Sobre o direito de ser normal: identidades normalizadas e a construção das políticas públicas de saúde para gays e lésbicas na cidade de São Paulo

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Characterization of monocarboxylate transporters (MCTs) expression in soft tissue sarcomas: distinct prognostic impact of MCT1 sub-cellular localization

Background: Soft tissue sarcomas (STSs) are a group of neoplasms, which, despite current therapeutic advances, still confer a poor outcome to half of the patients. As other solid tumors, STSs exhibit high glucose consumption rates, associated with worse prognosis and therapeutic response. As highly glycolytic tumors, we hypothesized that sarcomas should present an increased expression of lactate transporters (MCTs).Methods: Immunohistochemical expression of MCT1, MCT2, MCT4 and CD147 was assessed in a series of 86 STSs and the expression profiles were associated with patients' clinical-pathological parameters.Results: MCT1, MCT4 and CD147 were mainly observed in the plasma membrane of cancer cells (around 60% for MCTs and 40% for CD147), while MCT2 was conspicuously found in the cytoplasm (94.2%). Importantly, we observed MCT1 nuclear expression (32.6%). MCT1 and MCT4, alone or co-expressed with CD147 in the plasma membrane, were associated with poor prognostic variables including high tumor grade, disease progression and shorter overall survival. Conversely, we found MCT1 nuclear expression to be associated with low grade tumors and longer overall survival.Conclusions: The present work represents the first report of MCTs characterization in STSs. We showed the original finding of MCT1 expression in the nucleus. Importantly, opposite biological roles should be behind the dual sub-cellular localization of MCT1, as plasma membrane expression of MCT1 is associated with worse patients' prognosis, while nuclear expression is associated with better prognosis.

Morphological and biochemical alterations activated by antitumor clerodane diterpenes

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Gene expression profiling in leiomyosarcomas and undifferentiated pleomorphic sarcomas: SRC as a new diagnostic marker

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Estudos citogenéticos para detecção de marcadores de diagnóstico e prognóstico em sarcomas ósseos

A busca pela identificação de fatores que possam apontar o diagnóstico, a resposta terapêutica e a sobrevida dos pacientes portadores de sarcoma ósseos tem sido incessante. Presumir a agressividade tumoral, capacidade de invasão tecidual, probabilidade de recidiva, propensão ao desenvolvimento de metástases e resposta ao tratamento, poderá ser valioso expediente na escolha da proposta terapêutica. Embora fatores ambientais e dietéticos contribuam para a etiologia do câncer, as neoplasias se originam de um processo de múltiplos passos envolvendo alterações de genes e seleção clonal da progênie variante. Estas mutações ocorrem em classes de genes reguladores da proliferação celular como os oncogenes, genes supressores de tumor, fatores de crescimento, vias de sinalização e genes de reparo de DNA. Os conhecimentos sobre a biologia tumoral melhoraram o entendimento sobre os múltiplos aspectos da carcinogênese. No entanto, embora as perspectivas permaneçam, até agora, há poucos benefícios para prevenção, diagnóstico, tratamento e seguimento dos pacientes com sarcomas ósseos. Este trabalho teve por objetivo detectar e descrever alterações cromossômicas consistentes e recorrentes, através da utilização de análises com a citogenética clássica. Também descreveu o envolvimento dessas alterações com o prognóstico em sarcomas ósseos primários e secundários, na tentativa de contribuir para a realização de estratégias mais eficazes para melhorar as taxas de sobrevida e beneficiar maior número de pacientes portadores de sarcomas ósseos. As lesões ósseas apresentaram alterações citogenéticas clonas e recorrentes, das quais as principais foram: sarcoma pouco diferenciado, o qual apresentou del(7)(p21); osteossarcoma metastático, apresentando del(4)(q32), add(13)(p13), add(14)(p13); tumor de células gigantes com add(14)(p13); ...(Resumo completo, clicar acesso eletrônico abaixo)

Análise da expressão de genes oncogênicos selecionados do KSHV em células endoteliais TIVE-LTC co-cultivadas com células linfóides Jurkat com e sem expressão constitutiva da proteína tat do HIV-1

O Herpesvírus associado ao sarcoma de Kaposi (KSHV), ou Herpesvírus Humano tipo 8 (HHV-8), é o agente etiológico do sarcoma de Kaposi (SK), uma neoplasia maligna vascular. O ciclo biológico do KSHV apresenta duas fases, denominadas ciclo latente e ciclo lítico (ou produtivo). O ciclo latente é marcado pela expressão de um número reduzido de genes virais, com destaque para LANA e vFLIP. No ciclo lítico ocorre a replicação do genoma viral e a produção de novas partículas virais infecciosas; dentre seus principais produtos destacam-se as proteínas Rta, vGPCR e K1. LANA, vFLIP, vGPCR e K1 apresentam propriedades oncogênicas relatadas na literatura, enquanto Rta têm papel importante na regulação da transição entre os ciclos lítico e latente do KSHV. O KSHV é requerido para o desenvolvimento do SK. No entanto, a infecção pelo vírus não é suficiente para o desenvolvimento da doença. Por outro lado, sabe-se que o HIV é um co-fator importante, que favorece o desenvolvimento dessa neoplasia. Sugere-se que a proteína tat do HIV-1 amplifica a infectividade do KSHV, hiper-regulando a expressão de diferentes genes herpesvirais e colaborando para o crescimento e sobrevivência de células endoteliais que compõem as lesões do SK. A fim de contribuir para um melhor entendimento dos efeitos da proteína tat do HIV-1 em células infectadas pelo KSHV, o presente trabalho descreveu eventuais alterações na expressão dos genes codificadores de vFLIP, LANA, vGPCR, Rta e K1 em células endoteliais de veia umbilical humana imortalizada pela telomerase e infectada pelo KSHV a longo prazo (TIVE-LTCs) expostas à proteína tat do HIV-1 produzida por células linfóides T (CLTs) em co-cultivo. Células Jurkat contendo ou não vetor da proteína tat do HIV-1 foram utilizadas como CLTs e co-cultivadas com TIVE-LTCs por 48, 72 e 96 horas. Após extração do RNA total das...(Resumo completo, clicar acesso eletrônico abaixo)

Prevalence of the germline TP53 p.R337H mutation in families with multiple cases of cancer

Germline mutations in TP53 gene are associated with Li-Fraumeni syndrome (LFS) and its variants Li-Fraumeni-like (LFL). They predispose carriers to a wide variety of early onset tumors. In Brazil, there is a high frequency of a germline mutation in this gene (NC_000017.9: c.1010G>A; p.R337H) in Southern and Southeastern regions, due to a founder effect. It is estimated to be present in 0,3% ofthe local population, but only few families have been detected. Due to this significant divergence, the purpose of this study was to verify the effectiveness of wider criteria for detection of these individuals. Herein, clinical criteria were established, DNA samples were collected, analyzed by Restriction Fragment Length Polymorphism (RFLP) and sequenced. Thus, assessing the prevalence of this mutation in families with multiple cases of cancer. Based on our proposed criteria, one out of 31 patients (3,22%) was found to carry p.R337H mutation. The patient developed ductal invasive breast cancer at age 47, invasive adenocarcinoma of the lung at age 48 and soft-tissue sarcoma at age 49. In addition, an extensive cancer family history was referred, atypical for LFS, including a case of Ewing’s sarcoma. These outcomes indicate that the proposed criteria may detect probable carriers who did not fit previous LFS criteria. Nevertheless, additional studies, which might include a larger number of families and more stringent parameters, will be useful to improve screening sensibility

Antitumor activity of irradiated riboflavin on human renal carcinoma cell line 786-O

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Human gammaherpesviruses viraemia in HIV infected patients

The Epstein-Barr virus (EBV) and Kaposi's sarcoma associated herpesvirus (KSHV) are consistently associated with lymphoproliferative diseases and cancers in humans, notably in patients with HIV. Our aim was to evaluate whether EBV and/or KSHV viral loads regularly assessed in peripheral blood mononuclear cells (PBMC) correlate with clinical or laboratorial parameters retrieved for patients living with HIV. This was a longitudinal study with a cohort of 157 HIV positive patients attending an academic HIV outpatient clinic in São Paulo State, Brazil. For each patient, up to four blood samples were collected over a 1 year clinical follow-up: on enrolment into the study, and after 4, 8 and 12 months. Total DNA was extracted from PBMC, and EBV and KSHV viral loads were assessed by real time quantitative PCR. Higher viral loads for EBV were significantly associated with high HIV viraemia, a greater number of circulating T CD8+ cells and lack of virological response to the antiretroviral treatment. KSHV viral load was undetectable in virtually all samples. EBV viral load in PBMC correlated with the number of circulating T CD8+ lymphocytes and the response to the antiretroviral therapy in HIV infected patients. In contrast, KSHV was undetectable in PBMC, presumably an effect of the antiretroviral treatment. Therefore, either KSHV infection in the population studied was absent or viral load in PBMC was beyond the analytical limit of the assay.

Leishmania sp. amastigotes identification in canine transmissible venereal tumor

Leishmaniasis is a vector-borne disease with Leishmania chagasi being the etiological agent of canine visceral leishmaniasis in South America. Canine venereal tumor is a transplantable round cell tumor of histiocytic origin which is mostly observed in sexually active male and female intact dogs. It has been shown that Leishmania amastigotes have higher tropism for the canine male genital tract tissues and venereal leishmaniasis transmission has been documented in dogs but, to date, a canine venereal tumor-dependent transmission route has not been fully demonstrated. In this report, a 10-year-old, mixed breed, intact female dog presented a vaginal venereal transmissible tumor but no other clinical abnormalities otherwise. Unexpectedly, tumor tissue imprint smears examination revealed Leishmania sp. amastigotes within infiltrating macrophages. In addition to the cytological direct identification, the protozoan was confirmed within the neoplastic tissue by means of immunohistochemistry and polymerase chain reaction. This report illustrates an asymptomatic Leishmania sp. infection that may have started on or from the canine venereal tumor tissue, the latter option further supporting previous evidence of such an alternative vector-independent route of transmission for canine visceral leishmaniasis in areas where these diseases coexist.

Jatropha curcas pericarp toxicity in sheep

Physic nut (Jatropha curcas) is a plant cultivated for biofuel production. Pericarp is a potential livestock food source by-product. However, its use may be limited due to the presence of toxic compounds, mainly phorbol esters. Thus, this study aimed to evaluate pericarp toxicity. Twenty sheep were divided in four groups, one control group which did not receive the plant and three experimental groups which received pericarp in 15% (G15), 30% (G30) and 45% (G45) concentrations for 23 days. After 10 days of treatment, pericarp ingestion produced food intake decrease, diarrhea, dehydration and loss of body condition. All treated groups showed decrease in alkaline phosphatase activity. G30 animals presented reductions in urea and total protein concentrations, and increase in potassium and sodium levels. G45 animals showed increase in serum aspartate aminotransferase activity and in albumin, creatinin, total and indirect bilirubin levels. Anatomohistopathologic findings included ascites, hydropericardium, congestion of the gastintestinal tract and lungs, pulmonary edema and adhesions in the thoracic cavity, renal tubular cells and centrilobular cytoplasmic vacuolation and lymphohistiocytic pneumonia and lymphoplasmacytic and histiocytic enteritis. On the physiochemical analysis 0.3845mg of phorbol esters/g of pericarp were detected. It is concluded that J. curcas pericarp is toxic and is not recommended for sheep feeding.

Oral Lesions in Renal Transplant

To prevent rejection of kidney transplants, patients must be kept in immunosuppressive therapy for a long time, which includes the use of drugs such as cyclosporine, azathioprine, cyclophosphamide, and prednisone. The action of these drugs reduces the general immune response of transplant patients and thus increases their susceptibility to infections. Moreover, these drugs increase the potential of developing lesions. Therefore, oral hygiene in kidney transplant recipients contributes to maintenance of the transplanted organ and its function. Thus, an investigation of oral lesions could be counted as a notable work. The aim of this study was to investigate oral lesions in a group of 21 kidney transplant patients under immunosuppressive therapy attended during a 1-year period in the Nephrology Department of the Federal University of Sergipe, Brazil. Data related to sex, age, etiology of renal disease, types of renal transplant, time elapsed after transplantation, immunosuppressive treatment, use of concomitant agents, and presence of oral lesions were obtained. All patients received a kidney transplant from a living donor, and the mean posttransplantation follow-up time was 31.6 months; 71.5% used triple immunosuppressive therapy with cyclosporine A, azathioprine, and prednisone. Ten patients were also treated with calcium-channel blockers. Of the 21 transplant patients, 17 (81%) presented oral lesions. Gingival overgrowth was the most common alteration, followed by candidiasis and superficial ulcers. One case of spindle cell carcinoma of the lower lip was observed. Oral cavity can harbor a variety of manifestations related to renal transplantation under immunosuppressive therapy.

BCL2A1a Over-Expression in Murine Hematopoietic Stem and Progenitor Cells Decreases Apoptosis and Results in Hematopoietic Transformation

We previously reported the development of a lethal myeloid sarcoma in a non-human primate model utilizing retroviral vectors to genetically modify hematopoietic stem and progenitor cells. This leukemia was characterized by insertion of the vector provirus into the BCL2A1 gene, with resultant BCL2A1 over-expression. There is little information on the role of this anti-apoptotic member of the BCL2 family in hematopoiesis or leukemia induction. Therefore we studied the impact of Bcl2a1a lentiviral over-expression on murine hematopoietic stem and progenitor cells. We demonstrated the anti-apoptotic function of this protein in hematopoietic cells, but did not detect any impact of Bcl2a1a on in vitro cell growth or cell cycle kinetics. In vivo, we showed a higher propensity of HSCs over-expressing Bcl2a1a to engraft and contribute to hematopoiesis. Mice over-expressing Bcl2a1a in the hematologic compartment eventually developed an aggressive malignant disease characterized as a leukemia/lymphoma of B-cell origin. Secondary transplants carried out to investigate the primitive origin of the disease revealed the leukemia was transplantable. Thus, Bcl2a1 should be considered as a protooncogene with a potential role in both lymphoid and myeloid leukemogenesis, and a concerning site for insertional activation by integrating retroviral vectors utilized in hematopoietic stem cell gene therapy.

Transmission of Human Herpesvirus Type 8 Infection Within Families in American Indigenous Populations From the Brazilian Amazon

Background. The intrafamilial dynamics of endemic infection with human herpesvirus type 8 (HHV-8) in Amerindian populations is unknown. Methods. Serum samples were obtained from 517 Amerindians and tested for HHV-8 anti-latent nuclear antigen (anti-LANA) and antilytic antibodies by immunofluorescence assays. Logistic regression and mixed logistic models were used to estimate the odds of being HHV-8 seropositive among intrafamilial pairs. Results. HHV-8 seroprevalence by either assay was 75.4% (95% confidence interval [CI]: 71.5%-79.1%), and it was age-dependent (P-trend<.001). Familial dependence in HHV-8 seroprevalence by either assay was found between mother-offspring (odds ratio [OR], 5.44; 95% CI: 1.62-18.28) and siblings aged >= 10 years (OR 4.42, 95% CI: 1.70-11.45) or siblings in close age range (<5 years difference) (OR 3.37, 95% CI: 1.21-9.40), or in families with large (>4) number of siblings (OR, 3.20, 95% CI: 1.33-7.67). In separate analyses by serological assay, there was strong dependence in mother-offspring (OR 8.94, 95% CI: 2.94-27.23) and sibling pairs aged >= 10 years (OR, 11.91, 95% CI: 2.23-63.64) measured by LANA but not lytic antibodies. Conclusions. This pattern of familial dependence suggests that, in this endemic population, HHV-8 transmission mainly occurs from mother to offspring and between close siblings during early childhood, probably via saliva. The mother to offspring dependence was derived chiefly from anti-LANA antibodies.

Prognostication of Soft Tissue Sarcomas Based on Chromosome 17q Gene and Protein Status: Evaluation of TOP2A, HER-2/neu, and Survivin

Topoisomerase 2 alpha (), HER-2/ and are genes that lie on chromosome 17 and correlate with the prognosis and prediction of target-driven therapy against tumors. In a previous study, we showed that TOP2A transcripts levels were significantly higher in soft tissue sarcomas (STS) than in benign tumors and desmoid-type fibromatoses (FM). Because these genes have been insufficiently examined in STS, we aimed to identify alterations in TOP2A and HER-2 expression by fluorescent in situ hybridization and immunohistochemistry, as well as that of survivin, and correlate them with clinicopathologic findings to assess their prognostic value. Eighteen FM and 244 STS were included. Fluorescent in situ hybridization and immunohistochemistry were performed on a tissue microarray. TOP2A and survivin were more highly expressed in sarcomas than in FM. TOP2A was an independent predictor of an unfavorable prognosis; it was combined with formerly established prognostic factors (primarily histologic grade and tumor size at diagnosis) to create a prognostic index that evaluated overall survival. Gene amplification/polysomy (13%) did not correlate with protein overexpression. Survivin and HER-2 expression were not associated with patient outcomes. These findings might become valuable in the management of patients with STS and possibly in the prospective evaluation of responses to new target-driven therapies.