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1.
Front Immunol ; 13: 947648, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36172343

RESUMO

CAR-T cell therapies have been recognized as one of the most advanced and efficient strategies to treat patients with hematologic malignancies. However, similar results have not been observed for the treatment of solid tumors. One of the explanations is the fact that tumors have extremely hostile microenvironments for the infiltration and effector activity of T-cells, mainly due to the presence of highly suppressive cytokines, hypoxia, and reactive oxygen species. Taking advantage of cytokines functionally, new fourth-generation CAR constructs have been developed to target tumor cells and additionally release cytokines that can contribute to the cytotoxicity of T-cells. The manufacturing process, including the use of cytokines in the expansion and differentiation of T cells, is also discussed. Finally, the clinical aspects and the influence of cytokines on the clinical condition of patients, such as cytokine release syndrome, who receive treatment with CAR-T cells are addressed. Therefore, this review aims to highlight how important cytokines are as one of the major players of cell therapy.


Assuntos
Neoplasias , Receptores de Antígenos Quiméricos , Terapia Baseada em Transplante de Células e Tecidos , Citocinas , Citotoxicidade Imunológica , Humanos , Imunomodulação , Neoplasias/terapia , Espécies Reativas de Oxigênio , Receptores de Antígenos Quiméricos/genética , Microambiente Tumoral
2.
Cancers (Basel) ; 13(9)2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-34066355

RESUMO

Human papillomavirus (HPV)-induced carcinogenesis comprises alterations in the expression and activity of matrix metalloproteinases (MMP) and their regulators. Reversion-inducing Cysteine-rich protein with Kazal motifs (RECK) inhibits the activation of specific metalloproteinases and its expression is frequently lost in human cancers. Here we analyzed the role of RECK in cervical carcinogenesis. Cervical cancer derived cell lines over expressing RECK were used to determine tumor kinetics as well as, cellular, immune and molecular properties in vivo. Besides, we analyzed RECK expression in cervical cancer samples. RECK over expression (RECK+) delayed tumor growth and increased overall survival in vivo. RECK+ tumors displayed an increase in lymphoid-like inflammatory infiltrating cells, reduced number and viability of tumor and endothelial cells and lower collagenase activity. RECK+ tumors exhibited an enrichment of cell adhesion processes both in the mouse model and cervical cancer clinical samples. Finally, we found that lower RECK mRNA levels were associated with cervical lesions progression and worse response to chemotherapy in cervical cancer patients. Altogether, we show that increased RECK expression reduced the tumorigenic potential of HPV-transformed cells both in vitro and in vivo, and that RECK down regulation is a consistent and clinically relevant event in the natural history of cervical cancer.

3.
Front Oncol ; 10: 587132, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33330068

RESUMO

Cervical cancer, which main etiologic factor is Human Papillomavirus (HPV) infection, continues to be a burden for public health systems in developing countries. Our laboratory has been working with the hypothesis that signals generated in the tumor microenvironment can modulate local and systemic immune responses. In this context, it would be reasonable to think that tumors create pro-tumoral bias in immune cells, even before they are recruited to the tumor microenvironment. To understand if and how signaling started in the tumor microenvironment can influence cells within the tumor and systemically, we investigated the expression of key proteins in signaling pathways important for cell proliferation, viability, immune responses and tolerance. Besides, we used detection of specific phosphorylated residues, which are indicative of activation for Akt, CREB, p65 NFκB, and STAT3. Our findings included the observation of a significant STAT3 expression increase and p65 NFκB decrease in circulating leukocytes in correlation with lesion grade. In light of those observations, we started investigating the result of the inhibition of STAT3 in a tumor experimental model. STAT3 inhibition impaired tumor growth, increased anti-tumor T cell responses and decreased the accumulation of myeloid cells in the spleen. The concomitant inhibition of NFκB partially reversed these effects. This study indicates that STAT3 and NFκB are involved in immunomodulatory tumor effects and STAT3 inhibition could be considered as therapy for patients with cervical cancer.

4.
PLoS One ; 14(3): e0213184, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30840689

RESUMO

Cervical cancer, caused by high oncogenic risk Human Papillomavirus (HPV) infection, continues to be a public health problem, mainly in developing countries. Using peptide phage display as a tool to identify potential molecular targets in HPV associated tumors, we identified α-mannosidase, among other enriched sequences. This enzyme is expressed in both tumor and inflammatory compartment of the tumor microenvironment. Several studies in experimental models have shown that its inhibition by swainsonine (SW) led to inhibition of tumor growth and metastasis directly and indirectly, through activation of macrophages and NK cells, promoting anti-tumor activity. Therefore, the aim of this work was to test if swainsonine treatment could modulate anti-tumor immune responses and therefore interfere in HPV associated tumor growth. Validation of our biopanning results showed that cervical tumors, both tumor cells and leukocytes, expressed α-mannosidase. Ex vivo experiments with tumor associated macrophages showed that SW could partially modulate macrophage phenotype, decreasing CCL2 secretion and impairing IL-10 and IL-6 upregulation, which prompted us to proceed to in vivo tests. However, in vivo, SW treatment increased tumor growth. Investigation of the mechanisms leading to this result showed that SW treatment significantly induced the accumulation of myeloid derived suppressor cells in the spleen of tumor bearing mice, which inhibited T cell activation. Our results suggested that SW contributes to cervical cancer progression by favoring proliferation and accumulation of myeloid cells in the spleen, thus exacerbating these tumors systemic effects on the immune system, therefore facilitating tumor growth.


Assuntos
Proliferação de Células/efeitos dos fármacos , Swainsonina/farmacologia , Neoplasias do Colo do Útero/patologia , alfa-Manosidase/metabolismo , Animais , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Quimiocina CCL2/metabolismo , Progressão da Doença , Feminino , Humanos , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Leucócitos/citologia , Leucócitos/metabolismo , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/citologia , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/metabolismo , Swainsonina/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/virologia , alfa-Manosidase/antagonistas & inibidores
5.
Sci Rep ; 7(1): 9002, 2017 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-28827632

RESUMO

Cervical cancer is the last stage of a series of molecular and cellular alterations initiated with Human Papillomavirus (HPV) infection. The process involves immune responses and evasion mechanisms, which culminates with tolerance toward tumor antigens. Our objective was to understand local and systemic changes in the interactions between HPV associated cervical lesions and the immune system as lesions progress to cancer. Locally, we observed higher cervical leukocyte infiltrate, reflected by the increase in the frequency of T lymphocytes, neutrophils and M2 macrophages, in cancer patients. We observed a strong negative correlation between the frequency of neutrophils and T cells in precursor and cancer samples, but not cervicitis. In 3D tumor cell cultures, neutrophils inhibited T cell activity, displayed longer viability and longer CD16 expression half-life than neat neutrophil cultures. Systemically, we observed higher plasma G-CSF concentration, higher frequency of immature low density neutrophils, and tolerogenic monocyte derived dendritic cells, MoDCs, also in cancer patients. Interestingly, there was a negative correlation between T cell activation by MoDCs and G-CSF concentration in the plasma. Our results indicate that neutrophils and G-CSF may be part of the immune escape mechanisms triggered by cervical cancer cells, locally and systemically, respectively.


Assuntos
Fator Estimulador de Colônias de Granulócitos/sangue , Evasão da Resposta Imune , Neutrófilos/imunologia , Papillomaviridae/imunologia , Infecções por Papillomavirus/patologia , Neoplasias do Colo do Útero/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Dendríticas/imunologia , Feminino , Humanos , Macrófagos/imunologia , Pessoa de Meia-Idade , Infecções por Papillomavirus/complicações , Linfócitos T/imunologia , Adulto Jovem
6.
Artigo em Inglês | MEDLINE | ID: mdl-28293253

RESUMO

BACKGROUND: Snakes of the genus Bothrops, popularly known as pit vipers, are responsible for most cases of snakebite in Brazil. Within this genus, Bothrops jararacussu and B. jararaca deserve special attention due to the severity of their bites and for inhabiting densely populated areas. Regarding the treatment of snakebites by Bothrops jararacussu, questions have been raised about the effectiveness of the specific bothropic antivenom in neutralizing myotoxic effects; however, there are no accurate data for humans. Thus, the development of a differential diagnostic kit for this species would be of great interest because it provides, for healthcare professionals, a tool that would allow us to determine whether the accident was caused by B. jararacussu or other species of the genus. It would also make it possible to evaluate the specificity of the treatment and to provide data for epidemiological studies. METHODS: First, we produced a species-specific polyclonal antibody - a potential biomarker of Bothrops jararacussu venom - against bothropstoxin-I (BthTx-I), which is also found in smaller quantities in the venoms of B. jararaca from southern Brazil. RESULTS: Polyclonal antibodies against bothropstoxin-I could be separated into several species-specific immunoglobulins. Then, aiming to develop a system of safe and standardized immunoassay, we produced monoclonal antibodies. Seven hybridomas were obtained. Five of them were specific to the venom of B. jararacussu and two recognized the venom of B. jararaca from the southeastern population. The use of monoclonal antibodies also made it possible to differentiate B. jararacussu from B. jararaca venom obtained from the southern population. Analyzing the reactivity of monoclonal antibodies against other bothropic venoms, we found mAb Bt-3 to be more specific than others for B. jararacussu venom. CONCLUSIONS: These results show the potential of BthTx-I for producing monoclonal antibodies that differentiate between B. jararacussu and other Bothrops species venoms.

7.
Estud. psicol. (Natal) ; 22(1): 10-16, Mar. 2017. ilus, graf, tab
Artigo em Português | LILACS, Index Psicologia - Periódicos | ID: biblio-891912

RESUMO

Investigou-se a percepção monocular da profundidade ou relevo de máscaras policromadas objetivas côncava e convexa. Participaram do estudo 40 estudantes, que julgaram a profundidade ou relevo da máscara côncava e da máscara convexa. Mais da metade dos observadores, 67%, realizaram ou tenderam a realizar a inversão monocular da profundidade. Quando solicitados a avaliar em centímetros a distância da ponta do nariz da máscara à sua base, as maiores extensões foram designadas à máscara convexa, comparativamente à côncava. Porém, a inversão visual da profundidade de concavidades não foi afetada pela posição de apresentação das máscaras (vertical ou invertida) ou pela direção da fonte de iluminação incidente sobre elas (de cima ou por baixo). Os resultados confirmam que, na percepção de faces, o processo de alta ordem se sobrepõe ao processo de baixa ordem e que a ilusão da máscara côncava é um instrumento eficaz na verificação da percepção de profundidade.


It was investigated the monocular perception of depth or relief of objective concave and convex masks. The study included 40 students, who judge the depth or relief of a concave and a convex mask. More than half of observers, 67%, performed the monocular depth inversion. When asked to evaluate the distance in centimeters from the tip of the nose to the base of the mask, the major extensions were appointed to the convex mask, compared to concave. However, the visual inversion of depth of the concavities was not affected by the position of the masks (vertical or inverted) or by the direction of the light source incident on them (from top or bottom). The results confirm that in the face perception, the top-down process overlaps the bottom-up process and that the hollow-face illusion is an effective instrument in depth perception verification.


Se investigó la percepción monocular de profundidad o relieve de máscaras huecas y convexas objetivas. En el estudio participaron 40 estudiantes que juzgaron la profundidad o relieve de máscaras huecas y convexas. Más de la mitad de los observadores, el 67%, realizó la inversión monocular de la profundidad. Cuando se les pidió para evaluaren la distancia en centímetros desde la punta de la nariz hasta la base de la máscara, las más grandes extensiones fueron nombradas a la máscara convexa, en comparación con la máscara hueca. Sin embargo, la visual inversión de la profundidad de los huecos no ha sido afectada por la posición de presentación de las máscaras (vertical o invertida) o por la dirección de la fuente de luz incidente sobre ellas (desde arriba o abajo). Los resultados confirman que la percepción de las caras, los procesos de orden superior se superponen los procesos de orden inferior y la ilusión de la máscara hueca es una herramienta eficaz en la verificación de la percepción de profundidad.


Assuntos
Humanos , Masculino , Feminino , Percepção Visual , Acuidade Visual , Percepção de Profundidade , Máscaras Faciais , Estudantes/psicologia , Brasil , Análise de Variância
8.
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IBPROD, Sec. Est. Saúde SP | ID: but-ib15397

RESUMO

Background Snakes of the genus Bothrops, popularly known as pit vipers, are responsible for most cases of snakebite in Brazil. Within this genus, Bothrops jararacussu and B. jararaca deserve special attention due to the severity of their bites and for inhabiting densely populated areas. Regarding the treatment of snakebites by Bothrops jararacussu, questions have been raised about the effectiveness of the specific bothropic antivenom in neutralizing myotoxic effects; however, there are no accurate data for humans. Thus, the development of a differential diagnostic kit for this species would be of great interest because it provides, for healthcare professionals, a tool that would allow us to determine whether the accident was caused by B. jararacussu or other species of the genus. It would also make it possible to evaluate the specificity of the treatment and to provide data for epidemiological studies. Methods First, we produced a species-specific polyclonal antibody – a potential biomarker of Bothrops jararacussu venom – against bothropstoxin-I (BthTx-I), which is also found in smaller quantities in the venoms of B. jararaca from southern Brazil. Results Polyclonal antibodies against bothropstoxin-I could be separated into several species-specific immunoglobulins. Then, aiming to develop a system of safe and standardized immunoassay, we produced monoclonal antibodies. Seven hybridomas were obtained. Five of them were specific to the venom of B. jararacussu and two recognized the venom of B. jararaca from the southeastern population. The use of monoclonal antibodies also made it possible to differentiate B. jararacussu from B. jararaca venom obtained from the southern population. Analyzing the reactivity of monoclonal antibodies against other bothropic venoms, we found mAb Bt-3 to be more specific than others for B. jararacussu venom. Conclusions These results show the potential of BthTx-I for producing monoclonal antibodies that differentiate between B. jararacussu and other Bothrops species venoms.

9.
J. venom. anim. toxins incl. trop. dis ; 23: 12, 2017. tab, graf, ilus
Artigo em Inglês | LILACS, VETINDEX | ID: biblio-954830

RESUMO

Background Snakes of the genus Bothrops, popularly known as pit vipers, are responsible for most cases of snakebite in Brazil. Within this genus, Bothrops jararacussu and B. jararaca deserve special attention due to the severity of their bites and for inhabiting densely populated areas. Regarding the treatment of snakebites by Bothrops jararacussu, questions have been raised about the effectiveness of the specific bothropic antivenom in neutralizing myotoxic effects; however, there are no accurate data for humans. Thus, the development of a differential diagnostic kit for this species would be of great interest because it provides, for healthcare professionals, a tool that would allow us to determine whether the accident was caused by B. jararacussu or other species of the genus. It would also make it possible to evaluate the specificity of the treatment and to provide data for epidemiological studies. Methods First, we produced a species-specific polyclonal antibody - a potential biomarker of Bothrops jararacussu venom - against bothropstoxin-I (BthTx-I), which is also found in smaller quantities in the venoms of B. jararaca from southern Brazil. Results Polyclonal antibodies against bothropstoxin-I could be separated into several species-specific immunoglobulins. Then, aiming to develop a system of safe and standardized immunoassay, we produced monoclonal antibodies. Seven hybridomas were obtained. Five of them were specific to the venom of B. jararacussu and two recognized the venom of B. jararaca from the southeastern population. The use of monoclonal antibodies also made it possible to differentiate B. jararacussu from B. jararaca venom obtained from the southern population. Analyzing the reactivity of monoclonal antibodies against other bothropic venoms, we found mAb Bt-3 to be more specific than others for B. jararacussu venom. Conclusions These results show the potential of BthTx-I for producing monoclonal antibodies that differentiate between B. jararacussu and other Bothrops species venoms.(AU)


Assuntos
Animais , Mordeduras de Serpentes , Serpentes , Antivenenos , Biomarcadores , Bothrops , Venenos de Crotalídeos , Anticorpos , Imunoensaio
10.
PLoS One ; 10(7): e0131484, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26154103

RESUMO

BACKGROUND: Diarrhea is a prevalent pathological condition frequently associated to the colonization of the small intestine by enterotoxigenic Escherichia coli (ETEC) strains, known to be endemic in developing countries. These strains can produce two enterotoxins associated with the manifestation of clinical symptoms that can be used to detect these pathogens. Although several detection tests have been developed, minimally equipped laboratories are still in need of simple and cost-effective methods. With the aim to contribute to the development of such diagnostic approaches, we describe here two mouse hybridoma-derived single chain fragment variable (scFv) that were produced in E. coli against enterotoxins of ETEC strains. METHODS AND FINDINGS: Recombinant scFv were developed against ETEC heat-labile toxin (LT) and heat-stable toxin (ST), from previously isolated hybridoma clones. This work reports their design, construction, molecular and functional characterization against LT and ST toxins. Both antibody fragments were able to recognize the cell-interacting toxins by immunofluorescence, the purified toxins by ELISA and also LT-, ST- and LT/ST-producing ETEC strains. CONCLUSION: The developed recombinant scFvs against LT and ST constitute promising starting point for simple and cost-effective ETEC diagnosis.


Assuntos
Toxinas Bacterianas/imunologia , Escherichia coli Enterotoxigênica/metabolismo , Enterotoxinas/imunologia , Proteínas de Escherichia coli/imunologia , Anticorpos de Cadeia Única/biossíntese , Sequência de Aminoácidos , Escherichia coli Enterotoxigênica/isolamento & purificação , Dados de Sequência Molecular , Proteínas Recombinantes/isolamento & purificação , Anticorpos de Cadeia Única/química
11.
São Paulo; Pólis; 2002. 335 p. tab.
Monografia em Português | CidSaúde - Cidades saudáveis | ID: cid-47267

RESUMO

Busca apoiar o processo de reflexão a partir da busca de conceitos provisórios. Cada capítulo é resultado de uma questão que se identifica estar no presente no atual debate sobre o espaço de inovação local, incluindo a própria possibilidade de desenvolvimento local. Lança o desafio da construção de um marco conceitual inicial, a partir da reflexão sobre as lições da prática. Entende que a construção de idéias requer a diversidade e a divergência, especialmente quando estas têm impacto na prática democrática. (AU)


Assuntos
Administração Municipal , Formulação de Políticas , Inovação Organizacional , Política Pública , Brasil
12.
In. Oliveira, Francisco de; Dowbor, Ladislau; Bava, Silvio Caccia; Spink, Peter; Levy, Evelyn; Cruz, Maria do Carmo M. T.; Silveira, Caio; Bocayuva, Cunca; Zapata, Tania; Vaz, José Carlos; Kayano, Jorge; Caldas, Eduardo; Paulics, Veronika; org. Novos contornos da gestão local: conceitos em construção. São Paulo, Pólis, 2002. p.245-70.
Monografia em Português | CidSaúde - Cidades saudáveis | ID: cid-47275

RESUMO

Tem como centro de convergência a questão do desenvolvimento local, que hoje emerge e se torna visível no contexto brasileiro, na intencionalidade dos atores, nas práticas em gestação e nos debates. O apoio ao desenvolvimento local pode ser visto como uma importante reflexão na trajetória dos experimentos voltados para a reversão das dinâmicas geradoras de exclusão social, que marcaram a década de 90. Liga-se a tendências e oportunidades geradas no processo de globalização, reestruturação produtiva e crise nos padrões de desenvolvimento, tal como se expressa no contexto periférico e brasileiro, em particular. Os caminhos neste sentido vêm sendo trilhados e, no Brasil, ainda é um processo embrionário. Porém, estamos diante de alternativas nas quais a integração de ações e políticas públicas coloca-se sob novas bases de referência, articulando o tema do trabalho e da inserção produtiva com o exercício da cidadania e da participação democrática. (AU)


Assuntos
Planejamento Social , Política Pública , Estratégias de Saúde Locais , Formulação de Políticas , Relações Interinstitucionais , Relações Comunidade-Instituição , Colaboração Intersetorial , Brasil
13.
Rio de Janeiro; FASE - Federação de Órgãos para Assistência Social e Educacional;NAPP - Núcleo de Assessoria Planejamento e Pesquisa;FINEP - Financiadora de Estudos e Projetos; 1997. 146 p. ilus.
Monografia em Português | Sec. Munic. Saúde SP, COVISA-Acervo | ID: sms-4359
14.
Rio de Janeiro; FASE - Federação de Órgãos para Assistência Social e Educacional;NAPP - Núcleo de Assessoria Planejamento e Pesquisa;FINEP - Financiadora de Estudos e Projetos; 1997. 146 p. ilus.
Monografia em Português | LILACS, COVISA-Acervo | ID: lil-654717
15.
In. Albuquerque, Zuleica Portela; Costa, Maria Francisca Tereza Viana; Taddei, José Augusto de Aguiar Carrazedo. Prioridades de pesquisa aplicada ao planejamento em nutriçäo e alimentos. s.l, Conselho Nacional de Desenvolvimento Científico e Tecnológico, 1985. p.185-228, tab.
Monografia em Português | LILACS | ID: lil-67

RESUMO

Trata-se da continuidade da investigaçäo desenvolvida pelo Grupo de Pesquisas de Ciências Sociais em Nutriçäo, tendo-se em vista, a análise da pauta de consumo alimentar, onde procura-se verificar as razöes das diferenças nutricionais assinaladas por classe de despesa. O trabalho abrange 2 regiöes, Säo Paulo e Nordeste, sendo o exame de cada uma composto das seguintes seçöes: 1) análise da cesta básica de alimentos, segundo os critérios de alimentos mais importantes em porcentagem do dispêndio total com alimentaçäo e enquanto fontes de calorias e proteínas: apontando-se, assim, as principais semelhanças e diferenças na seleçäo dos alimentos da cesta e na sua hierarquizaçäo pelos critérios mencionados; 2) análise das variaçöes intergrupos nos gastos com cada alimento, nas quantidades consumidas e nos preços pagos; 3) análise dos locais de aquisiçäo privilegiados por cada grupo; 4) análise do grau de processamento dos alimentos consumidos e de sua importância relativa; 5) finalmente, à guisa de conclusäo, säo sumarizados os principais resultados encontrados, sendo devidamente ressaltadas as convergências e contrastes regionais mais significativos


Assuntos
Ingestão de Alimentos , Brasil , População Urbana
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