Paola Muti

McMaster University, Hamilton, Ontario, Canada

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Publications (159)738.63 Total impact

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    ABSTRACT: Aspirin, the pro-drug of salicylate, is associated with reduced incidence of death from cancers of the colon, lung and prostate and is commonly prescribed in combination with metformin in individuals with type 2 diabetes. Salicylate activates the AMP-activated protein kinase (AMPK) by binding at the A-769662 drug binding site on the AMPK β1subunit, a mechanism, that is distinct from metformin which disrupts the adenylate charge of the cell. A hallmark of many cancers is high rates of fatty acid synthesis and AMPK inhibits this pathway through phosphorylation of acetyl-CoA carboxylase (ACC). It is currently unknown whether targeting the AMPK-ACC-lipogenic pathway using salicylate and/or metformin may be effective for inhibiting cancer cell survival. Salicylate suppresses clonogenic survival of prostate and lung cancer cells at therapeutic concentrations achievable following the ingestion of aspirin (<1.0mM); effects not observed in prostate (PNT1A) and lung (MRC-5) epithelial cell lines. Salicylate concentrations of 1mM increased the phosphorylation of ACC and suppressed de novo lipogenesis and these effects were enhanced with the addition of clinical concentrations of metformin (100 mM) and eliminated in mouse embryonic fibroblasts (MEFs) deficient in AMPK b1. Supplementation of media with fatty acids and/or cholesterol reverses the suppressive effects of salicylate and metformin on cell survival indicating the inhibition of de novo lipogenesis is likely important. Pre-clinical studies evaluating the use of salicylate based drugs alone and in combination with metformin to inhibit de novo lipogenesis and the survival of prostate and lung cancers are warranted.
    Biochemical Journal 05/2015; DOI:10.1042/BJ20150122 · 4.78 Impact Factor
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    PLoS ONE 04/2015; 10(4):e0124894. DOI:10.1371/journal.pone.0124894 · 3.53 Impact Factor
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    ABSTRACT: Background: Oral squamous cell carcinoma (OSCC) is the sixth most common cancer worldwide with a high rate of recurrence. MicroRNAs (miRNAs) are gene regulators playing an important role in oral carcinogenesis. We aimed to identify and functionally characterize miRNAs that predict recurrence in OSCC.Methods: We collected 92 OSCC with their normal tissue counterparts and we performed miRNAs expression profiling on 74 OSCC and 38 normal tissues. The association between the expression of microRNAs and clinical outcome was evaluated in 69 followed-up patients.Results: Four of the miRNAs deregulated between OSCC and normal tissues. areprognostic for recurrence either when considered individually or as a group. Depletion of the expression of prognostic miRNAs inhibits the proliferation of OSCC cells Conclusions: MicroRNAs are differentially expressed in OSCC versus normal samples. The expression of 4 prognostic microRNAs signature is able to predict recurrence risk independently from other clinical factors in OSCC. This article is protected by copyright. All rights reserved.
    Head & Neck 12/2014; DOI:10.1002/hed.23969 · 3.01 Impact Factor
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    ABSTRACT: Background: MicroRNAs (miRNAs) have been implicated in the regulation of key metabolic, inflammatory and malignant pathways, hence they might be considered both predictors and players of cancer development. Methods: Using a case-control study design nested in the ORDET prospective cohort study, we addressed the possibility that specific microRNAs can serve as early predictors of breast cancer incidence in postmenopausal women. We compared leucocyte miRNA profiles of 133 incident postmenopausal breast cancer cases and profiles of 133 women who remained healthy over a follow-up period of twenty years. Results: The analysis identified 20 differentially expressed miRNAs, 15 of them were down-regulated. Among the 20 miRNAs, miRNA-145-5p and miRNA-145-3p, each derived from another arm of the respective pre-miRNA, were consistently and significantly down-regulated in all databases we surveyed. For example, analysis of more than 1,500 patients (the UK Metabric cohort) indicated that high abundance of miRNA 145-3p and miRNA-145-5p was associated with longer, and for miRNA-145-3p also statistically significant, survival. The experimental data attributed different roles to the identified microRNAs: while the 5p isoform was associated with invasion and metastasis the other isoform appears related to cell proliferation. Conclusions: These observations and the prospective design of our study lend support to the hypothesis that down-regulation of specific microRNAs constitutes an early event in cancer development. This finding might be utilized for breast cancer prevention. Impact: The identification of the miRNAs as long-term biomarkers of breast cancer may have an impact of breast cancer prevention and early detection.
    Cancer Epidemiology Biomarkers & Prevention 07/2014; DOI:10.1158/1055-9965.EPI-14-0398 · 4.32 Impact Factor
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    ABSTRACT: Chemoresistance is one of the main problems in the therapy of cancer. There are a number of different molecular mechanisms through which a cancer cell acquires resistance to a specific treatment, such as alterations in drug uptake, drug metabolism and drug targets. There are several lines of evidence showing that miRNAs are involved in drug sensitivity of cancer cells in different tumor types and by different treatments. In this review, we provide an overview of the more recent and significant findings on the role of miRNAs in cancer cell drug resistance. In particular, we focus on specific miRNA mechanisms of action that in various steps lead from drug cell sensitivity to drug cell resistance. We also provide evidence on how miRNA profiling may unveil relevant predictive biomarkers for therapy outcomes.
    06/2014; 2. DOI:10.1186/2052-8426-2-16
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    ABSTRACT: Increasing evidence witnesses that cancer metabolism alterations represent a critical hallmark for many types of human tumors. There is a strong need to understand and dissect the molecular mechanisms underlying cancer metabolism to envisage specific biomarkers and underpin critical molecular components that might represent novel therapeutic targets. One challenge, that is the focus of this review, is the reprogramming of the altered metabolism of a cancer cell toward that of un-transformed cell. The anti-hyperglicemic agent, metformin has proven to be effective in reprogramming the metabolism of cancer cells even from those subpopulations endowed with cancer stem like features and very high chemoresistenace to conventional anticancer treatments. A functional interplay involving selective modulation of microRNAs (miRNAs) takes place along the anticancer metabolic effects exerted by metformin. The implications of this interplay will be also discussed in this review.
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    ABSTRACT: There is growing evidence that 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) plays a role in breast cancer prevention and survival. It elicits a variety of antitumor activities like controlling cellular differentiation, proliferation and angiogenesis. Most of its biological effects are exerted via its nuclear receptor which acts as a transcriptional regulator. Here, we carried out a genome-wide investigation of the primary transcriptional targets of 1α,25(OH)2D3 in breast epithelial cancer cells using RNA-Seq technology. We identified early transcriptional targets of 1α,25(OH)2D3 involved in adhesion, growth regulation, angiogenesis, actin cytoskeleton regulation, hexose transport, inflammation and immunomodulation, apoptosis, endocytosis and signaling. Furthermore, we found several transcription factors to be regulated by 1α,25(OH)2D3 that subsequently amplify and diversify the transcriptional output driven by 1α,25(OH)2D3 leading finally to a growth arrest of the cells. Moreover, we could show that 1α,25(OH)2D3 elevates the trimethylation of histone H3 lysine 4 at several target gene promoters. Our present transcriptomic analysis of differential expression after 1α,25(OH)2D3 treatment provides a resource of primary 1α,25(OH)2D3 targets that might drive the antiproliferative action in breast cancer epithelial cells.
    The Journal of steroid biochemistry and molecular biology 04/2014; 143. DOI:10.1016/j.jsbmb.2014.03.007 · 4.05 Impact Factor
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    ABSTRACT: Tumor initiation and progression are the outcomes of a stepwise accumulation of genetic alterations. Among these, gene amplification and aberrant expression of oncogenic proteins, as well as deletion or inactivation of tumor suppressor genes, represent hallmark steps. Mounting evidence collected over the last few years has identified different populations of non-coding RNAs as major players in tumor suppression in almost all cancer types. Elucidating the diverse molecular mechanisms underlying the roles of non-coding RNAs in tumor progression might provide illuminating insights, potentially able to assist improved diagnosis, better staging and effective treatments of human cancers. Here we focus on several groups of tumor suppressor microRNAs, whose downregulation exerts a profound oncologic impact and might be harnessed for the benefit of cancer patients.
    FEBS letters 03/2014; 588(16). DOI:10.1016/j.febslet.2014.03.033 · 3.34 Impact Factor
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    ABSTRACT: Metabolic remodeling is a hallmark of cancer progression and may affect tumor chemoresistance. Here we investigated by 1H-NMR/PCA analysis the metabolic profile of chemoresistant breast cancer cell subpopulations (ALDHbright cells) and their response to metformin, a promising anticancer metabolic modulator. The purified ALDHbright cells exhibited a different metabolic profile as compared to their chemosensitive ALDHlow counterparts. Metformin treatment strongly affected the metabolism of the ALDHbright cells thereby affecting, among the others, the glutathione metabolism, whose upregulation is a feature of progenitor-like, chemoresistant cell subpopulations. Globally, metformin treatment reduced the differences between ALDHbright and ALDHlow cells, making the former more similar to the latter. Metformin broadly modulated microRNAs in the ALDHbright cells, with a large fraction of them predicted to target the same metabolic pathways experimentally identified by 1H-NMR. Additionally, metformin modulated the levels of c-MYC and IRS-2, and this correlated with changes of the microRNA-33a levels. In summary, we observed, both by 1H-NMR and microRNA expression studies, that metformin treatment reduced the differences between the chemoresistant ALDHbright cells and the chemosensitive ALDHlow cells. This works adds on the potential therapeutic relevance of metformin and shows the potential for metabolic reprogramming to modulate cancer chemoresistance.
    Oncotarget 03/2014; · 6.63 Impact Factor
  • Paola Muti
    Nature Reviews Cancer 01/2014; DOI:10.1038/nrc3518-c1 · 29.54 Impact Factor
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    ABSTRACT: Cancer metabolism is the focus of intense research, which witnesses its key role in human tumors. Diabetic patients treated with metformin exhibit a reduced incidence of cancer and cancer-related mortality. This highlights the possibility that the tackling of metabolic alterations might also hold promising value for treating cancer patients. Here, we review the emerging role of metformin as a paradigmatic example of an old drug used worldwide to treat patients with type II diabetes which to date is gaining strong in vitro and in vivo anticancer activities to be included in clinical trials. Metformin is also becoming the focus of intense basic and clinical research on chemoprevention, thus suggesting that metabolic alteration is an early lesion along cancer transformation. Metabolic reprogramming might be a very efficient prevention strategy with a profound impact on public health worldwide.
    12/2013; 3(4):1051-75. DOI:10.3390/metabo3041051
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    ABSTRACT: MicroRNAs (miRNAs) are characterized as small RNA molecules that modulate gene transcription in a posttranslational manner. Functionally, miRNAs play important roles in a diverse number of biological processes, including cell development, differentiation, proliferation, and apoptosis. Consequently, changes in the expression pattern of miRNAs have been associated with multiple human pathologies, including cancer. Based on these alterations, distinct miRNAs can be utilized as markers for cancer risk evaluation or used in tumour detection. Recent evidence has indicated that lifestyle factors, such as nutrition, physical activity, and glycemic control provide health benefits through regulation of miRNA expression. In this review, we provide a concise overview of miRNA regulation, biosynthesis, and their expression patterns in normal and malignant tissue. We then summarize the emerging knowledge of how lifestyle factors, including nutrients, exercise, and hypoglycemic agents modify miRNAs and are involved in cancer prevention. Finally, we conclude by providing recommendation for future investigations into novel agents that can modulate miRNAs and act as chemotherapeutic agents against cancer.
    09/2013; 2(2):82-90. DOI:10.2174/22115366113029990013
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    ABSTRACT: Objective Chronic lung disease is exacerbated by comorbid psychiatric issues and treatment of depression may improve disease symptoms. We sought to add to the literature as to whether depression is associated with pulmonary function in healthy adults.Methods In 2551 healthy adults from New York State, we studied the association of depression via the Center for Epidemiologic Studies Depression scale (CES-D) scale score and forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) using general linear models and a cross-sectional design.ResultsWe identified statistically significant inverse trends in FEV1, FVC, FEV1%, and FVC% by CES-D category, especially in ever-smokers and men. When adjusted for covariates, the difference in FEV1 and FEV1% for smokers with more than 18.5 lifetime pack-years from CES-D scores 0 to 3 to 16 or more (depressed) is approximately 0.25 l and 5.0% (adjusted p values for trend are <.001 and .019, respectively). In men, we also observed statistically significant inverse trends in pulmonary function with increasing CES-D.Conclusions We identified an inverse association of depressive symptoms and pulmonary function in healthy adults, especially in men and individuals with a heavy smoking history. Further studies of these associations are essential for the development and tailoring of interventions for the prevention and treatment of chronic lung disease.
    Psychosomatic Medicine 08/2013; DOI:10.1097/PSY.0b013e3182a15672 · 4.09 Impact Factor
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    ABSTRACT: INTRODUCTION: Previous studies showed higher testosterone levels are associated with higher risk of breast cancer in premenopausal women, but literature is scant and inconsistent. METHODS: In a prospective nested case-control study of 104 premenopausal women with incident breast cancer and 225 matched controls, all characterized by regular menstrual cycles throughout their lifetime, we measured the concentration of estradiol, total and free testosterone (FT), progesterone, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in blood samples collected on the 20-24th day of their cycle. RESULTS: In logistic regression models, the multivariate odds ratios (OR) of invasive breast cancer for women in the highest tertile of circulating free testosterone compared with the lowest was 2.43 (95% confidence interval [95% CI], 1.15-5.10; Ptrend = 0.03), while for total testosterone the association had the same direction but was not statistically significant (OR, 1.27; 95% CI= 0.62-2.61; Ptrend = 0.51]. Endogenous Progesterone was not statistically associated with breast cancer (OR, 1.16, 95% CI, 0.60-2.27; Ptrend = 0.75), nor were the other considered hormones. CONCLUSIONS: Consistent with previous prospective studies in premenopausal women and our own earlier investigation, we observed that higher levels of free testosterone are positively associated with breast cancer risk in women with regular menstrual cycles throughout their lifetime. There was no evidence of risk associated with the other endogenous sex steroids.
    Breast cancer research: BCR 06/2013; 15(3):R46. DOI:10.1186/bcr3438 · 5.88 Impact Factor
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    ABSTRACT: High circulating glucose has been associated with increased risk of breast cancer (BC). There may also be a link between serum glucose and prognosis in women treated for BC. We assessed the effect of peridiagnostic fasting blood glucose and body mass index (BMI) on long-term BC prognosis. We retrospectively investigated 1,261 women diagnosed and treated for stage I-III BC at the National Cancer Institute, Milan, in 1996, 1999 and 2000. Data on blood tests and follow-up were obtained by linking electronic archives, with follow-up to end of 2009. Multivariate Cox modelling estimated hazard ratios (HR) with 95 % confidence intervals (CI) for distant metastasis, recurrence and death (all causes) in relation to categorized peridiagnostic fasting blood glucose and BMI. Mediation analysis investigated whether blood glucose mediated the BMI-breast cancer prognosis association. The risks of distant metastasis were significantly higher for all other quintiles compared to the lowest glucose quintile (reference <87 mg/dL) (respective HRs: 1.99 95 % CI 1.23-3.24, 1.85 95 % CI 1.14-3.0, 1.73 95 % CI 1.07-2.8, and 1.91 95 % CI 1.15-3.17). The risk of recurrence was significantly higher for all other glucose quintiles compared to the first. The risk of death was significantly higher than reference in the second, fourth and fifth quintiles. Women with BMI ≥ 25 kg/m(2) had significantly greater risks of recurrence and distant metastasis than those with BMI < 25 kg/m(2), irrespective of blood glucose. The increased risks remained invariant over a median follow-up of 9.5 years. Mediation analysis indicated that glucose and BMI had independent effects on BC prognosis. Peridiagnostic high fasting glucose and obesity predict worsened short- and long-term outcomes in BC patients. Maintaining healthy blood glucose levels and normal weight may improve prognosis.
    Breast Cancer Research and Treatment 04/2013; 138(3). DOI:10.1007/s10549-013-2519-9 · 4.20 Impact Factor
  • Paola Muti, Punam Rana
    Polskie archiwum medycyny wewnȩtrznej 03/2013; 123(3):83-84. · 2.05 Impact Factor
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    ABSTRACT: PURPOSE: Indirect evidence from experimental and epidemiological studies suggests that prolactin may be involved in ovarian cancer development. However, the relationship between circulating prolactin levels and risk of ovarian cancer is unknown. METHODS: We conducted a nested case-control study of 230 cases and 432 individually matched controls within three prospective cohorts to evaluate whether pre-diagnostic circulating prolactin is associated with subsequent risk of ovarian cancer. We also assessed whether lifestyle and reproductive factors are associated with circulating prolactin among controls. RESULTS: Prolactin levels were significantly lower among post- versus pre-menopausal women, parous versus nulliparous women, and past versus never users of oral contraceptives in our cross-sectional analysis of controls. In our nested case-control study, we observed a non-significant positive association between circulating prolactin and ovarian cancer risk (OR(Q4vsQ1) 1.56, 95 % CI 0.94, 2.63, p trend 0.15). Our findings were similar in multivariate-adjusted models and in the subgroup of women who donated blood ≥5 years prior to diagnosis. We observed a significant positive association between prolactin and risk for the subgroup of women with BMI ≥25 kg/m(2) (OR(Q4vsQ1) 3.10, 95 % CI 1.39, 6.90), but not for women with BMI <25 kg/m(2) (OR(Q4vsQ1) 0.81, 95 % CI 0.40, 1.64). CONCLUSIONS: Our findings suggest that prolactin may be associated with increased risk of ovarian cancer, particularly in overweight/obese women. Factors associated with reduced risk of ovarian cancer, such as parity and use of oral contraceptives, were associated with lower prolactin levels, which suggests that modulation of prolactin may be a mechanism underlying their association with risk.
    Cancer Causes and Control 02/2013; DOI:10.1007/s10552-013-0156-6 · 2.96 Impact Factor
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    ABSTRACT: Melatonin has been known to be a chemopreventive agent, since its levels inversely correlate with the risk of developing cancer. We have recently shown that melatonin induces p38-dependent phosphorylation of both p53 and histone H2AX. This is associated with a p53-mediated increase in repair of both endogenous and chemotherapy-induced DNA damage. In addition, the inhibition of p38 activities impairs melatonin's capability to induce a p53-dependent DNA damage response and thus its ability to maintain genome integrity. Since melatonin-induced p53 phosphorylation requires an intact p38 phosphorylation cascade and p38 can be activated by G-proteins, we supposed that melatonin's activities could be mediated by its G-proteins coupled membrane receptors, MT1 and MT2. Here, we show that the activation of the p53-dependent DNA damage response by melatonin is indeed mediated by MT1 and MT2. As a result, the absence of either receptor impairs melatonin's ability to reduce both cell proliferation and clonogenic potential of cancer cells. In addition, this causes an impairment of the p53-dependent DNA damage response. By providing molecular insight, our findings might have translational impact, suggesting the involvement of melatonin receptors in tumorigenesis.
    Carcinogenesis 01/2013; DOI:10.1093/carcin/bgt025 · 5.27 Impact Factor
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    ABSTRACT: Deregulated proliferation is a hallmark of cancer cells. Here, we show that microRNA-10b* is a master regulator of breast cancer cell proliferation and is downregulated in tumoural samples versus matched peritumoural counterparts. Two canonical CpG islands (5 kb) upstream from the precursor sequence are hypermethylated in the analysed breast cancer tissues. Ectopic delivery of synthetic microRNA-10b* in breast cancer cell lines or into xenograft mouse breast tumours inhibits cell proliferation and impairs tumour growth in vivo, respectively. We identified and validated in vitro and in vivo three novel target mRNAs of miR-10b* (BUB1, PLK1 and CCNA2), which play a remarkable role in cell cycle regulation and whose high expression in breast cancer patients is associated with reduced disease-free survival, relapse-free survival and metastasis-free survival when compared to patients with low expression. This also suggests that restoration of microRNA-10b* expression might have therapeutic promise.
    EMBO Molecular Medicine 11/2012; 4(11):1214-29. DOI:10.1002/emmm.201201483 · 8.25 Impact Factor
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    ABSTRACT: Background: Circulating estrogens are associated with increased breast cancer risk, yet the role of estrogen metabolites in breast carcinogenesis remains unclear. This combined analysis of 5 published studies evaluates urinary 2-hydroxyestrone (2-OHE1), 16α-hydroxyestrone (16α-OHE1), and their ratio (2:16α-OHE1) in relation to breast cancer risk. 
Methods: Primary data on 726 premenopausal women (183 invasive breast cancer cases and 543 controls) and 1,108 postmenopausal women (385 invasive breast cancer cases and 723 controls) were analyzed. Urinary estrogen metabolites were measured using enzyme linked immunosorbent assays. Study-specific and combined multivariable adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated based on tertiles of estrogen metabolites. Multinomial logistic regression models were fit according to hormone receptor status.
Results: Higher premenopausal 2:16α-OHE1 was suggestive of reduced breast cancer risk overall (study-adjusted ORIIIvsI=0.80; 95% CI: 0.49-1.32) and for estrogen receptor negative (ER-) subtype (ORIIIvsI=0.33; 95% CI: 0.13-0.84). Among postmenopausal women, 2:16α-OHE1 was unrelated to breast cancer risk (study-adjusted ORIIIvsI=0.93; 95% CI: 0.65-1.33); however, the association between 2-OHE1 and risk varied by body mass index (p-interaction=0.003). 
Conclusions: Premenopausal urinary 2:16α-OHE1 may play a role in breast carcinogenesis; however, larger studies are needed. Our findings do not support reduced breast cancer risk with higher postmenopausal 2:16α-OHE1 overall, although obesity may modify associations with 2-OHE1.
    The International journal of biological markers 08/2012; 28(1). DOI:10.5301/JBM.2012.9353 · 1.36 Impact Factor

Publication Stats

4k Citations
738.63 Total Impact Points

Institutions

  • 2010–2014
    • McMaster University
      • • Juravinski Cancer Centre
      • • Department of Oncology
      Hamilton, Ontario, Canada
  • 2005–2013
    • Istituto Regina Elena - Istituti Fisioterapici Ospitalieri
      • S.C. Laboratorio "C" Oncogenesi Molecolare
      Roma, Latium, Italy
    • University of Naples Federico II
      Napoli, Campania, Italy
  • 2012
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1996–2011
    • Fondazione IRCCS Istituto Nazionale dei Tumori di Milano
      Milano, Lombardy, Italy
  • 2008
    • Harvard Medical School
      • Department of Medicine
      Boston, MA, United States
    • Sapienza University of Rome
      Roma, Latium, Italy
  • 2000–2008
    • University at Buffalo, The State University of New York
      • • Department of Medicine
      • • Department of Social and Preventive Medicine
      Buffalo, NY, United States
    • Hannover Medical School
      Hanover, Lower Saxony, Germany
    • Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
      Meldola, Emilia-Romagna, Italy
  • 2006–2007
    • CRO Centro di Riferimento Oncologico di Aviano
      Aviano, Friuli Venezia Giulia, Italy
    • Cornell University
      Итак, New York, United States
  • 2004–2007
    • Roswell Park Cancer Institute
      • Department of Epidemiology
      Buffalo, New York, United States
    • New York University
      • Department of Obstetrics and Gynecology
      New York City, NY, United States
  • 2003–2005
    • State University of New York
      New York City, New York, United States
  • 2002
    • University of Vermont
      Burlington, Vermont, United States
  • 2001
    • University of Tours
      Tours, Centre, France