[Role of metalloproteinases and their inhibitors in tumors]. / Rol de las metaloproteinasas y sus inhibidores en patología tumoral.

Metalloproteinases (MMPs) are involved in different physiological and pathological processes. They regulate several signaling pathways in cell growth, inflammation and angiogenesis. The MMPs modulate the complex tumor microenvironment and are involved in the early stages of carcinogenesis, tumor invasion and metastasic processes. MMPs participate in the processing of bioactive molecules such as cytokines, chemokines and growth factors. Their substrates are the extracellular matrix proteins and endogenous inhibitors (TIMPs) regulate their functions. The accurate balance between these two molecules, MMPs and TIMPs, is critical for maintaining homeostasis. Due to their role in cancer biology, MMPs are potential targets for future therapeutic strategies of this malignant disease.

Pretreatment with adalimumab reduces ventilator-induced lung injury in an experimental model. / Tratamento prévio com adalimumabe reduz lesão pulmonar induzida por ventilação mecânica em um modelo experimental.

OBJECTIVE: To determine whether adalimumab administration before mechanical ventilation reduces ventilator-induced lung injury (VILI). METHODS: Eighteen rats randomized into 3 groups underwent mechanical ventilation for 3 hours with a fraction of inspired oxygen = 0.40% including a low tidal volume group (n = 6), where tidal volume = 8mL/kg and positive end-expiratory pressure = 5cmH2O; a high tidal volume group (n = 6), where tidal volume = 35mL/kg and positive end-expiratory pressure = 0; and a pretreated + high tidal volume group (n = 6) where adalimumab (100ug/kg) was administered intraperitoneally 24 hours before mechanical ventilation + tidal volume = 35mL/kg and positive end-expiratory pressure = 0. ANOVA was used to compare histological damage (ATS 2010 Lung Injury Scoring System), pulmonary edema, lung compliance, arterial partial pressure of oxygen, and mean arterial pressure among the groups. RESULTS: After 3 hours of ventilation, the mean histological lung injury score was higher in the high tidal volume group than in the low tidal volume group (0.030 versus 0.0051, respectively, p = 0.003). The high tidal volume group showed diminished lung compliance at 3 hours (p = 0.04) and hypoxemia (p = 0,018 versus control). Pretreated HVt group had an improved histological score, mainly due to a significant reduction in leukocyte infiltration (p = 0.003). CONCLUSION: Histological examination after 3 hours of injurious ventilation revealed ventilator-induced lung injury in the absence of measurable changes in lung mechanics or oxygenation; administering adalimumab before mechanical ventilation reduced lung edema and histological damage.

Profile of immune cells in lymph nodes draining human malignant tumors.

The purpose of this study was to characterize and quantify cells involved in immune response in metastasis-free regional lymph nodes (RLNs) draining different human epithelial tumors and compare them (by immunohistochemistry) with control lymph nodes from patients with non malignant diseases. We showed that T cells number was decreased in RLNs as compared to the controls with reduction in both CD4+ T cells and CD8+ T cells subsets and an inverted ratio (CD4+: CD8+). B lymphocytes and follicular dendritic cells were decreased with respect to the controls. S100+ dendritic cells (DCs) and mature DCs were detected in T dependent areas. Their mean number was significantly lower as compared to control. Immature DCs were significantly diminished compared to RLN and control nodes. CD57+ cells, follicular T helper cells and/or NK cells, were localized in the clear zone of germinal centres and their mean number was significantly increased. There were no CD57+ cells in hypoplastic follicles. In this study we show that RLNs draining human cancer present reduction in almost all immune cells, except CD57+ cells. These findings may be related to the deficient anti-tumor immune response in patients with cancer and subsequent tumor progression.

Tratamento prévio com adalimumabe reduz lesão pulmonar induzida por ventilação mecânica em um modelo experimental / Pretreatment with adalimumab reduces ventilator-induced lung injury in an experimental model

RESUMO Objetivo: Determinar se a administração de adalimumabe previamente à ventilação mecânica reduz a lesão pulmonar induzida por ventilação mecânica. Métodos: Randomizaram-se 18 ratos em três grupos submetidos à ventilação mecânica por 3 horas com uma fração inspirada de oxigênio de 0,40%. Os três grupos foram assim caracterizados: um grupo com baixo volume corrente (n = 6), no qual se utilizaram volume corrente de 8mL/kg e pressão expiratória final positiva de 5cmH2O; um grupo com alto volume corrente (n = 6), no qual se utilizaram volume corrente de 35mL/kg e pressão expiratória final positiva de zero; e um grupo pré-tratado com alto volume corrente (n = 6), no qual se administraram adalimumabe (100µg/kg) por via intraperitoneal 24 horas antes do início da ventilação mecânica, volume corrente de 35mL/kg e pressão expiratória final positiva de zero. Realizou-se ANOVA para comparação de dano histológico (com utilização de escores segundo o ATS 2010 Lung Injury Scoring System), edema pulmonar, complacência pulmonar, pressão parcial de oxigênio arterial e pressão arterial média entre os grupos. Resultados: Após 3 horas de ventilação, o escore médio de lesão histológica pulmonar foi mais elevado no grupo com alto volume corrente do que no grupo com baixo volume corrente (0,030 versus 0,0051; p = 0,003). O grupo com alto volume corrente demonstrou complacência pulmonar diminuída após 3 horas (p = 0,04) e hipoxemia (p = 0,018 versus controle). O grupo alto volume corrente tratado previamente teve melhora do escore histológico, principalmente devido à redução significante da infiltração leucocitária (p = 0,003). Conclusão: O exame histológico após 3 horas de ventilação lesiva revelou lesão pulmonar induzida por ventilação mecânica na ausência de modificações mensuráveis na mecânica pulmonar e na oxigenação; a administração de adalimumabe antes da ventilação mecânica diminuiu o edema pulmonar e o dano histológico.

ABSTRACT Objective: To determine whether adalimumab administration before mechanical ventilation reduces ventilator-induced lung injury (VILI). Methods: Eighteen rats randomized into 3 groups underwent mechanical ventilation for 3 hours with a fraction of inspired oxygen = 0.40% including a low tidal volume group (n = 6), where tidal volume = 8mL/kg and positive end-expiratory pressure = 5cmH2O; a high tidal volume group (n = 6), where tidal volume = 35mL/kg and positive end-expiratory pressure = 0; and a pretreated + high tidal volume group (n = 6) where adalimumab (100ug/kg) was administered intraperitoneally 24 hours before mechanical ventilation + tidal volume = 35mL/kg and positive end-expiratory pressure = 0. ANOVA was used to compare histological damage (ATS 2010 Lung Injury Scoring System), pulmonary edema, lung compliance, arterial partial pressure of oxygen, and mean arterial pressure among the groups. Results: After 3 hours of ventilation, the mean histological lung injury score was higher in the high tidal volume group than in the low tidal volume group (0.030 versus 0.0051, respectively, p = 0.003). The high tidal volume group showed diminished lung compliance at 3 hours (p = 0.04) and hypoxemia (p = 0,018 versus control). Pretreated HVt group had an improved histological score, mainly due to a significant reduction in leukocyte infiltration (p = 0.003). Conclusion: Histological examination after 3 hours of injurious ventilation revealed ventilator-induced lung injury in the absence of measurable changes in lung mechanics or oxygenation; administering adalimumab before mechanical ventilation reduced lung edema and histological damage.

Human regional lymph nodes draining cancer exhibit a profound dendritic cell depletion as comparing to those from patients without malignancies.

Dendritic cells (DCs) are bone-marrow derived 'professional' antigen presenting cells (APC). They are considered as the most potent APC able to induce primary immune responses. DC efficiently capture and process proteic and non-proteic antigens. They are widely distributed throughout the body and occupy sentinel positions such as epithelia. Establishment of an immune response against cancer may depend of the capacity of DCs to transfer (to capture, to process and to present) tumor antigens into regional lymph nodes where they can induce a specific response leading to tumor rejection. Because host 'professional' DCs are one of the most important elements in the induction of specific anti-tumor responses and lymph nodes are the places where the immune response takes place, we investigated the densities of DCs within regional metastasis-free lymph nodes from 47 patients with different malignant epithelial tumors as comparing with lymph nodes from 11 patients without malignancies using an immunohistochemistry method with anti-S100 protein, CD86 and CD1a antibodies. By means of morphometric analysis, we observed that S100+ and CD1a+ DCs densities in regional lymph nodes from cancer patients were significatively decreased as compared with control lymph nodes (P<0.0001 and 0.003, respectively). S100+ DCs and CD86+ DCs densities in lymph nodes draining cancer were similar. Taken together, these data indicated that lymph nodes draining cancer had significantly less CD1a+ DCs than S100+ and possibly CD86+ DCs. These findings may represent another mechanism by which tumors evade the immune recognition.

[Tumor markers in breast neoplasm]. / Marcadores tumorales en cáncer de mama.

Breast cancer is the most frequently diagnosed cancer among women in the western world. In spite of a great deal of scientific information in relation to its origin, of new diagnostic methods and treatments, mortality rate due to breast cancer has virtually remained stable over the past 20 years. Recent advances in molecular biology have improved the understanding of the basic biology of breast cancer. This fact has led to the identification of new tumor markers the ultimate goal of which is to reduce mortality by identifying women at risk as well as predicting the prognosis of existing disease and the response to different therapies. This article focuses on both traditional and new molecular markers, their clinical utility and their relevance in the routine evaluation of patients with breast cancer.

Rol de las metaloproteinasas y sus inhibidores en patología tumoral / Role of metalloproteinases and their inhibitors in tumors

Las metaloproteinasas (MMPs) intervienen en diversos procesos fisiológicos y patológicos del organismo. Regulan, por ejemplo, las vías de señalización que controlan el crecimiento celular, la inflamación y la angiogénesis. Cumplen funciones moduladoras en el complejo microambiente tumoral interviniendo en las etapas tempranas de la carcinogénesis, en la invasión y la producción de metástasis tumorales. Participan en el procesamiento de moléculas bioactivas como citoquinas, quemoquinas y factores de crecimiento. Las MMPs tienen como substrato a las proteínas de la matriz extracelular (MEC) y su actividad es regulada por inhibidores endógenos (TIMPs). El adecuado balance entre ambas moléculas es fundamental para mantener la homeostasis. Debido al papel que desempeñan en diferentes etapas de la biología del cáncer, son un blanco potencial para futuras estrategias en la terapéutica de esta enfermedad.

Metalloproteinases (MMPs) are involved in different physiological and pathological processes. They regulate several signaling pathways in cell growth, inflammation and angiogenesis. The MMPs modulate the complex tumor microenvironment and are involved in the early stages of carcinogenesis, tumor invasion and metastasic processes. MMPs participate in the processing of bioactive molecules such as cytokines, chemokines and growth factors. Their substrates are the extracellular matrix proteins and endogenous inhibitors (TIMPs) regulate their functions. The accurate balance between these two molecules, MMPs and TIMPs, is critical for maintaining homeostasis. Due to their role in cancer biology, MMPs are potential targets for fu ture therapeutic strategies of this malignant disease.

Profile of immune cells in lymph nodes draining human malignant tumors / Perfil de las células inmunes en los ganglios linfáticos que drenan tumores malignos humanos

The purpose of this study was to characterize and quantify cells involved in immune response in metastasis-free regional lymph nodes (RLNs) draining different human epithelial tumors and compare them (by immunohistochemistry) with control lymph nodes from patients with non malignant diseases. We showed that T cells number was decreased in RLNs as compared to the controls with reduction in both CD4+ T cells and CD8+ T cells subsets and an inverted ratio (CD4+: CD8+). B lymphocytes and follicular dendritic cells were decreased with respect to the controls. S100+ dendritic cells (DCs) and mature DCs were detected in T dependent areas. Their mean number was significantly lower as compared to control. Immature DCs were significantly diminished compared to RLN and control nodes. CD57+ cells, follicular T helper cells and/or NK cells, were localized in the clear zone of germinal centres and their mean number was significantly increased. There were no CD57+ cells in hypoplastic follicles. In this study we show that RLNs draining human cancer present reduction in almost all immune cells, except CD57+ cells. These findings may be related to the deficient anti-tumor immune response in patients with cancer and subsequent tumor progression.

El objetivo del trabajo fue caracterizar y cuantificar utilizando inmuno-histoquímica, las células involucradas en la respuesta inmune en ganglios linfáticos regionales (GLRs) que drenan distintos tumores epiteliales malignos humanos y compararlas con ganglios controles (GLCs) provenientes de pacientes sin enfermedad neoplásica maligna. Determinamos que los GLRs presentaban una marcada depleción de linfocitos B y T, células dendríticas (CD) foliculares y CD interdigitantes maduras respecto a los controles. En los linfocitos T, además de estar disminuidos, se observó una inversión de la relación T CD4+: T CD8+, a favor de los T CD8+. La depleción de CD inmaduras fue mayor respecto a las maduras. Las células CD57+, células foliculares T helper y/o células NK, localizadas en las zonas claras de los centros germinativos, presentaron un marcado incremento en los GLRs comparados con los GLCs, excepto en los casos de ganglios linfáticos con folículos hipoplásicos. En este estudio, demostramos que los GLRs que drenan carcinomas humanos presentan una significativa reducción en casi todas las células de la respuesta inmune, excepto las células NK. Estos hallazgos podrían estar relacionados con la deficiente respuesta antitumoral de los pacientes con cáncer y la subsiguiente progresión tumoral.

Revisión acerca de la biología y las funciones inmunológicas de los mastocitos / Review of the biology and immunological functions of mast cells

Los mastocitos o células cebadas son células que se hallan ampliamente distribuidas en todos los tejidos, principalmente en la piel y en las superficies mucosas cerca de los vasos sanguíneos y linfáticos. Pueden ser activadas por diversos estímulos de origen inmunitario o no inmunitario, liberando un amplio espectro de mediadores que incluyen histamina, proteasas, citoquinas, factores de crecimiento y metabolitos del ácido araquidónico. Estas moléculas juegan un importante papel en numerosos procesos fisiológicos y patológicos. La función mejor conocida de los mastocitos es la defensa contra infestaciones parasitarias; sin embargo, son importantes en la defensa del huésped a través de su participación en la inmunidad innata y adaptativa. Median la respuesta inflamatoria, la remodelación de los tejidos y la angiogénesis. Intervienen en las reacciones de hipersensibilidad tipo I y tienen un papel contradictorio en la progresión tumoral. En esta revisión se analiza el origen, la distribución y las funciones de los mastocitos en condiciones fisiológicas y en distintas enfermedades humanas.

Marcadores tumorales en cancer de mama / Tumor markers in breast neoplasm

Breast cancer is the most frequently diagnosed cancer among women in the western world. In spite of a great deal of scientific information in relation to its origin, of new diagnostic methods and treatments, mortality rate due to breast cancer has virtually remained stable over the past 20 years. Recent advances in molecular biology have improved the understanding of the basic biology of breast cancer. This fact has led to the identification of new tumor markers the ultimate goal of which is to reduce mortality by identifying women at risk as well as predicting the prognosis of existing disease and the response to different therapies. This article focuses on both traditional and new molecular markers, their clinical utility and their relevance in the routine evaluation of patients with breast cancer.

Identificacion de un antigeno tumoral asociado al receptor estrogenico en ganglios linfaticos axilares de pacientes con cancer mamario / Identification of a tumor antigen associated to the estrogen receptor in axillary lymph nodes of breast cancer patients

Dieciseis ganglios linfáticos axilares fueron enfrentados con suero de pacientes portadoras de cáncer mamario, encontrándose que dichos sueros reconocían determinantes antigénicos en células foliculares dendríticas (CFD) de los centros germinativos. Este hecho fue corroborado con CFD aisladas y cultivadas a las que se enfretó con los sueros experimentales. Con sueros normales, los resultados fueron negativos. Posteriormente sobre los mismos ganglios y las CFD aisladas, se realizó técnica de inmunoperoxidasa con anticuerpos monoclonales anti-proteína asociada al receptor estrogénico (ERAP). En el 75 por ciento de los casos, los ganglios mostraron células anti-ERAP+ en el seno subcapsular, sinusoides corticales y centros germinativos. El fenotipo de las células correspondió a macrófagos y células foliculares dentríticas respectivamente. Controles utilizando ganglios que drenan otros tumores malignos fueron negativos. Estoshallazgos sugieren que el antígeno tumoral podría corresponder a la proteína asociada al receptor de estrógenos o tal vez al mismo receptor, capaz de ser captado y transportado por células presentadoras de antígenos desde el tumor a los ganglios linfáticos regionales donde se produce la respuesta inmune del huésped. El posible reconocimiento de un antígeno tumoral mamario abre una perspectiva futura para el manipuleo terapéutico de esta enfermedad.

Acción del cloruro de sodio al 33% sobre el mesotelio peritoneal del ratón: estudio ultraestructural / Effecto of 33% sodium chloride on the peritoneum of the mouse: ultrastructutal study

Para visualizar los cambios ultraestructurales que produce el CINa al 33% sobre las serosas, se inyecta dicha solución en el peritoneo de ratones sacrificándolos a 3 términos: inmediato, 2 y 5 minutos. Se observa, con microscopia electrónica, la secuencia de cambios en la serosa intestinal a partir de testigos no inyectados que muestran un mesotelio normal (con microvellosidades hacia superficie libre), haces de colágeno submesoteliales y más abajo miocélulas lisas. Todos estos tejidos se modifican profundamente por el gradiente osmolar del CINa al 33% que provoca deshidratación celular y edema intersticial. En 5 desaparece el mesotelio, queda el colágeno desnudo y edematoso y se necrosan las mio-células lisas. Considerando la importancia de las funciones peritoneales y las lógicas alteraciones comprobadas a tan corto término, se apoya la tesis de que el lavaje peritoneal salino hipertónico" debe contraindicarse absolutamente en terapia humana

Biologia de las proteinas del shock térmico / Biology of heat shock proteins

Las proteínal del shock térmico (Hsp) constituyen una família que se encuentra en forma constitutiva en todas las células pro y eucariotas. Cumplen diversas funciones fisiológicas: colaboran en la adquisición de la estructura terciarua de las proteínas en formación, interviniendo en su ensamble, translocación y secreción así como también en la degradación o reparación de proteínas anormales, actuando como chaperonas moleculares. Cuando las células son sometidas a distintos estímulos como el estrés del shock calórico, radiaciones, diversas drogas, infecciones virales, etc, las Hsp se sobreexpresan. De esta manera confieren protección a las células, volviéndolas resistentes a la apoptosis. Esta familia de proteínas comprende numerosos miembros que se agrupan según su peso molecular. En los seres humanos, las Hsp se expresan también en tejidos neoplásicos de ovario, endometrio, mama, aparato digestivo, etc. En algunos casos, la sobreexpresión está asociada a mal pronóstico de la enfermedad debido a que podría favorecer el proceso metastásico. Algunos autores las correlacionan tanto con la proliferación como con la diferenciación de los tejidos neoplásicos. Recientes estudios muestran su influencia en el desarrollo de la resistencia a drogas quimioterapéuticas. En enfermedades autoimunes, como artritis reumatoidea, las Hsp pueden suprimir la respuesta inflamatoria. En otras enfermedades pueden resultar inmunógenas por sí mismas. Por consiguiente su papel en el sistema inmune aún no está bien definido.

Celulas dendriticas y su papel en patologia / Dendritic cells: their role in pathology

La finalidad de esta revisión es aportar un conocimiento general sobre las células dendríticas (CD), células accesorias de la respuesta inmune. Se las reconoce como las células presentadoras de antígenos por excelencia (APC) y por lo tanto expresan antígenos clase II del complejo mayor de histocompatibilidad (MHC). Los diversos tipos de CD tienen un origen común en la médula ósea diferenciándose luego bajo la influencia de variados estímulos y distribuyéndose en órganos linfoideos y no linfoideos. Desde los tejidos periféricos migran a los ganglios linfáticos donde presentan el antígeno a los linfocitos T. Dependiendo del microambiente expresan diversos marcadores de superfície siendo capaces de la secreción de citoquinas como IL-12, IL-1 y TNFalpha. Como APC cumplen un importante papel en la patogenia de enfermedades autoinmunes y virales destacándose su participación en la infección por HIV. Se las encuentran en el infiltrado de numerosos cánceres humanos donde actuando como APC podrían incluir una respuesta inmune antitumoral. En esta propiedad se basa su utilización para el tratamiento de linfomas y melanomas llevada a cabo actualmente en diversos laboratorios.

Modelo experimental de apoptosis "in vitro" en células HEP-2: el paclitaxel como agente inductor / Experiental model of apoptosis in vitro with HEP-2 cells: paclitaxel inducing agent

Apoptosis is an active form of cell death that can be observed both in physiological and pathological conditions. The apoptotic process (programmed cell death) can be studied "in vivo" and "in vitro" conditions. It is a programmed and organized energy dependent response to cellular media changes, and sometimes it requires genetic expression The typical morphological changes of apoptosis are: condensation of the cytoplasm and the nuclear chromatin, early cytoplasmatic blebs, DNA degradation preferentially between the nucleosomes and generation of apoptotic bodies. The aim of this paper is to describe an experimental model of apoprosis using Hep-2 cul-tured cells, and as inductor agent a culture medium solution with Paclitaxel at the concentra-tion of 5 (M/ml during 20 hours. Paclitaxel is a potent antitumor drug which acts by stabilizing microtubules (irreversible tubulin polymerization), preventing normal mitosis, and resulting in a blockage of the cell cycle at G2 - M and cell death from apoptosis. In the present work, we could appreciate the presence ofi apoptotic cells, cells blocked in mitosis, multinucleated interphase cells, and cells resembling controls. Our findings support the use of Paclitaxel for the development of experimental model of apoptosis "in vitro".