David L Rimm

Yale-New Haven Hospital, New Haven, Connecticut, United States

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Publications (374)2682.69 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Archived tumor specimens, particularly those collected by large cooperative groups and trials, provide a wealth of material for post hoc clinical investigation. As these tissues are rigorously collected and preserved for many decades, subsequent use of the specimens to answer clinical questions must rely on the assumption that expression and detection of target biomarkers are not degraded with time. To test this assumption, we measured the expression of estrogen receptor (ER), human epidermal growth receptor 2 (HER2), and Ki67 in human breast carcinoma using quantitative immunofluorescence (QIF) in a series of formalin-fixed paraffin-embedded (FFPE) tissues from 1295 individual patients preserved for 7 to 53 years in four cohorts on tissue microarrays. Protein expression was measured using the automated quantitative analysis method for QIF. Change in quantitative protein expression over time was estimated in positive cases using both Pearson's correlation and a polynomial regression analysis with a random effects model. The average signal decreased with preservation time for all biomarkers measured. For ER and HER2, there was an average of 10% signal loss after 9.9 years and 8.5 years, respectively, compared with the most recent tissue. Detection of Ki67 expression was lost more rapidly, with 10% signal loss in just 4.5 years. Overall, these results demonstrate the need for adjustment of tissue age when studying FFPE biospecimens. The rate of antigenicity loss is biomarker specific and should be considered as an important variable for studies using archived tissues.Laboratory Investigation advance online publication, 16 November 2015; doi:10.1038/labinvest.2015.138.
    Laboratory Investigation 11/2015; DOI:10.1038/labinvest.2015.138 · 3.68 Impact Factor
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    ABSTRACT: IMPORTANCE Early-phase trials with monoclonal antibodies targeting PD-1 (programmed cell death protein 1) and PD-L1 (programmed cell death 1 ligand 1) have demonstrated durable clinical responses in patients with non–small-cell lung cancer (NSCLC). However, current assays for the prognostic and/or predictive role of tumor PD-L1 expression are not standardized with respect to either quantity or distribution of expression. OBJECTIVE To demonstrate PD-L1 protein distribution in NSCLC tumors using both conventional immunohistochemistry (IHC) and quantitative immunofluorescence (QIF) and compare results obtained using 2 different PD-L1 antibodies. DESIGN, SETTING, AND PARTICIPANTS PD-L1 was measured using E1L3N and SP142, 2 rabbit monoclonal antibodies, in 49 NSCLC whole-tissue sections and a corresponding tissue microarray with the same 49 cases. Non–small-cell lung cancer biopsy specimens from 2011 to 2012 were collected retrospectively from the Yale Thoracic Oncology Program Tissue Bank. Human melanoma Mel 624 cells stably transfected with PD-L1 as well as Mel 624 parental cells, and human term placenta whole tissue sections were used as controls and for antibody validation. PD-L1 protein expression in tumor and stroma was assessed using chromogenic IHC and the AQUA (Automated Quantitative Analysis) method of QIF. Tumor-infiltrating lymphocytes (TILs) were scored in hematoxylin-eosin slides using current consensus guidelines. The association between PD-L1 protein expression, TILs, and clinicopathological features were determined. MAIN OUTCOMES AND MEASURES PD-L1 expression discordance or heterogeneity using the diaminobenzidine chromogen and QIF was the main outcome measure selected prior to performing the study. RESULTS Using chromogenic IHC, both antibodies showed fair to poor concordance. The PD-L1 antibodies showed poor concordance (Cohen κ range, 0.124-0.340) using conventional chromogenic IHC and showed intra-assay heterogeneity (E1L3N coefficient of variation [CV], 6.75%-75.24%; SP142 CV, 12.17%-109.61%) and significant interassay discordance using QIF (26.6%). Quantitative immunofluorescence showed that PD-L1 expression using both PD-L1 antibodies was heterogeneous. Using QIF, the scores obtained with E1L3N and SP142 for each tumor were significantly different according to nonparametric paired test (P < .001). Assessment of 588 serial section fields of view from whole tissue showed discordant expression at a frequency of 25%. Expression of PD-L1 was correlated with high TILs using both E1L3N (P = .007) and SP142 (P = .02). CONCLUSIONS AND RELEVANCE Objective determination of PD-L1 protein levels in NSCLC reveals heterogeneity within tumors and prominent interassay variability or discordance. This could be due to different antibody affinities, limited specificity, or distinct target epitopes. Efforts to determine the clinical value of these observations are under way.
    11/2015; JAMA Oncol. doi:10.1001/jamaoncol.2015.3638. DOI:10.1001/jamaoncol.2015.3638

  • International journal of radiation oncology, biology, physics 11/2015; 93(3):S141. DOI:10.1016/j.ijrobp.2015.07.335 · 4.26 Impact Factor

  • Neuro-Oncology 11/2015; 17(suppl 5):v96-v96. DOI:10.1093/neuonc/nov215.21 · 5.56 Impact Factor

  • 11/2015; 3(Suppl 2):P415. DOI:10.1186/2051-1426-3-S2-P415
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    ABSTRACT: Purpose: Tumor-infiltrating lymphocytes (TILs) in the residual disease (RD) of triple-negative breast cancers (TNBCs) after neoadjuvant chemotherapy (NAC) are associated with improved survival, but insight into tumor cell-autonomous molecular pathways affecting these features are lacking. Experimental design: We analyzed TILs in the RD of clinically and molecularly characterized TNBCs after NAC and explored therapeutic strategies targeting combinations of MEK inhibitors with PD-1/PD-L1-targeted immunotherapy in mouse models of breast cancer. Results: Presence of TILs in the RD was significantly associated with improved prognosis. Genetic or transcriptomic alterations in Ras/MAPK signaling were significantly correlated with lower TILs. MEK inhibition up-regulated cell-surface major histocompatibility complex (MHC) expression and PD-L1 in TNBC cells both in vivo and in vitro. Moreover, combined MEK and PDL-1/PD-1 inhibition enhanced anti-tumor immune responses in mouse models of breast cancer. Conclusions: These data suggest the possibility that Ras/MAPK pathway activation promotes immune-evasion in TNBC, and support clinical trials combining MEK- and PD-L1-targeted therapies. Furthermore, Ras/MAPK activation and MHC expression may be predictive biomarkers of response to immune checkpoint inhibitors.
    Clinical Cancer Research 10/2015; DOI:10.1158/1078-0432.CCR-15-1125 · 8.72 Impact Factor
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    ABSTRACT: Purpose: Programmed death-ligand 1 (PD-L1; also known as CD274 or B7-H1), expression represents a mechanism of immune escape for cancer. Our purpose was to characterize tumor PD-L1 expression and associated T cell infiltration in primary laryngeal squamous cell carcinomas (SCC). Experimental design: A well annotated cohort of 260 operable primary laryngeal SCCs (formalin-fixed paraffin embedded [FFPE] specimens) was morphologically characterized for stromal tumor infiltrating lymphocytes (TILs), on hematoxylin/eosin-stained whole sections and for PD-L1 mRNA expression by qRT-PCR in formalin-fixed paraffin embedded (FFPE) specimens. For PD-L1 protein expression automated quantitative protein analysis (AQUA) was applied on tissue microarrays consisting of two cores from these tumors. In addition, PD-L1 mRNA expression in fresh frozen tumors and normal adjacent tissue specimens was assessed in a second independent cohort of 89 patients with primary laryngeal SCC. Results: PD-L1 mRNA levels were upregulated in tumors compared to surrounding normal tissue (p=0.009). TILs density correlated with tumor PD-L1 AQUA levels (p=0.021). Both high TILs density and high PD-L1 AQUA levels were significantly associated with superior disease-free survival (DFS) (TILs: p=0.009 and PD-L1: p=0.044) and overall survival (OS) (TILs: p=0.015 and PD-L1: p=0.059) of the patients and retained significance in multivariate analysis. Conclusions: Increased TILs density and PD-L1 levels are associated with better outcome in laryngeal squamous cell cancer. Assessment of TILs and PD-L1 expression could be useful to predict response to immune checkpoint inhibitors.
    Clinical Cancer Research 09/2015; DOI:10.1158/1078-0432.CCR-15-1543 · 8.72 Impact Factor
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    ABSTRACT: Copy number alterations have been shown to be involved in melanoma pathogenesis. The randomized, phase III clinical trial E2603: carboplatin, paclitaxel, +/- sorafenib (CP vs. CPS) offers a large collection of tumor samples to evaluate association of somatic mutations, genomic alterations, and clinical outcomes, prior to current FDA approved therapies. Copy number and mutational analysis on 119 pretreatment samples was performed. CPS therapy was associated with improved PFS compared to CP in patients with tumors with RAF1 (cRAF) gene copy gains (HR=0.372, P=0.025) or CCND1 gene copy gains (HR=0.45, P=0.035). CPS therapy was associated with improved OS compared to CP in patients with tumors with KRAS gene copy gains (HR=0.25, P=0.035). BRAF gene copy gain and MET amplification were more common in samples with V600K vs V600E mutations (P<0.001), which was validated in the TCGA data set. We observed improved treatment response with CPS in melanoma patients whose tumors have RAF1 (cRAF), KRAS or CCND1 amplification, all of which can be attributed to sorafenib targeting CRAF. These genomic alterations should be incorporated in future studies for evaluation as biomarkers. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 08/2015; DOI:10.1158/1078-0432.CCR-15-1162 · 8.72 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):1310-1310. DOI:10.1158/1538-7445.AM2015-1310 · 9.33 Impact Factor
  • Kurt A. Schalper · Cliff Hoyt · Chichung Wang · David Rimm ·

    Cancer Research 08/2015; 75(15 Supplement):2347-2347. DOI:10.1158/1538-7445.AM2015-2347 · 9.33 Impact Factor
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    ABSTRACT: We have previously reported the 2D PAGE-based proteomic profiling of a prospective cohort of 78 triple negative breast cancer (TNBC) patients, and the establishment of a cumulative TNBC protein database. Analysis of this database identified a number of proteins as being specifically overexpressed in TNBC samples. One such protein was D-3-phosphoglycerate dehydrogenase (Phgdh), a candidate oncogene. We analysed expression of Phgdh in normal and TNBC mammary tissue samples by 2D gel-based proteomics and immunohistochemistry (IHC), and show here that high-level expression of Phgdh in mammary epithelial cells is primarily associated with cell lineage, as we found that Phgdh expression was predominant in CK5-positive cells, normal as well as malignant, thus identifying an association of this protein with the basal phenotype. Quantitative IHC analysis of Phgdh expression in normal breast tissue showed high-level expression of Phgdh in normal CK5-positive mammary epithelial cells, indicating that expression of this protein was not associated with malignancy, but rather with cell lineage. However, proteomic profiling of Phgdh showed it to be expressed in two major protein forms, and that the ratio of expression between these variants was associated with malignancy. Overexpression of Phgdh in CK5-positive cell lineages, and differential protein isoform expression, was additionally found in other tissues and cancer types, suggesting that overexpression of Phgdh is generally associated with CK5 cells, and that oncogenic function may be determined by isoform expression. Copyright © 2015 Federation of European Biochemical Societies. All rights reserved.
    Molecular oncology 05/2015; 9(8). DOI:10.1016/j.molonc.2015.05.003 · 5.33 Impact Factor

  • Cancer Research 05/2015; 75(9 Supplement):S1-08-S1-08. DOI:10.1158/1538-7445.SABCS14-S1-08 · 9.33 Impact Factor
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    Brian D Adams · Lajos Pusztai · David L Rimm · Frank J Slack ·
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    ABSTRACT: Triple-negative breast cancer (TNBC) accounts for a disproportionate share of the total breast cancer morbidity because of its aggressive behavior and lack of effective targeted therapies to treat the disease. MicroRNAs, global regulators of survival and proliferation pathways important in tumor development and maintenance, are highly dysregulated in cancer. We identified miR-34a to be aberrantly lost in TNBC lines when compared to both a luminal cancer subtype as well as normal breast cells. Re-introduction of miR-34a in TNBC lines results in inhibition of cell proliferation and invasion, reactivation of senescence, and enhanced sensitivity to apoptosis-inducing agents. Furthermore, intratumoral delivery of miR-34a into subcutaneous tumors in nude mice, as well as systemic delivery of poly(amine-co-ester) PACE-loaded miR-34a in an orthotopic setting, delayed tumor growth. In conclusion, re-introduction of miR-34a in TNBC promotes potent anti-tumorigenic phenotypes in vitro and in vivo, and could be a promising targeted therapeutic agent to treat the disease.
    Cancer Research 05/2015; 75(9 Supplement):P4-07-12. DOI:10.1158/1538-7445.SABCS14-P4-07-12 · 9.33 Impact Factor
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    ABSTRACT: Background: Studies have shown that antibodies targeting the intracellular (ICD) or extracellular domains (ECD) of human epidermal growth factor receptor 2 (HER2) are equivalent when traditional methods are used. We describe a new method to quantify ICD and ECD expression separately and assess the prognostic value of domain-specific HER2 results in patients who received adjuvant trastuzumab therapy. Methods: We measured HER2 protein expression with quantitative immunofluorescence (QIF) in tissue microarrays (TMA) using two different antibodies targeting the ICD (CB11 and A0485) and ECD (SP3 and D8F12). We assessed the prognostic value of ICD and ECD expression in 180 patients from a clinical trial of adjuvant chemotherapy followed by trastuzumab (HeCOG 10/05). We performed an exploratory univariate domain-specific, disease-free survival (DFS) analysis and compared DFS functions with Kaplan-Meier estimates. All statistical tests were two-sided. Results: HER2 ICD expression by QIF showed slightly higher sensitivity to predict ERBB2 (HER2) gene amplification than ECD expression, which was more specific and had higher positive predictive value. In the HeCOG 10/05 trial specimens, 15% of cases showed discordant results for ICD and ECD expression. High ECD was statistically associated with longer DFS (log-rank P = .049, HR = 0.31, 95% CI = 0.144 to 0.997), while ICD status was not. Among patients with low ECD, there was no difference in DFS by ICD status. However, when ICD was high, high ECD was statistically associated with longer DFS (log-rank P = .027, HR = 0.23, 95% CI = 0.037 to 0.82) compared with low ECD. Conclusion: Quantitative measurements of HER2 ICD and ECD expression in breast cancer suggest a subclassification of HER2-positive tumors. Trastuzumab-treated patients with high ECD showed better DFS than patients with low ECD. This suggests differential benefit from trastuzumab therapy based on HER2 ECD expression.
    Cancer Research 05/2015; 75(9 Supplement):P3-06-26-P3-06-26. DOI:10.1158/1538-7445.SABCS14-P3-06-26 · 9.33 Impact Factor
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    ABSTRACT: Programmed death ligand-1 (PD-L1) tumor expression represents a mechanism of immune escape for melanoma cells. Drugs blocking PD-L1 or its receptor have shown unprecedented activity in melanoma, and our purpose was to characterize tumor PD-L1 expression and associated T-cell infiltration in metastatic melanomas. We used a tissue microarray (TMA) consisting of two cores from 95 metastatic melanomas characterized for clinical stage, outcome and anatomic site of disease. We assessed PD-L1 expression and tumor infiltrating lymphocytes (TIL) content (total T cells and CD4/CD8 subsets) by quantitative immunofluorescence. High PD-L1 expression was associated with improved survival (P=0.02) and higher T cell content (P=0.0005). Higher T cell content (total and CD8 cells) were independently associated with improved overall survival; PD-L1 expression was not independently prognostic. High TIL content in extra-cerebral metastases was associated with increased time to developing brain metastases (P=0.03). Cerebral and dermal metastases had slightly lower PD-L1 expression than other sites, not statistically significant. Cerebral metastases had less T cells (P=0.01). T cell infiltrated melanomas, particularly those with high CD8 T cell content, are more likely to be associated with PD-L1 expression in tumor cells, an improved prognosis, and increased time to development of brain metastases. Studies of T cell content and subsets should be incorporated into trials of PD-1/PD-L1 inhibitors to determine their predictive value. Furthermore, additional studies of anatomic sites with less PD-L1 expression and T cell infiltrate are needed to determine if discordant responses to PD-1/PD-L1 inhibitors are seen at those sites. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 03/2015; 21(13). DOI:10.1158/1078-0432.CCR-14-3073 · 8.72 Impact Factor
  • Nancy E Davidson · David L Rimm ·

    JAMA The Journal of the American Medical Association 03/2015; 313(11):1109-1110. DOI:10.1001/jama.2015.1945 · 35.29 Impact Factor
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    ABSTRACT: Many tumor cells are fueled by altered metabolism and increased glutamine (Gln) dependence. We identify regulation of the L-glutamine carrier proteins SLC1A5 and SLC38A2 (SLC1A5/38A2) by the ubiquitin ligase RNF5. Paclitaxel-induced ER stress to breast cancer (BCa) cells promotes RNF5 association, ubiquitination, and degradation of SLC1A5/38A2. This decreases Gln uptake, levels of TCA cycle components, mTOR signaling, and proliferation while increasing autophagy and cell death. Rnf5-deficient MMTV-PyMT mammary tumors were less differentiated and showed elevated SLC1A5 expression. Whereas RNF5 depletion in MDA-MB-231 cells promoted tumorigenesis and abolished paclitaxel responsiveness, SLC1A5/38A2 knockdown elicited opposing effects. Inverse RNF5(hi)/SLC1A5/38A2(lo) expression was associated with positive prognosis in BCa. Thus, RNF5 control of Gln uptake underlies BCa response to chemotherapies. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cancer cell 03/2015; 27(3):354-69. DOI:10.1016/j.ccell.2015.02.006 · 23.52 Impact Factor
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    ABSTRACT: Purpose Prostate cancer aggressiveness and appropriate therapy are routinely determined following biopsy sampling. Current clinical and pathologic parameters are insufficient for accurate risk prediction leading primarily to overtreatment but also missed opportunities for curative therapy. Experimental design An 8-biomarker proteomic assay for intact tissue biopsies predictive of prostate pathology was defined in a study of 381 patient biopsies with matched prostatectomy specimens. A second blinded study of 276 cases validated this assay's ability to distinguish 'favorable' versus 'non-favorable' pathology independently and relative to current risk classification systems (NCCN and D'Amico). Results A favorable biomarker risk score of ≤0.33, and a non-favorable risk score of >0.80 (possible range between 0 and 1) were defined on 'false negative' and 'false positive' rates of 10% and 5%, respectively. At a risk score ≤0.33, predictive values for favorable pathology in very low- and low-risk NCCN and low-risk D'Amico groups were 95%, 81.5%, and 87.2%, respectively, higher than for these current risk classification groups themselves (80.3%, 63.8%, and 70.6%, respectively). The predictive value for non-favorable pathology was 76.9% at biomarker risk scores >0.8 across all risk groups. Increased biomarker risk scores correlated with decreased frequency of favorable cases across all risk groups. The validation study met its two co-primary endpoints, separating favorable from non-favorable pathology (AUC, 0.68, P<0.0001, odds ratio=20.9) and GS-6 versus non-GS-6 pathology (AUC, 0.65, P<0.0001, OR=12.95). Conclusion The 8-biomarker assay provided individualized, independent prognostic information relative to current risk stratification systems, and may improve the precision of clinical decision-making following prostate biopsy. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 03/2015; 21(11). DOI:10.1158/1078-0432.CCR-14-2603 · 8.72 Impact Factor
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    ABSTRACT: Background: Tumor-infiltrating lymphocytes (TILs) are usually measured using subjective methods. Studies suggest that TIL subtypes have independent roles in cancer and that they could support the use of novel immunostimulatory therapies. We simultaneously measured TIL subtypes in non-small cell lung cancer (NSCLC) samples using objective methods and determined their relationship with clinico-pathologic characteristics and survival. Methods: Using multiplexed quantitative fluorescence (QIF), we measured the levels of CD3, CD8, and CD20 in 552 NSCLC from two independent collections represented in tissue microarrays (YTMA79, n = 202 and YTMA140, n = 350). The level of TILs was obtained in different tumor compartments using cytokeratin stain to define tumor cells and 4',6-Diamidino-2-Phenylindole. Association of TILs with clinical parameters was determined using univariate and multivariable analyses. All statistical tests were two-sided. Results: In both NSCLC collections there was a low correlation between the three TIL markers (linear regression coefficients (R(2)) = 0.19-0.22, P < .001 for YTMA79 and R(2) = 0.23-0.32, P < .001 for YTMA140). No consistent association between the level of TIL subtypes and age, sex, smoking history, tumor size, stage, and histology type was found. In univariate analysis, an elevated CD3 or CD8 signal was statistically significantly associated with longer survival in both collections. However, only CD8 was independent from age, tumor size, histology, and stage in multivariable analysis. High CD20 was associated with longer survival in the YTMA79 cohort. Conclusions: Increased levels of CD3 and CD8 + TILs are associated with better outcome in NSCLC, but only CD8 is independent from other prognostic variables. Objective measurement of TIL subpopulations could be useful to predict response or evaluate the local immune effect of anticancer immune checkpoint inhibitors.
    JNCI Journal of the National Cancer Institute 03/2015; 107(3). DOI:10.1093/jnci/dju435 · 12.58 Impact Factor
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    ABSTRACT: Anaplastic thyroid carcinoma (ATC) is a frequently lethal malignancy that is often unresponsive to available therapeutic strategies. The tumorigenesis of ATC and its relationship to the widely prevalent well-differentiated thyroid carcinomas are unclear. We have analyzed 22 cases of ATC as well as 4 established ATC cell lines using whole-exome sequencing. A total of 2,674 somatic mutations (121/sample) were detected. Ontology analysis revealed that the majority of variants aggregated in the MAPK, ErbB, and RAS signaling pathways. Mutations in genes related to malignancy not previously associated with thyroid tumorigenesis were observed, including mTOR, NF1, NF2, MLH1, MLH3, MSH5, MSH6, ERBB2, EIF1AX and USH2A; some of which were recurrent and were investigated in 24 additional ATC cases and 8 ATC cell lines. Somatic mutations in established thyroid cancer genes were detected in 14 of 22 (64%) tumors and included recurrent mutations in BRAF, TP53, and RAS-family genes (6 cases each), as well as PIK3CA (2 cases) and single cases of CDKN1B, CDKN2C, CTNNB1 and RET mutations. BRAF V600E and RAS mutations were mutually exclusive; all ATC cell lines exhibited a combination of mutations in either BRAF and TP53 or NRAS and TP53. A hypermutator phenotype in two cases with >8 times higher mutational burden than the remaining mean was identified; both cases harbored unique somatic mutations in MLH mismatch-repair genes. This first comprehensive exome-wide analysis of the mutational landscape of ATC identifies novel genes potentially associated with ATC tumorigenesis, some of which may be targets for future therapeutic intervention. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Human Molecular Genetics 01/2015; 24(8). DOI:10.1093/hmg/ddu749 · 6.39 Impact Factor

Publication Stats

16k Citations
2,682.69 Total Impact Points


  • 1997-2015
    • Yale-New Haven Hospital
      • Department of Pathology
      New Haven, Connecticut, United States
  • 1994-2015
    • Yale University
      • School of Medicine
      New Haven, Connecticut, United States
  • 2013
    • University of Pennsylvania
      • "Abramson" Cancer Center
      Philadelphia, Pennsylvania, United States
  • 2012
    • Dana-Farber Cancer Institute
      • Department of Medical Oncology
      Boston, MA, United States
  • 2011
    • University of Texas MD Anderson Cancer Center
      • Department of Systems Biology
      Houston, Texas, United States
  • 2008
    • CUNY Graduate Center
      New York, New York, United States
  • 2007
    • Fox Chase Cancer Center
      Filadelfia, Pennsylvania, United States
  • 2003
    • Robert Wood Johnson University Hospital
      New Brunswick, New Jersey, United States
  • 1999
    • University of Michigan
      • Medical School
      Ann Arbor, Michigan, United States
  • 1996-1997
    • Virginia Commonwealth University
      • Department of Pathology
      Richmond, Virginia, United States
  • 1995
    • Cold Spring Harbor Laboratory
      Cold Spring Harbor, New York, United States
  • 1988-1991
    • Johns Hopkins Medicine
      • Department of Molecular Biology and Genetics
      Baltimore, Maryland, United States
  • 1986
    • Johns Hopkins University
      • Department of Medicine
      Baltimore, Maryland, United States