Gilberto Schwartsmann

Universidade Federal do Rio Grande do Sul, Pôrto de São Francisco dos Casaes, Rio Grande do Sul, Brazil

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Publications (234)880.99 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: A LC-MSMS method for the simultaneous determination of tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen in dried blood spots samples was developed and validated. The method employs an ultrasound-assisted liquid extraction and a reversed phase separation in an Acquity(®) C18 column (150×2.1mm, 1.7µm). Mobile phase was a mixture of formic acid 0.1% (v/v) pH 2.7 and acetonitrile (gradient from 60:40 to 50:50, v/v). Total analytical run time was 8min. Precision assays showed CV % lower than 10.75% and accuracy in the range 94.5 to 110.3%. Mean analytes recoveries from DBS ranged from 40% to 92%. The method was successfully applied to 91 paired clinical DBS and plasma samples. Dried blood spots concentrations were highly correlated to plasma, with rs>0.83 (P<0.01). Median estimated plasma concentrations after hematocrit and partition factor adjustment were: TAM 123.3ngmL(-1); NDT 267.9ngmL(-1), EDF 10.0ngmL(-1) and HTF 1.3ngmL(-1,) representing in average 98 to 104% of the actually measured concentrations. The DBS method was able to identify 96% of patients with plasma EDF concentrations below the clinical threshold related to better prognosis (5.9ngmL(-1)). The procedure has adequate analytical performance and can be an efficient tool to optimize adjuvant breast cancer treatment, especially in resource limited settings. Copyright © 2014 Elsevier B.V. All rights reserved.
    Talanta 01/2015; 132:775-84. · 3.50 Impact Factor
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    ABSTRACT: TP53 mutation is a common event in many cancers, including pancreatic adenocarcinoma, where it occurs in 50-70 % of cases. In an effort to reactivate mutant p53 protein, several new drugs are being developed, including PRIMA-1 and PRIMA-1(Met)/APR-246 (p53 reactivation and induction of massive apoptosis). PRIMA-1 has been shown to induce apoptosis in tumor cells by reactivating p53 mutants, but its effect in pancreatic cancer remains unclear. Here we investigated the effects of PRIMA-1 on cell viability, cell cycle and expression of p53-regulated proteins in PANC-1 and BxPC-3 (mutant TP53), and CAPAN-2 (wild-type TP53) pancreatic cell lines. Treatment with PRIMA-1 selectively induced apoptosis and cell cycle arrest in p53 mutant cells compared to CAPAN-2 cells. The growth suppressive effect of PRIMA-1 was markedly reduced in p53 mutant cell lines transfected with p53 siRNA, supporting the role of mutant p53 in PRIMA-1 induced cell death. Moreover, treatment with the thiol group donor N-acetylcysteine completely blocked PRIMA-1-induced apoptosis and reinforced the hypothesis that thiol modifications are important for PRIMA-1 biological activity. In combination treatments, PRIMA-1 enhanced the anti-tumor activity of several chemotherapic drugs against pancreatic cancer cells and also exhibited a pronounced synergistic effect in association with the Mdm2 inhibitor Nutlin-3. Taken together, our data indicate that PRIMA-1 induces apoptosis in p53 mutant pancreatic cancer cells by promoting the re-activation of p53 and inducing proapoptotic signaling pathways, providing in vitro evidence for a potential therapeutic approach in pancreatic cancer.
    Investigational New Drugs 05/2014; · 3.50 Impact Factor
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    ABSTRACT: To develop and validate a method for determination of dextromethorphan (DMT) and dextrorphan (DTP) in plasma samples using HPLC-FL and to apply it to CYP2D6 phenotyping of a population from the south of Brazil. Samples were prepared by hydrolysis and liquid-liquid extraction. Analysis was conducted in a reversed phase column, with isocratic elution and fluorescence detection. One hundred and forty patients being treated with tamoxifen were given 30mg of dextromethorphan and their CYP2D6 phenotypes were determined on the basis of [DMT]/[DTP] metabolic ratios in plasma samples collected after 3hours. total chromatography running time was 12min. Precision (CV %) was below 9.7 % and accuracy was between 92.1 and 106.9 %. The lower limits of quantification were 1ngmL(-1) for DMT and 10ngmL(-1) for DTP. Mean extraction yield of analytes was 86.6 %. Mean age of patients was 55.7years. Phenotype frequencies were as follows: 7.1% poor metabolizers, 13.6% intermediate metabolizers, 77.1 % extensive metabolizers and 2.1 ultra-rapid metabolizers. Metabolic ratios for patients on strong (n=11) and weak (n=16) CYP2D6 activity inhibitors were different from each other and also different from ratios for patients not taking enzyme inhibitors (n=113). A sensitive method for determination of dextromethorphan and its metabolite in plasma samples was developed and successfully applied, providing evidence of the impact of that CYP2D6 inhibitors have on the enzyme's metabolic capacity.
    Clinical biochemistry 04/2014; · 2.02 Impact Factor
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    ABSTRACT: Research endeavours require the collaborative effort of an increasing number of individuals. International scientific collaborations are particularly important for HIV and HPV co-infection studies, since the burden of disease is rising in developing countries, but most experts and research funds are found in developed countries, where the prevalence of HIV is low. The objective of our study was to investigate patterns of international scientific collaboration in HIV and HPV research using social network analysis. Through a systematic review of the literature, we obtained epidemiological data, as well as data on countries and authors involved in co-infection studies. The collaboration network was analysed in respect to the following: centrality, density, modularity, connected components, distance, clustering and spectral clustering. We observed that for many low- and middle-income countries there were no epidemiological estimates of HPV infection of the cervix among HIV-infected individuals. Most studies found only involved researchers from the same country (64%). Studies derived from international collaborations including high-income countries and either low- or middle-income countries had on average three times larger sample sizes than those including only high-income countries or low-income countries. The high global clustering coefficient (0.9) coupled with a short average distance between researchers (4.34) suggests a "small-world phenomenon." Researchers from high-income countries seem to have higher degree centrality and tend to cluster together in densely connected communities. We found a large well-connected community, which encompasses 70% of researchers, and 49 other small isolated communities. Our findings suggest that in the field of HIV and HPV, there seems to be both room and incentives for researchers to engage in collaborations between countries of different income-level. Through international collaboration resources available to researchers in high-income countries can be efficiently used to enroll more participants in low- and middle-income countries.
    PLoS ONE 03/2014; 9(3):e93376. · 3.53 Impact Factor
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    ABSTRACT: Established fear-related memories can undergo phenomena such as extinction or reconsolidation when recalled. Extinction probably involves the creation of a new, competing memory trace that decreases fear expression, whereas reconsolidation can mediate memory maintenance, updating, or strengthening. The factors determining whether retrieval will initiate extinction, reconsolidation, or neither of these two processes include training intensity, duration of the retrieval session, and age of the memory. However, previous studies have not shown that the same behavioral protocol can be used to induce either extinction or reconsolidation and strengthening, depending on the pharmacological intervention used. Here we show that, within an experiment that leads to extinction in control rats, memory can be strengthened if rolipram, a selective inhibitor of phosphodiesterase type 4 (PDE4), is administered into the dorsal hippocampus immediately after retrieval. The memory-enhancing effect of rolipram lasted for at least 1 week, was blocked by the protein synthesis inhibitor anisomycin, and did not occur when drug administration was not paired with retrieval. These findings indicate that the behavioral outcome of memory retrieval can be pharmacologically switched from extinction to strengthening. The cAMP/protein kinase A (PKA) signaling pathway might be a crucial mechanism determining the fate of memories after recall.
    Frontiers in Behavioral Neuroscience 03/2014; 8:91. · 4.16 Impact Factor
    This article is viewable in ResearchGate's enriched format
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    ABSTRACT: Epigenetic alterations have been increasingly implicated in glioblastoma (GBM) pathogenesis, and epigenetic modulators including histone deacetylase inhibitors (HDACis) have been investigated as candidate therapies. GBMs are proposed to contain a subpopulation of glioblastoma stem cells (GSCs) that sustain tumor progression and therapeutic resistance and can form tumorspheres in culture. Here, we investigate the effects of the HDACi trichostatin A (TSA) in U87 GBM cultures and tumorsphere-derived cells. Using approaches that include a novel method to measure tumorsphere sizes and the area covered by spheres in GBM cultures, as well as a nuclear morphometric analysis, we show that TSA reduced proliferation and colony sizes, led to G2/M arrest, induced alterations in nuclear morphology consistent with cell senescence, and increased the protein content of GFAP, but did not affect migration, in cultured human U87 GBM cells. In cells expanded in tumorsphere assays, TSA reduced sphere formation and induced neuron-like morphological changes. The expression of stemness markers in these cells was detected by reverse transcriptase polymerase chain reaction. These findings indicate that HDACis can inhibit proliferation, survival, and tumorsphere formation, and promote differentiation of U87 GBM cells, providing further evidence for the development of HDACis as potential therapeutics against GBM.
    Journal of Molecular Neuroscience 01/2014; · 2.76 Impact Factor
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    ABSTRACT: Gastrin releasing peptide, the mammalian counterpart of the amphibian peptide, Bombesin, has been increasingly implicated in regulating normal brain function as well as in the pathogenesis of psychiatric and/or neurodevelopmental disorders. We have previously shown that the neonatal blockade of the gastrin-releasing peptide receptor (GRPr) in rats produces long-lasting consequences during central nervous system development that are commonly observed in neurodevelopmental disorders such as autism spectrum disorders. The present investigation assessed in further detail, long-term behavioral effects of neonatal GRPr blockade. During postnatal days 1 to10, male Wistar rat pups (n=5-10/litter) were injected (subcutaneously) with the GRPr antagonist, RC-3095 (1mg/kg), or a vehicle (control), twice daily. Following the drug treatment regimen, several behaviors were assessed (starting on postnatal day 14) including specific social behaviors (namely, group huddling characteristics, social interaction, and social approach), restrictive/repetitive and stereotyped behaviors (y-maze, repetitive novel objection contact task, observation for stereotypies) and anxiety/fear-related responses (open field, elevated plus maze and contextual fear conditioning). Rats treated neonatally with RC-3095 showed reduced sociability, restrictive interests, motor stereotypies and enhanced learned fear response compared to the controls (vehicle-treated rats). These behavioral abnormalities are consistent with those observed in autism spectrum disorders and provide further evidence that neonatal blockade of GRPr could potentially serve as a useful model to gain a better understanding of the underlying neurodevelopmental disruptions contributing to the expression of autism-relevant phenotypes.
    Behavioural brain research 01/2014; · 3.22 Impact Factor
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    ABSTRACT: Context.-Gastrin-releasing peptide receptors (GRPRs) activate mitogen-activated protein kinase signaling pathway primarily through epidermal growth factor receptor activation and are under investigation as a molecular target because they are overexpressed in several solid tumors. Objective.-To determine GRPR expression in both non-small cell lung carcinoma and small cell lung carcinoma, comparing results with clinical stages and demographic data. Design.-We analyzed the immunohistochemical expression of GRPR in 200 non-small cell lung carcinoma and 38 small cell lung carcinoma archival cases from 2004 to 2008. Results.-Non-small cell lung carcinoma cases tended to be higher GRPR expressers at a rate of 62.5% (weak, moderate, and strong expression in 41.5%, 13.5%, and 7.5%, respectively), compared with 52.62% in small cell lung carcinoma cases (weak, moderate, and strong expression in 34.21%, 15.78%, and 2.63%, respectively; P = .30). In non-small cell lung carcinoma there was a trend for higher percentages of strong expression in adenocarcinoma cases (10%; P = .67), and in patients with advanced stages (III and IV; 9.43% and 6.9%; P = .01). Conclusions.-To the best of our knowledge, this is the first study to demonstrate GRPR tissue expression in a large population of patients with lung cancer. Although GRPR expression was similar in small cell and non-small cell carcinoma, the expression was more pronounced in an advanced-stage lung cancer, particularly in adenocarcinoma cases, and may represent a potential target for the development of new treatment approaches in this population.
    Archives of pathology & laboratory medicine 01/2014; 138(1):98-104. · 2.88 Impact Factor
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    ABSTRACT: Context: The spinocerebellar ataxia type 2 (SCA-2) is a progressive neurodegenerative disorder without specific therapy identified, and it is related to the loss of function in the cerebellum, mitochondrial dysfunction, oxidative stress and neurotoxic processes. Scientific evidence indicates that Mangifera indica L. aqueous extract (MiE) and its major constituent (mangiferin) display antioxidant, anti-inflammatory and neuroprotective actions. Aims: To investigate the MiE and mangiferin effects on behavioral outcomes of neurological function in SCA-2 transgenic mice. Methods: The SCA-2 transgenic mice were daily and orally administered during 12 months with MiE (10, 50, and 100 mg/kg), mangiferin (10 mg/kg) or vehicle. It was evaluated locomotion (open-field), aversive memory (inhibitory avoidance) and declarative memory (object recognition). To explore possible cellular mechanisms underlying the in vivo effects was also evaluated their effects on nerve grow factor (NGF) and tumor necrosis factor-α (TNF-α) levels in the human glioblastoma cell line U138-MG supernatant. Results: MiE administration did not affect the object recognition memory, but mangiferin did. The natural extract improved selectively the aversive memory in SCA-2 mice, indicating that MiE can affect behavioral parameters regarding fear-related memory. MiE also induced a significant increase in supernatant levels of NGF and TNF-α in vitro in human U138-MG glioblastoma cells. Conclusions: The results suggest that MiE enhances the aversive memory through a mechanism that might involve an increase in neurotrophin and cytokine levels. These findings constitute the basis for the use of the natural extract in the prevention/treatment of memory deficits in SCA-2.
    Journal of Pharmacy & Pharmacognosy Research. 01/2014; 2(3):63-72.
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    ABSTRACT: Medulloblastoma is the most common malignant childhood brain tumor for which the development of new molecularly targeted therapies is needed. Novel therapeutic targets under investigation include growth factor receptors. Here, we show that the combined inhibition of the epidermal growth factor receptor (EGFR) and neuromedin B receptor (NMBR, BB1) results in increased cell death in human medulloblastoma cell lines. DAOY and D283 human medulloblastoma cells were treated with human recombinant neuromedin B (NMB, an NMBR agonist), the NMBR antagonist BIM-23127, the anti-EGFR monoclonal antibody cetuximab, or BIM-23127 combined with cetuximab. Cell death was examined with trypan blue cell counting. Both cell lines expressed mRNA for EGFR, NMB, and NMBR detected by reverse transcriptase polymerase chain reaction. Cetuximab at 10 μg/ml significantly reduced the number of DAOY cells, but did not affect D283 cells. NMB and BIM-23127 did not change cell number when used alone. However, cetuximab, at a dose that did not have an effect by itself, was able to reduce the number of DAOY cells when combined with BIM-23127. These results provide preliminary evidence that NMBR blockade can potentiate the antitumor effect of anti-EGFR therapy in medulloblastoma.
    Child s Nervous System 10/2013; · 1.24 Impact Factor
  • Rafael Roesler, Gilberto Schwartsmann
    The Lancet Oncology 10/2013; 14(11):e436-e437. · 25.12 Impact Factor
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    ABSTRACT: The possible association of three DEFB1 gene polymorphisms with susceptibility to develop ulcerative colitis (UC) and Crohn's disease (CD) was investigated in Brazilian patients and controls. Although a clear and strong association between functional 5'-UTR DEFB1 SNPs and susceptibility/protection to IBDs cannot be drawn, our results suggest a possible involvement of DEFB1 gene in inflammatory bowel diseases, especially with the colonic localization of Crohn's disease.
    International Journal of Immunogenetics 09/2013; · 1.34 Impact Factor
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    ABSTRACT: Neuropeptides act as signaling molecules that regulate a range of aspects of brain function. Gastrin-releasing peptide (GRP) is a 27-amino acid mammalian neuropeptide, homolog of the amphibian peptide bombesin. GRP acts by binding to the GRP receptor (GRPR, also called BB2), a member of the G-protein coupled receptor (GPCR) superfamily. GRP produced by neurons in the central nervous system (CNS) plays a role in synaptic transmission by activating GRPRs located on postsynaptic membranes, influencing several aspects of brain function. Here we review the role of GRP/GRPR as a system mediating both stress responses and the formation and expression of memories for fearful events. GRPR signaling might integrate the processing of stress and fear with synaptic plasticity and memory, serving as an important component of the set of neurobiological systems underlying the enhancement of memory storage by aversive information.
    Neurobiology of Learning and Memory 08/2013; · 4.04 Impact Factor
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    ABSTRACT: Gastrin-releasing peptide is a neuroendocrine homolog of bombesin that demonstrated important growth-stimulatory effects in various types of cancer. High levels of expression of gastrin-releasing peptide receptors (GRPR) has been found in different malignancies, and the studies exploring the therapeutic use of GRPR antagonists have shown promising results. Our aim was to determine the GRPR expression in epidermoid carcinoma of the anal canal and discuss its potential clinical applications. We performed immunohistochemical analysis for GRPR on formalin-fixed and paraffin-embedded tumor samples obtained from 35 patients with anal cancer. As a control group, we analyzed 24 samples of nonmalignant anal tissues (hemorrhoidectomy specimens). GRPR expression was evaluated using a semiquantitative approach according to the intensity and distribution of staining. All analyzed tissues, except 1 control sample, showed positive GRPR immunoexpression. GRPR was strongly expressed in 54% of cancer specimens as compared with only 12% of the control specimens (P<0.003). In tumors, the receptor showed a diffuse and homogenous pattern of distribution within the specimens. In contrast, control specimens showed a focal pattern of staining restricted to the basal half of the epithelium. In conclusion, we demonstrated that GRPR is highly expressed in epidermoid carcinoma of the anal canal, suggesting this receptor might have a role in anal carcinogenesis. Our results provide a basis for exploiting GRPR as a target for diagnostic and therapeutic purposes in the anal cancer.
    Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry 08/2013; · 1.63 Impact Factor
  • Rafael Roesler, Gilberto Schwartsmann
    Nature Reviews Urology 06/2013; · 4.79 Impact Factor
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    ABSTRACT: Breast cancer is the main cause of cancer-related death among women, with a 0.5% increase in incidence per year. Natural killer cells (NK) are part of the innate immune system recognizing class I HLA molecules on target cells through their membrane receptors, called killer cell immunoglobulin-like receptors (KIR). The aim of our study was to evaluate the association between the KIR genes and HLA alleles in patients with breast cancer and healthy controls. Two hundred thirty patients with breast cancer and 272 healthy controls were typed for HLA class I and KIR genes by PCR-SSO. When both groups were compared, the presence of inhibitory KIR2DL2 receptors was significantly higher in breast cancer patients than in healthy controls. No significant differences were found for HLA-C2 and HLA-Bw4. However, a higher frequency of HLA-C1 in breast cancer patients was observed. These findings suggest a potential role for the KIR gene system in breast cancer. Further studies to confirm this observation are warranted.
    Human immunology 06/2013; · 2.55 Impact Factor
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    D R Mans, A B da Rocha, G Schwartsmann
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    D R Mans, A B da Rocha, G Schwartsmann
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    ABSTRACT: A large number of plants are known to possess strong antitumor properties. Previous studies have verified the antiproliferative activity of the extracts and fractions from six species of Hypericum spp. growing in southern Brazil. In the present study, the in-vitro antiproliferative effects of two dimeric phloroglucinols (japonicin A and uliginosin B, isolated from Hypericum myrianthum) and two benzophenones (cariphenone A and cariphenone B, isolated from H. carinatum) were investigated against three tumor cell lines (HT-29 - human colon carcinoma cells; U-251 - human glioma cell line, and OVCAR-3 - human ovarian carcinoma cells). In addition, different doses of these compounds were associated with cytotoxic drugs commonly used as chemotherapy in the clinic. Cariphenone A and cariphenone B showed moderate antiproliferative activity against all tumor cell lines at a dose of 100 μg/ml. Unlike benzophenones, japonicin A and uliginosin B exerted antiproliferative effects only in the OVCAR-3 cell line. Moreover, a very strong synergistic effect was demonstrated by the association of subeffective doses of japonicin A with the chemotherapeutic drug paclitaxel, decreasing cellular proliferation of the OVCAR-3 cell line. These preliminary results provide a scientific basis to further pursue these compounds as potential combined therapy for certain tumor types.
    Anti-cancer drugs 05/2013; · 2.23 Impact Factor
  • B F Marrone, L Meurer, A Moretto, W Kleina, G Schwartsmann
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    ABSTRACT: BACKGROUND: Gastrin-releasing peptide (GRP) is a neuroendocrine peptide shown to possess growth-stimulatory effects in many types of human cancers. High levels of GRP receptors have been found in various types of human cancers, and preclinical studies exploring the therapeutic use of GRP receptor (GRPR) antagonists have been reported, with promising results. Data on GRPR expression in human malignant melanoma (MM) are scanty. AIM: To determine GRPR expression in biopsy material obtained from patients diagnosed with cutaneous MM. METHODS: Immunohistochemistry was performed on formalin-fixed, paraffin wax-embedded tissue samples obtained from 51 patients with cutaneous MM. The relationship between GRPR expression and the clinicopathological features was analysed using the Fisher exact test. RESULTS: GRPR immunoexpression was found in 42/51 cutaneous melanoma samples (82.4%). It was strongly expressed in 30 cases (58.9%). There was no significant difference in the levels of GRPR expression between primary or metastatic lesions. We correlated the GRPR expression score with pathological features associated with prognosis in cutaneous MM. There was no significant difference in GRPR expression in relation to Clark level (CL; P = 0.35) or Breslow Index (BI; P = 0.17). CONCLUSIONS: GRPR expression levels were high in tissue specimens of MM (82.4%), but did not correlate with pathological features related to prognosis, such as CL or BI. Further studies, preferably in a larger patient population, are warranted.
    Clinical and Experimental Dermatology 04/2013; · 1.23 Impact Factor

Publication Stats

3k Citations
880.99 Total Impact Points


  • 1999–2014
    • Universidade Federal do Rio Grande do Sul
      • • Institute of Basic Sciences and Health
      • • Faculty of Medicine
      Pôrto de São Francisco dos Casaes, Rio Grande do Sul, Brazil
  • 1991–2013
    • Hospital De Clínicas De Porto Alegre
      Pôrto de São Francisco dos Casaes, Rio Grande do Sul, Brazil
  • 2010
    • London School of Hygiene and Tropical Medicine
      • Department of Health Services Research and Policy
      London, ENG, United Kingdom
    • University of Havana
      • Instituto de Farmacia y Alimentos (IFAL)
      Havana, Provincia de La Habana, Cuba
  • 2007–2010
    • Pontifícia Universidade Católica de Goiás (PUC Goiás)
      Goyaz, Goiás, Brazil
  • 2006–2010
    • Universidade do Extremo Sul Catarinense (UNESC)
      Cresciúma, Santa Catarina, Brazil
  • 2008
    • Hospital Samaritano Rio de Janeiro
      Rio de Janeiro, Rio de Janeiro, Brazil
  • 2003
    • Stanford University
      • Department of Medicine
      Stanford, CA, United States
  • 2002
    • Institut Jules Bordet
      • Department of Nuclear Medicine
      Bruxelles, Brussels Capital Region, Belgium
  • 2000–2002
    • Universidade Luterana do Brasil
      Canoas, Rio Grande do Sul, Brazil
  • 1997
    • Federal University of Minas Gerais
      • Hospital das Clínicas
      Belo Horizonte, Estado de Minas Gerais, Brazil
  • 1990
    • Netherlands Cancer Institute
      Amsterdamo, North Holland, Netherlands
  • 1987–1990
    • VU University Amsterdam
      • Department of Medical Oncology
      Amsterdam, North Holland, Netherlands
  • 1987–1989
    • University of Amsterdam
      Amsterdamo, North Holland, Netherlands