjects were randomized (27/22/26 to observations/13-cis RA/13-cis RA/alpha toco); 59 completed the trial; 55 had both baseline and follow-up bronchoscopy. The risk of treatment failure was 55.6% (15 of 27) and 50% (24 of 48) in the observation and combined (13 cis RA plus 13 cis RA/alpha toco) treatment arms, respectively (odds ratio adjusted for baseline histology, 0.97; 95% confidence interval, 0.36-2.66; P = 0.95). Among subjects with complete histology data, maximum histology score in the observation arm increased by 0.37 units and by 0.03 units in the treated arms (difference adjusted for baseline, -0.18; 95% confidence interval, -1.16 to 0.81; P = 0.72). Similar (nonsignificant) results were observed for treatment effects on endobronchial proliferation as assessed by Ki-67 immunolabeling. Twelve-month treatment with 13-cis RA produced nonsignificant changes in bronchial histology, consistent with results in other trials. Agents advancing to phase III randomized trials should produce greater histologic changes. The addition of alpha tocopherol did not affect toxicity.
    Cancer Prevention Research 04/2009; 2(5):440-9. · 4.89 Impact Factor
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    ABSTRACT: The primary objective of this study was to evaluate the benefit of using a new fluorescence-reflectance imaging system, Onco-LIFE, for the detection and localization of intraepitheal neoplasia and early invasive squamous cell carcinoma. A secondary objective was to evaluate the potential use of quantitative image analysis with this device for objective classification of abnormal sites. This study was a prospective, multicenter, comparative, single arm trial. Subjects for this study were aged 45 to 75 years and either current or past smokers of more than 20 pack-years with airflow obstruction, forced expiratory volume in 1 second/forced vital capacity less than 75%, suspected to have lung cancer based on either sputum atypia, abnormal chest roentgenogram/chest computed tomography, or patients with previous curatively treated lung or head and neck cancer within 2 years. The primary endpoint of the study was to determine the relative sensitivity of white light bronchoscopy (WLB) plus autofluorescence-reflectance bronchoscopy compared with WLB alone. Bronchoscopy with Onco-LIFE was carried out in two stages. The first stage was performed under white light and mucosal lesions were visually classified. Mucosal lesions were classified using the same scheme in the second stage when viewed with Onco-LIFE in the fluorescence-reflectance mode. All regions classified as suspicious for moderate dysplasia or worse were biopsied, plus at least one nonsuspicious region for control. Specimens were evaluated by the site pathologist and then sent to a reference pathologist, each blinded to the endoscopic findings. Positive lesions were defined as those with moderate/severe dysplasia, carcinoma in situ (CIS), or invasive carcinoma. A positive patient was defined as having at least one lesion of moderate/severe dysplasia, CIS, or invasive carcinoma. Onco-LIFE was also used to quantify the fluorescence-reflectance response (based on the proportion of reflected red light to green fluorescence) for each suspected lesion before biopsy. There were 115 men and 55 women with median age of 62 years. Seven hundred seventy-six biopsy specimens were included. Seventy-six were classified as positive (moderate dysplasia or worse) by pathology. The relative sensitivity on a per-lesion basis of WLB + FLB versus WLB was 1.50 (95% confidence interval [CI], 1.26-1.89). The relative sensitivity on a per-patient basis was 1.33 (95% CI, 1.13-1.70). The relative sensitivity to detect intraepithelial neoplasia (moderate/severe dysplasia or CIS) was 4.29 (95% CI, 2.00-16.00) and 3.50 (95% CI, 1.63-12.00) on a per-lesion and per-patient basis, respectively. For a quantified fluorescence reflectance response value of more than or equal to 0.40, a sensitivity and specificity of 51% and 80%, respectively, could be achieved for detection of moderate/severe dsyplasia, CIS, and microinvasive cancer. Using autofluorescence-reflectance bronchoscopy as an adjunct to WLB with the Onco-LIFE system improves the detection and localization of intraepitheal neoplasia and invasive carcinoma compared with WLB alone. The use of quantitative image analysis to minimize interobserver variation in grading of abnormal sites should be explored further in future prospective clinical trial.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 02/2009; 4(1):49-54. · 4.55 Impact Factor
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    ABSTRACT: The development of lung cancer (LC) is accompanied by field changes in the airway mucosa that may have prognostic importance. To compare patients with prevalent LC to control subjects regarding their histologic dysplasia scores and chromosomal aneusomy as measured by fluorescence in situ hybridization (FISH). The most advanced bronchial histology lesion was assessed from each of 44 LC cases and 90 cancer-free control subjects using a four-color FISH probe set encompassing the chromosome 6 centromere, 5p15.2, 7p12 (epidermal growth factor receptor), and 8q24 v-myc myelocytomatosis viral oncogene homolog (MYC) sequences. Histology grades were coded as dysplasia (moderate or severe) or carcinoma in situ (CIS). CIS was the highest histologic grade for 32 subjects, and dysplasia was the highest grade for 102 subjects (54 moderate, 48 severe). Chromosomal aneusomy was seen in 64% of the LC cases, but in only 31% of the control subjects (odds ratio [OR], 4.68; 95% confidence interval [CI]. 1.97-11.04). Among those with any level of dysplasia, the OR for positive FISH and LC was 2.28 (95% CI, 0.75-6.86). Among those with CIS, the OR for positive FISH and LC was 5.84 (95% CI, 1.31-26.01). Chromosomal aneusomy is associated with LC. Prospective examination of aneusomy as a precursor lesion that predicts LC is needed.
    American Journal of Respiratory and Critical Care Medicine 03/2008; 177(3):342-7. · 11.04 Impact Factor
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    ABSTRACT: There is a need for early detection methods for lung cancer. Radiologic imaging may be more sensitive for peripheral cancers than for cancers arising in the central airways, from which bronchial epithelial cells are exfoliated into the sputum. Sputum samples were collected at baseline and periodically thereafter in a cohort of smokers and former smokers with chronic obstructive lung disease. The association between cytologic atypia and incident lung cancer was assessed by hazard ratios (HR; 95% confidence intervals) using Cox regression and by odds ratios (95% confidence intervals) using logistic regression, adjusting for potential confounding factors. We observed 174 incident lung cancers in a cohort of 2,521 people over 9,869 person-years of observation. Risk for incident lung cancer was increased among those with cytologic atypia graded as moderate or worse (adjusted HR, 2.37; 1.68-3.34). The association between sputum atypia and lung cancer incidence was greatest for those sputum samples collected 5 months or less before the diagnosis of lung cancer (odds ratio, 10.32; 5.34-19.97). The association was substantially stronger for squamous cell lung cancers (HR, 5.13; 2.89-9.10) than for adenocarcinomas (HR, 1.85; 0.94-3.65). Cytologic atypia is a marker for increased lung cancer risk. These cytologic changes seem to arise from late events that are most apparent for cancers arising in the central respiratory airways. Whether cytologic atypia might complement radiologic imaging in a combined approach to lung cancer, early detection requires additional evaluation of those two methods used together.
    Cancer Epidemiology Biomarkers &amp Prevention 02/2008; 17(1):158-62. · 4.56 Impact Factor
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    ABSTRACT: To determine whether increased bronchial epithelial proliferation is associated with histology, smoking status, gender, age, chronic obstructive pulmonary disease (COPD), or lung cancer. Cross-sectional study of 113 subjects undergoing white light and autofluorescence bronchoscopy: 27 never smokers; 27 current or ex-smokers with normal spirometry; 31 current or ex-smokers with COPD; and 28 current, ex-, or never smokers with lung cancer. Ki-67 expression was determined by immunohistochemistry on all evaluable biopsy sites without carcinoma. Relationships between Ki-67 index (percentage of epithelial cells expressing Ki-67), demographic variables, smoking, histology, and the presence of COPD and/or lung cancer were determined. Results for both maximal and mean Ki-67 index are similar, so only the former are reported. Average maximal Ki-67 index was higher in current smokers than either ex-smokers or never smokers (48.0% versus 30.6% versus 22.6%; P<0.001). Males had higher Ki-67 index than females (39.9% versus 23.6%; P<0.001). Compared with subjects without disease (Ki-67 index=30.0%), maximal Ki-67 index was not significantly elevated (P=0.44) in subjects with either lung cancer (Ki-67=39.1%) or COPD (Ki-67=38.9%). Smoking status, bronchial histology, and gender were significantly associated with Ki-67 index. No increase in Ki-67 index was found in the nonmalignant epithelium of patients with lung cancer or COPD. Although Ki-67 index may provide insight into the short-term effects of chemoprevention agents on cell proliferation, its lack of association with lung cancer or COPD raises question regarding its utility as a lung cancer risk biomarker.
    Cancer Epidemiology Biomarkers &amp Prevention 11/2007; 16(11):2425-31. · 4.56 Impact Factor
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    ABSTRACT: Lung cancer is a multistep process that is preceded and often accompanied by molecular cytogenetic lesions in benign bronchial epithelium, the precise character, extent and timing of which are not well defined. In this study we comprehensively defined molecular cytogenetic changes in bronchial cells that may precede lung carcinoma using spectral karyotyping (SKY). SKY was applied to cultured benign bronchial cells from 43 high-risk smokers without carcinoma, 14 patients with concurrent lung carcinoma, and 14 never-smoker healthy volunteers. The proportion of cells displaying numeric or structural anomalies/total number of metaphase cells was calculated for each case and was referred to as the chromosomal abnormality index. Mean chromosomal abnormality indices were 15.8, 10.1, and 0.7% for patients with cancer, high-risk smokers, and never-smokers, respectively. Clonal abnormalities were found in 17 (40%) of the high-risk smokers without carcinoma and 7 (50%) of the patients with carcinoma, but in none of 14 (0%) never-smokers. Chromosomal gains observed by SKY were confirmed in interphase cultured cells or paraffin sections of biopsy specimens by fluorescence in situ hybridization in 11 of 13 cases for which appropriate probes were available. In 6 of 57 high-risk patients or those with carcinoma, identical clonal abnormalities were dispersed at multiple bronchial sites and were admixed with nonclonal cells. Clonal and single-cell chromosomal abnormalities are frequent in benign bronchial epithelium during lung carcinogenesis, indicating that chromosomal missegregation and other chromosomal rearrangements occur before overt malignancy.
    American Journal of Respiratory and Critical Care Medicine 10/2007; 176(5):505-12. · 11.04 Impact Factor
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    ABSTRACT: An evidence-based approach is necessary for the localization and management of intraepithelial and microinvasive non-small cell lung cancer in the central airways. Material appropriate to this topic was obtained by literature search of a computerized database. Recommendations were developed by the writing committee and then reviewed by the entire guidelines panel. The final recommendations were made by the Chair and were voted on by the entire committee. White light bronchoscopy has diagnostic limitations in the detection of microinvasive lesions. Autofluorescence bronchoscopy (AFB) is a technique that has been shown to be a sensitive method for detecting these lesions. In patients with moderate dysplasia or worse on sputum cytology and normal chest radiographic findings, bronchoscopy should be performed. If moderate/severe dysplasia or carcinoma in situ (CIS) is detected in the central airways, then bronchoscopic surveillance is recommended. The use of AFB is preferred if available. In a patient being considered for curative endobronchial therapy to treat microinvasive lesions, AFB is useful. A number of endobronchial techniques as therapeutic options are available for the management of CIS and can be recommended to patients with inoperable disease. In patients with operable disease, surgery remains the mainstay of treatment, although patients may be counseled about these techniques. AFB is a useful tool for the localization of microinvasive neoplasia. A number of endobronchial techniques available for the curative treatment can be considered first-line therapy in inoperable cases. For operable cases, the techniques may be considered and discussed with the patients.
    Chest 10/2007; 132(3 Suppl):221S-233S. · 5.85 Impact Factor
  • Journal of Thoracic Oncology - J THORAC ONCOL. 01/2007; 2.
  • Journal of Thoracic Oncology - J THORAC ONCOL. 01/2007; 2.
  • Journal of Thoracic Oncology - J THORAC ONCOL. 01/2007; 2.
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    ABSTRACT: Lung cancer is preceded by a premalignant phase during which intervention could decrease associated morbidity and mortality. Molecular characterization of factors involved in controlling progression of bronchial dysplasias will provide markers of premalignant change and identify targets for chemoprevention. Immunohistochemical analysis of epidermal growth factor receptor (EGFR; c-ErbB1/EGFR), HER-2/neu (c-ErbB2/HER-2), Ki-67, and minichromosome maintenance protein 2 (MCM2) expression in bronchial dysplasia was undertaken to characterize molecular alterations associated with the progression of these lesions in 268 bronchoscopically obtained biopsies from 134 subjects. Analysis of biopsies with the most severe diagnosis from each subject showed a linear relationship between increasing marker expression and severity of dysplastic change for EGFR (P < 0.001), Ki-67 (P < 0.001), and MCM2 (P = 0.001) but not HER-2 (P = 0.102). Increased expression of either EGFR or HER-2 was associated with increased levels of Ki-67 and MCM2 expression, and combined overexpression of these receptors was associated with the highest levels of proliferation, suggesting a synergistic effect. Finally, the lack of an associated trend toward increased EGFR expression when comparing the worst and best biopsies within each subject indicated a potential field effect in the induction of EGFR expression. The results suggest a prominent role for EGFR overexpression in the development and progression of bronchial dysplasia and provide rationale for exploring inhibition of EGFR signaling in lung cancer chemoprevention.
    Clinical Cancer Research 04/2006; 12(7 Pt 1):2281-8. · 7.84 Impact Factor
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    ABSTRACT: Early stage radiographically occult lung cancer has a high cure rate, but comprises a small fraction of all lung cancer. Abnormal sputum cytology is one indication for bronchoscopy in patients with chest imaging that is not suspicious for lung cancer. While there is good evidence that sputum cytologic findings of carcinoma, carcinoma in situ or severe atypia predict high rates of diagnosis of lung cancer, less is known of the frequency in which lung cancer is diagnosed in bronchoscopies carried out for the indication of moderate sputum atypia. One small series, published in abstract form only, reported an 8% rate of diagnosis of lung cancer in subjects bronchoscoped for moderate atypia. We tested the hypothesis that moderate sputum atypia is an indicator of occult central airway cancer in a retrospective analysis of a group of high risk subjects, defined as current or former smokers with >30 pack-years tobacco smoking and airflow obstruction with moderate atypia sputum cytology. Seventy-nine such subjects with no evidence of malignancy on chest radiograph at the time bronchoscopy was scheduled underwent white light and autofluorescence bronchoscopy. Lung cancer was found in five subjects; three had invasive squamous cell carcinomas and two had carcinoma in situ. Seven additional subjects had severe dysplasia found on endobronchial biopsy. Moderate sputum atypia may be an important marker of risk for occult endobronchial malignancy in high risk subjects.
    Lung Cancer 08/2005; 49(2):187-91. · 3.39 Impact Factor
  • Lung Cancer. 01/2005; 49.
  • Lung Cancer. 01/2005; 49.
  • Lung Cancer. 01/2005; 49.

Publication Stats

762 Citations
131.34 Total Impact Points

Institutions

  • 2006–2012
    • University of Colorado
      • • Division of Medical Oncology
      • • Division of Pulmonary Sciences and Critical Care Medicine
      • • Department of Pathology
      Denver, CO, United States
  • 2007
    • Indiana University-Purdue University Indianapolis
      Indianapolis, Indiana, United States
  • 2004
    • National Cancer Institute (USA)
      Maryland, United States