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A multiplica??o celular descontrolada constitui a ess?ncia do comportamento biol?gico das neoplasias malignas e envolve mecanismos altamente complexos. Eventos celulares relacionados ? respira??o s?o respons?veis pela produ??o de energia e, por isso, essenciais ? sobreviv?ncia celular. A compreens?o dos processos neopl?sicos ? um desafio, e o conhecimento de biomarcadores espec?ficos envolvidos na capta??o energ?tica das c?lulas malignas ? crucial para o melhor entendimento do c?ncer. O presente estudo teve por objetivo investigar a express?o dos transportadores de monocarboxilato 1 (MCT1) e 4 (MCT4), bem como sua rela??o com a taxa de prolifera??o celular (Ki67) e caracter?sticas cl?nicas em diferentes tipos histol?gicos de tumores da cavidade oral. Prontu?rios e esp?cimes de bi?psia de tumores orais foram distribu?dos nos seguintes grupos: (1) 14 linfomas; (2) 5 melanomas; (3) 11 adenocarcinomas (prim?rios e met?stases); (4) 15 carcinomas espinocelulares (CEC); e (5) grupo-controle: 15 hiperplasias fibroepiteliais. Os prontu?rios foram revisados considerando idade e sexo dos pacientes; uso de ?lcool e tabaco; sintomas; e s?tio anat?mico, tamanho e tempo de evolu??o das les?es. Os esp?cimes foram submetidos a processamento imunoistoqu?mico para avaliar a express?o dos marcadores MCT1, MCT4 e Ki-67. De modo geral, os tumores orais avaliados tiveram coexpress?o de MCT1 e MCT4, especialmente o CEC e o melanoma. MCT1 e MCT4 exibiram correla??o positiva entre si; MCT1 tamb?m teve correla??o positiva com Ki67, enquanto o MCT4 n?o teve. Os tr?s marcadores exibiram correla??o positiva com tamanho do tumor, enquanto somente o MCT4 teve correla??o negativa com o tempo de evolu??o. Conclus?o: O perfil de express?o dos marcadores MCT1 e MCT4 corrobora sua rela??o com fatores progn?sticos, bem como a participa??o do efeito Warburg reverso no perfil energ?tico do c?ncer oral. S?o necess?rios novos estudos para subsidiar evid?ncias desses fatores como um novo alvo na terap?utica oncol?gica. Uncontrolled cell proliferation is the essence of biological behavior of malignancies, comprising highly complex mechanisms. Cellular processes related to respiration are responsible for the energy production and, therefore, essential for cell surviving. Understanding tumor biology is a challenging task, and the knowledge of biomarkers involved in the energy processes of cancer cells is extremely important to better understand the cancer itself. The aim of the present study was to analyze the expression of monocarboxylate transporter 1 (MCT1) and 4 (MCT4) and the relationship of these transporters to cell proliferation rate (Ki67) and clinical features in malignant tumors of the oral cavity. Paraffin-embedded oral biopsy specimens were allocated into the following groups: (1) 14 lymphomas; (2) 5 melanomas; (3) 11 adenocarcinomas (primary and metastases); (4) 15 squamous cell carcinomas (SCCs); and (5) 15 fibroepithelial hyperplasias (control group). Medical records were reviewed considering patients? age and sex, alcohol and tobacco use, symptoms, and the anatomical site, evolution time and size of the tumor. The immunohistochemical expression of Ki67, MCT1 and MCT4 was analyzed in the sample. Overall, MCT1 and MCT4 were co-expressed in the oral tumors analyzed, especially in SCC and melanoma. MCT1 and MCT4 were positively correlated to each other; MCT1 was also correlated to Ki67, whereas MCT4 was not. These three markers were positively correlated to tumor size, whereas only MCT4 was negatively correlated to the evolution time of the tumor. Conclusion: MCT1 and MCT4 expression supports reverse Warburg effect as an energy profile in oral cancer and its relationship to prognostic factors. Further studies analyzing the specificities of this relationship are needed to provide evidence of a new target in oral oncology therapeutics. Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES

Submitted by WALTER HEINZ FERINGER JUNIOR null (walterferinger@gmail.com) on 2018-03-22T22:47:37Z No. of bitstreams: 1 TESE_WALTER_HEINZ_FERINGER_JUNIOR.pdf: 2433033 bytes, checksum: 618fd780a0ad05e04e544c2769f96c3d (MD5) Approved for entry into archive by Alexandra Maria Donadon Lusser Segali null (alexmar@fcav.unesp.br) on 2018-03-23T10:43:56Z (GMT) No. of bitstreams: 1 feringerjunior_wh_dr_jabo.pdf: 2433033 bytes, checksum: 618fd780a0ad05e04e544c2769f96c3d (MD5) Made available in DSpace on 2018-03-23T10:43:56Z (GMT). No. of bitstreams: 1 feringerjunior_wh_dr_jabo.pdf: 2433033 bytes, checksum: 618fd780a0ad05e04e544c2769f96c3d (MD5) Previous issue date: 2017-11-13 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) O principal mecanismo de transporte dos íons lactato e H+ em equinos e cães é o complexo transportador formado pelos transportadores de monocarboxilatos, isoformas 1 (MCT1) e 4 (MCT4) juntamente com a proteína auxiliar CD147. Objetivando identificar diferenças entre equinos com desempenho distinto, 16 equinos da raça Brasileiro de Hipismo (BH) foram distribuídos em dois grupos, desempenho inferior (DI, n=8) e desempenho superior (DS, n=8) que foram submetidos a teste de salto incrementai (TSI). Realizou-se biópsia do músculo Gluteus medius para tipificação e análise das expressões das isoformas MCT1, MCT4 e CD147. Amostras sanguíneas foram colhidas para avaliar as expressões MCT1 e CD147 das hemácias. Aplicaram-se testes de normalidade de Shapiro Wilk e homogeneidade de Levene. As medidas morfométricas foram submetidas ao teste de Tukey. Teste “t” de Student não pareado para a comparação das médias dos grupos DI e DS. Aplicou-se correlação de Spearman para as expressões dos transportadores. Para todas as análises utilizou-se p≤0,05. Não houve diferença entre os grupos quanto à frequência de cada tipo de fibra e constatou-se maior quantidade das fibras tipo I em relação às fibras IIA e IIX em todos os equinos avaliados. Não houve diferença entre os pesos moleculares e a expressão das proteínas MCT1, MCT4, e CD147 musculares ou sanguíneas. Houve correlações positivas entre MCT1 vs. CD147 e MCT4 vs. CD147 musculares dos grupos DI e DS. As correlações encontradas foram esperadas uma vez que as isoformas estudadas dependem intimamente da proteína auxiliar CD147 para o transporte. Os equinos BH não apresentaram diferenças nas expressões dos MCT1,4 e CD147, musculares ou sanguíneos, mesmo com níveis de condicionamento diferentes. Com o objetivo de investigar as concentrações de lactato plasmático e das hemácias e avaliar as expressões eritrocitáras do complexo transportador MT1/CD147, 6 cães da raça American Pitbull Terrier (APBT) foram submetidos ao teste de esforço incremental (TEI) em esteira. No final de cada incremento de velocidade foi coletado sangue da veia cefálica. Foram mensuradas concentrações de lactato sanguíneo (LS), plasmático (LP), pH e hematócrito (Ht). A concentração do lactato dentro das hemácias (LH) foi estimada e estabeleceu-se a relação LH:LP. As expressões sanguíneas do complexo MCT1/CD147 foram avaliadas por Western Bloting. Aplicou-se análise de variância de uma via seguido pelo teste de Dunn’s. Para pH e Ht aplicou-se teste t de student para amostras pareadas e a correlação de Pearson foi utilizada para MCT1 e CD147, estabeleceu-se nível de significância P≤0,05. LS, LP e LH e pH não apresentaram diferenças entre si, a relação LH:LP foi próxima de 1 com tendência de aumento. MCT1 e CD147 apresentaram 48 e 59 kDa de peso molecular e 1,27 e 1,05 de unidades ópticas arbitrárias (UOA). Não foram encontradas correlações entre MCT1 e CD147. A grande velocidade de transporte do MCT1/CD147 explica a relação LP:LH próxima de 1, esta velocidade e o mecanismo de arquejo podem explicar os valores de pH constantes. A raça APBT, quando submetidos à atividade física apresentaram tendência de aumento da relação LH:LP e expressam de maneira homogênea o complexo MCT1/CD147. The central transport mechanism of lactate and H+ ions in horses and dogs is the carrier complex formed by the monocarboxylate, isoform 1 (MCT1) and 4 (MCT4) associated with the ancillary protein CD147. This study aimed to identify possible differences between horses with different performances levels, 16 horses of the Brazilian Sport Horse breed (BH) were distributed in two groups, inferior performance (IP, n = 8) and superior performance (SP, n = 8). A Gluteus medius muscle biopsy was performed for cellular typing and analysis of MCT1, MCT4, and CD147 muscle expressions. By jugular venipuncture, blood samples were collected to evaluate MCT1 and CD147 expressions in the red blood cells (RBC). Normality Shapiro Wilk test and homogeneity of Levene were applied. The morphometric measurements were submitted to the Tukey test, and not paired Student's t-test were applied to compare the mean of the IP and SP groups for all variables and was used Spearman's correlation for isoform expressions, for all analyzes, p≤0.05. There were no differences between the groups regarding the frequency of each type of fiber and a higher number of type I fibers were observed about the IIA and IIX fibers in all groups. There was no difference between molecular weights and expressions of MCT1, MCT4, and CD147 in muscle or blood. There were positive correlations between muscles MCT1 vs CD147 and MCT4 vs CD147 in both groups. The relationships found were expected since the MCT1 and 4 depended on the CD147 ancillary protein for correct functioning. The BH horses do not present differences in the muscle or RBC expressions of MCT1, 4 and CD147, even with different conditioning levels. To investigate plasma and erythrocyte lactate concentrations and to evaluate erythrocyte expression of the MT1/CD147 transporter complex, six dogs of the American Pit Bull Terrier breed (APBT) were submitted to a treadmill incremental effort test (IET). At the end of each increment of speed, blood was collected from the cephalic vein. Concentrations of blood (BL) and plasma lactate (PL), pH and hematocrit (Ht) were measured. The concentration of lactate inside the red blood cells (LC) was estimated and the LC: PL ratio was established, the blood expressions of the MCT1/CD147 transporter complex were evaluated by western blot. Data were submitted to the Shapiro-Wilks normality test, one-way ANOVA and Dunn's test. For pH and Ht, paired Student's t-test was applied, and Pearson's correlation was used for MCT1 and CD147 analysis, for all analyzes, p≤0.05. BL, PL, LC, pH showed no differences, the LC: PL ratio was close to 1 with an increasing tendency. MCT1 and CD147 presented 48 and 59 kDa of molecular weight and 1.27 and 1.05 of arbitrary optical units (AOU). No correlations were found between MCT1 and CD147. The high transport velocity of the MCT1/CD147 could explain the LC: PL ratio close to 1, this velocity plus the grasping mechanism may explain the constant of pH values. The APBT submitted to intense physical activity showed a tendency to increase the LC: PL ratio, and homogeneously express the MCT1/CD147 complex FAPESP: 11/11080-0