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1.
Gastroenterol. hepatol. (Ed. impr.) ; 42(9): 534-541, nov. 2019. ilus, graf, tab
Artigo em Inglês | IBECS | ID: ibc-187914

RESUMO

Introduction and aim: Thromboxane (TX) A2 was identified as an important vasoconstrictor during Zymosan induced portal perfusion pressure (PP) increase. We aimed at investigating whether hepatic steatosis influences the extent of TXA2-induced portal hypertension. Materials and methods: Sprague-Dawley rats were randomly divided into control and steatosis (induced by the special diet) groups. PP and TXB2 (stable degradation product of TXA2) in the perfusate were measured after in situ liver perfusion with Zymosan (150μg/ml, 40-46min) or U46619 (TXA2 analog, 0.1μM/ml, 40-46min). The number of Kupffer cell (KC) was measured by immunohistochemistry with CD163. Results: Zymosan induced more TXB2 production and a higher PP increase in control group than in steatosis group despite more CD163 positive KCs in fatty livers. PP and TXB2 efflux revealed a strong correlation in control group and a moderate correlation in steatosis group. Contrary to the effect of Zymosan, U46619 induced a much higher PP increase in steatosis group than in control group. Conclusion: Severe steatosis increased number of KCs, however, PP increase and TXB2 efflux caused by Zymosan infusion in fatty livers were lower than those in healthy livers. In contrast, TXA2 analog caused higher PP increase in fatty livers. Targeting the more sensitive response to TXA2 in fatty livers might be a potential therapy of severe steatosis


Introducción y objetivos: Se ha identificado al tromboxano (TX) A2 como importante vasoconstrictor durante el aumento de la presión de perfusión portal (PP) inducida por zymosan. El objetivo ha sido analizar si la esteatosis hepática influye en el grado de hipertensión portal inducida por TXA2. Materiales y métodos: Las ratas Sprague-Dawley(R) se han dividido aleatoriamente en grupos de control y esteatosis (inducida por una dieta especial). Se midieron la PP y el TXB2 (producto de degradación estable de TXA2) en la perfusión después de la perfusión hepática in situ de zymosan (150μg/ml, minuto 40-46) o U46619 (análogo de TXA2, 0,1μM/ml, minuto 40-46). El número de células de Kupffer (CK) se midió mediante inmunohistoquímica con CD163. Resultados: Zymosan provocó más producción de TXB2 y mayor aumento de la PP en el grupo de control que en el grupo de esteatosis a pesar de hallar más CK positivas para CD163 en hígados grasos. El flujo de salida de la PP y el TXB2 reveló una fuerte correlación en el grupo de control y una correlación moderada en el grupo de esteatosis. De manera diferente al efecto de zymosan, U46619 indujo un aumento de la PP mucho mayor en el grupo de esteatosis que en el grupo de control. Conclusión: La esteatosis grave aumentó el número de CK; sin embargo, el aumento de la PP y el flujo de TXB2 provocado por la perfusión de zymosan en hígados grasos fueron menores que en los hígados sanos. En cambio, el análogo de TXA2 provocó un aumento de la PP en hígados grasos. Centrarse en la respuesta más sensible al TXA2 en hígados grasos podría convertirse en un tratamiento potencial de la esteatosis grave


Assuntos
Animais , Ratos , Fígado Gorduroso/complicações , Hipertensão Portal/induzido quimicamente , Pressão na Veia Porta/efeitos dos fármacos , Tromboxano B2/biossíntese , Zimosan/farmacologia , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Fígado Gorduroso/patologia , Fígado Gorduroso/fisiopatologia , Macrófagos do Fígado/química , Macrófagos do Fígado/citologia , Perfusão/métodos , Pressão na Veia Porta/fisiologia , Tromboxano A2/análogos & derivados , Ratos Sprague-Dawley
2.
J. investig. allergol. clin. immunol ; 29(4): 287-293, 2019. tab, graf
Artigo em Inglês | IBECS | ID: ibc-188749

RESUMO

BACKGROUND: T cells play a major role in delayed-type hypersensitivity reactions. Their reactivity can be assessed by measuring the upregulation of the activation marker CD69, followed by assessment of proliferation and cytokine production. The aim of our study was to develop a novel, whole blood-based, quantitative, absolute count activation index (AI) for analysis of CD69 upregulation in various subsets of T cells in nickel-hypersensitive patients and compare it with previously reported approaches. METHODS: The study population comprised 10 patients with nickel allergy and 9 healthy controls. CD69 expression of CD3+, CD3+CD4+, and CD3+CD8+ T cells in heparinized blood was determined with flow cytometry after incubation with nickel sulfate for 48 hours. The absolute count of CD69+ cells was determined using microbeads. Production of the cytokines IL-2, IL-5, IL-13, and IFN-γ was determined after stimulation of peripheral blood mononuclear cells with nickel sulfate for 48 hours. RESULTS: We showed absolute AI to be the most sensitive approach. The index was calculated as the ratio of the absolute count of nickel-stimulated CD69-positive T cells to the absolute count of CD69-positive T cells in nonstimulated blood. This novel quantitative approach was more discriminative than previously reported approaches in which the T-cell CD69 percentage AI and cytokine production are measured. CONCLUSIONS: Our results demonstrated that measuring the absolute CD69 AI is a novel and accurate approach for quantification of antigen-specific T cells in the blood of patients with hypersensitivity reactions to nickel. This approach may be useful for better in vitro assessment of patients with delayed-type hypersensitivity reactions


ANTECEDENTES: Los linfocitos T juegan un papel importante en las reacciones de hipersensibilidad de tipo retardado. Su actividad puede evaluarse midiendo la expresión del marcador de activación CD69, seguido de la proliferación y la producción de citocinas. El objetivo de nuestro estudio ha sido el desarrollar un novedoso análisis cuantitativo del índice de activación absoluto (AI) en sangre completa de la expresión de CD69, en diferentes subconjuntos de linfocitos T, en pacientes con hipersensibilidad al níquel, y compararlo con los métodos existentes. MÉTODOS: Se estudiaron diez pacientes con alergia al níquel y nueve controles sanos. La expresión de CD69 de los linfocitos T CD3+, CD3+CD4+ y CD3+ CD8+ en sangre heparinizada se determinó con citometría de flujo, después de una incubación con sulfato de níquel durante 48 h. El recuento absoluto de células CD69+ se determinó con microesferas. La producción de las citocinas IL-2, IL-5, IL-13 e IFN-γ se cuantificó después de la estimulación de células mononucleares periféricas, durante 48 h, con sulfato de níquel. RESULTADOS: Se demuestra que la determinación del índice AI absoluto es la metodología más sensible. Se calculó como la relación entre el recuento absoluto de linfocitos T CD69-positivos estimulados con níquel y el recuento absoluto de linfocitos T CD69-positivos en sangre no estimulada. Este nuevo enfoque cuantitativo fue más discriminativo que los enfoques publicados previamente en los que se midió el porcentaje de CD69 de linfocitos T y la producción de citocinas. CONCLUSIONES: Nuestros resultados demostraron que la medición del AI absoluto de CD69 es un enfoque nuevo y preciso para cuantificar los linfocitos T específicos de antígeno en la sangre de pacientes con reacciones de hipersensibilidad al níquel. Este enfoque puede ser útil para una mejor evaluación in vitro de los pacientes con reacciones de hipersensibilidad de tipo retardado


Assuntos
Humanos , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Hipersensibilidade Tardia/diagnóstico , Hipersensibilidade Tardia/etiologia , Lectinas Tipo C/metabolismo , Contagem de Linfócitos , Níquel/efeitos adversos , Biomarcadores/sangue , Estudos de Casos e Controles , Citocinas/metabolismo , Imunofenotipagem , Ativação Linfocitária , Linfócitos T/imunologia , Linfócitos T/metabolismo , Alérgenos/imunologia
3.
Rev. osteoporos. metab. miner. (Internet) ; 9(1): 5-12, ene.-mar. 2017. tab, ilus, graf
Artigo em Espanhol | IBECS | ID: ibc-162865

RESUMO

El tejido adiposo contiene un gran número de células madre mesenquimales (Adipose Stem Cells, ASCs) que residen en su estroma vascular. Aunque existe controversia acerca de la capacidad de generar tejido óseo de estas células in vivo, in vitro constituyen un buen modelo de diferenciación osteogénica debido a su semejanza fenotípica con las células estromales de la médula ósea (Bone Marrow Stromal Cells, BMSCs) en cultivo. La diferenciación de las poblaciones osteoprogenitoras de la médula ósea está intensamente regulada por factores locales, como el factor de crecimiento endotelial vascular (VEGF) y la proteína relacionada con la parathormona (PTHrP), que modulan la proliferación de estas poblaciones en distintos estadios de diferenciación. Tanto el VEGF como el fragmento N-terminal de la PTHrP ejercen efectos osteogénicos. En este estudio hipotetizamos que sus efectos sobre la proliferación celular de los osteoprogenitores son dependientes del estadio de diferenciación osteoblástica. Tras confirmar su capacidad de diferenciación in vitro por expresión génica de Runx2 y acumulación de calcio, se analizó la respuesta proliferativa a estímulos con VEGF o PTHrP(1-36) de ASCs sometidas o no a inducción osteogénica. VEGF pero no PTHrP(1-36) estimuló la capacidad proliferativa de las ASCs no inducidas mientras que PTHrP(1-36), pero no VEGF, estimuló la proliferación de las ASCs inducidas, corroborando el papel diferencial de estos factores de crecimiento en distintos estadios de diferenciación (AU)


Adipose tissue contains a large number of mesenchymal stem cells (ASCs) residing in their vascular stroma. Although there is controversy regarding the ability to generate bone tissue from these cells in vivo, the in vitro cells offer a good model of osteogenic differentiation due to its phenotypic similarity with the bone marrow stromal cells (BMSCs) in culture. The differentiation of osteo-progenitor populations of bone marrow is intensely regulated by local factors, such as vascular endothelial growth factor (VEGF) and parathyroid hormone-related protein (PTHrP), which modulate these populations' proliferation in different stages of differentiation. Both the VEGF and the N-terminal fragment of the PTHrP exert osteogenic effects. In this study, we posited that its effects on proliferation of osteo-progenitors are stage dependent of osteoblastic differentiation. After confirming its capacity to in vitro differentiation by Runx2 gene expression and accumulation of calcium, the proliferative response to stimuli was analyzed with VEGF or PTHrP (1-36) of ASCs submitted or not to osteogenic induction. VEGF, but not PTHrP (1- 36), stimulated the proliferative capacity of uninduced ASCs, whereas BMSCs, but not VEGF, stimulated the proliferation of induced ASCs, corroborating the differential role of this growth in different stages of differentiation (AU)


Assuntos
Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Fatores de Crescimento do Endotélio Vascular/análise , Células-Tronco/metabolismo , Tecido Adiposo/cirurgia , Tecido Adiposo/metabolismo , Medula Óssea/metabolismo , Anticorpos Monoclonais Murinos/análise , Citometria de Fluxo , Antígenos de Diferenciação/análise , Antígenos CD/análise , Proliferação de Células , Reação em Cadeia da Polimerase
4.
Rev. esp. patol ; 49(4): 254-258, oct.-dic. 2016. ilus
Artigo em Espanhol | IBECS | ID: ibc-155907

RESUMO

El sarcoma histiocítico es un tumor maligno infrecuente, de patogenia incierta, caracterizado por una proliferación de células neoplásicas con morfología e inmunofenotipo de los histiocitos tisulares maduros. Aunque existen pocas referencias bibliográficas, afecta a pacientes de ambos sexos, de amplio rango de edad y afectación nodal y/o extranodal. Se ha señalado la existencia en muchos casos de una estrecha relación entre esta entidad y varias neoplasias hematolinfoides en un mismo paciente, lo que ha dado lugar a múltiples estudios para esclarecer su etiología y su patogenia. Su curso suele ser rápidamente progresivo y no se conoce una pauta terapéutica eficaz. Actualmente su diagnóstico sigue siendo por exclusión. Presentamos el caso de un paciente de 82años con perforación de un asa yeyunal con una tumoración maligna que infiltra transmuralmente la pared y solo expresa CD68, CD45RO, CD163, lisozima y vimentina, junto con un reordenamiento clonal linfoideB con escasa amplificación (AU)


Histiocytic sarcoma is a rare malignant tumour of unknown pathogenesis characterized by proliferation of neoplastic cells morphologically and immunophenotypically similar to mature tissue histiocytes. There are only a few reported cases, but they have been described in both males and females of all ages and with nodal and extranodal involvement. A close relationship has often been observed with other haematolymphoid neoplasms which might provide clues to its etiology and pathogenesis. To date, diagnosis is by exclusion of other entities. The clinical course usually progresses rapidly and an effective therapeutic regime has not yet been established. We report a case in an 82year old male who had suffered a perforation of the jejunal loop and was found to have a malignant tumour infiltrating the wall of the small bowel. The tumour was positive only for CD68, CD45RO, CD163, lysozyme and vimentin and showed a Blymphoid clonal rearrangement with little amplification (AU)


Assuntos
Humanos , Masculino , Idoso de 80 Anos ou mais , Sarcoma Histiocítico/patologia , Neoplasias Intestinais/patologia , Intestino Delgado/patologia , Rearranjo Gênico , Sistema Linfático/patologia , Antígenos CD/análise
7.
Clin. transl. oncol. (Print) ; 18(10): 988-995, oct. 2016. tab, graf
Artigo em Inglês | IBECS | ID: ibc-155961

RESUMO

Purpose: hENT1 is a transmembrane protein which acts as a nucleoside transporter and is the main mediator of Gemcitabine (GEM) uptake into human cells. In this retrospective study we compared GEM versus FOLFIRINOX in patients with metastatic pancreatic cancer in which hENT1 evaluation was available. Methods: 149 patients affected by unresectable metastatic pancreatic cancer, treated in our institution from 2009 to 2013, have been screened for inclusion in this retrospective study. Seventy patients, treated with GEM or FOLFIRINOX in first-line therapy, fulfilled clinical inclusion criteria for survival analysis. Thirty-one patients were available and contained sufficient quality/quantity RNA for evaluation of hENT1 expression by RT-PCR. The primary endpoint was OS and the secondary endpoint was PFS. Results: The survival analysis, carried out on 70 patients regardless of hENT1 expression, showed a statistically longer OSandPFS in the group treated with FOLFIRINOX compared to GEM. Within the exploratory analysis, which included 31 patients, no differences were found in hENT1 positive patients treated with FOLFIRINOX compared to GEM in terms of OS (8.5 vs 7 months, HR: 0.89; 95 % CI 0.3-2.5; p = 0.8) and PFS (5.5 vs 5 months, HR: 0.8, 95 % CI 0.2-2.2; p = 0.61). GEM-treated hENT1 positive patients showed a statistically significant improvement both of OS (8 vs 2 months; p = 0.0012) and PFS (5 vs 1 months; p = 0.0004) in comparison to GEM-treated hENT1 negative patients. Conclusions: In our exploratory analysis GEM seems as effective as FOLFIRINOX in terms of survival with a better safety profile in hENT1 positive metastatic pancreatic cancer (AU)


No disponible


Assuntos
Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Metástase Neoplásica/tratamento farmacológico , Antineoplásicos/farmacocinética , Transportador Equilibrativo 1 de Nucleosídeo/análise , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Antígenos CD/análise , Receptores do Fator de Necrose Tumoral/análise , Proteínas de Transporte de Nucleosídeos/fisiologia
9.
Med. oral patol. oral cir. bucal (Internet) ; 19(6): 584-591, nov. 2014. tab
Artigo em Inglês | IBECS | ID: ibc-130353

RESUMO

Objectives: The aim of this investigation was to characterise and compare the inflammatory infiltrates in patients with orofacial granulomatosis solely (OFG-S) and OFG with coexisting Crohn’s disease (OFG+CD). Study Design: Biopsy specimens with granulomas were obtained from patients with OFG-S (n=11) and OFG+CD (n=11) and immunostained with antibodies against CD1a, CD3, CD4, CD8, CD11c, CD20, CD68 and mast cell tryptase, followed by quantitative analysis. Results: Analyses of the connective tissue revealed a significantly higher number of CD3-expressing T cells and CD11c-expressing dendritic cells in the connective tissue of patients with OFG-S compared to patients with OFG+CD. Mast cells displayed a high level of activation, although no significant difference was detected when comparing the two groups. Conclusions: The results show a different composition of the inflammatory infiltrate in patients with OFG-S compared to patients with OFG+CD. The present observations support that partlydivergent immune mechanisms are involved in these two different subcategories of OFG (AU)


Assuntos
Humanos , Imunofenotipagem/métodos , Granulomatose Orofacial/diagnóstico , Doença de Crohn/epidemiologia , Autoimunidade , Triptases/análise , Antígenos CD/análise , Células Dendríticas
10.
J. physiol. biochem ; 69(2): 199-205, jun. 2013.
Artigo em Inglês | IBECS | ID: ibc-121968

RESUMO

Endothelial plasma membrane lipid microdomains, so called lipid rafts/caveolae, are rich in neutral glycosphingolipid, globotriaosylceramide, Gb3Cer, or CD77. Several plasma membrane Ca2+channels and pumps are located in lipid rafts/caveolae. Increased Ca2+ influx could cause the development of an endothelial proinflammatory phenotype. Therefore, the aim of this study was to estimate the effects of hypercalcemia in rats by determination of CD77 expression on CD34+ endothelial cells in the heart, kidney, and vena cava. In addition, potential proinflammatory calcium effect was estimated by CD11b and CD15s expression on leukocytes. To achieve hypercalcemia, Sprague–Dawley male rats were given CaCl2 solution with a concentration of 1.5 % elemental calcium during 14 days. CD77 expression on CD34+ endothelial cells in cell suspensions of the heart, kidney, and vena cava, as well as leukocyte expression of CD11b and CD15s in hypercalcemic and control rats were determined by flow cytometry. Ionized calcium concentration in plasma was 1.37 ± 0.01 mM in hypercalcemic vs. 1.19 ± 0.03 mM in control rats. Hypercalcemic group showed statistically significantly decreased proportion of endothelial CD34+ CD77− cells in the kidney and vena cava in parallel with increase of CD11b and CD15s leukocyte proinflammatory markers. In conclusion, it is tempting to speculate that plasma membranes of glycosphingolipid CD77− endothelial cells are poorer in caveolae lipid microdomains and therefore weaker in controlling of Ca2+ influx. The percentage of CD11b+ CD15s+ leukocytes could be a measure of proinflammatory effects of mild hypercalcemia (AU)


Assuntos
Animais , Ratos , Hipercalcemia/fisiopatologia , Mediadores da Inflamação/análise , Inflamação/fisiopatologia , Leucócitos , Células Endoteliais , Antígenos CD/fisiologia
11.
Clin. transl. oncol. (Print) ; 13(5): 189-293, mayo 2011. tab
Artigo em Inglês | IBECS | ID: ibc-124438

RESUMO

The cancer stem cell (CSC) theory is currently a very important field in cancer research. This theory states that tumours are organised in a hierarchical manner with a subpopulation of limited number called CSCs with the ability to self-renew and undergo asymmetrical divisions, giving rise to a differentiated progeny that represents most of the tumour populations. CSCs are metastatic and chemoresistant, two features that very likely contribute to the poor response of locally advanced lung cancer. CSCs have been identified in non-small-cell lung cancer cell lines as well as those from patient primary samples. A correlation has been found in terms of chemoresistance and bad prognosis in patient-derived samples enriched with CSCs, indicating that these cells are an important target for future therapy combinations. Therefore, understanding the biology and exploring cell markers and signalling pathways specific for CSCs of lung cancer may help in achieving progress in the treatment of the disease (AU)


Assuntos
Humanos , Masculino , Feminino , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Células-Tronco Neoplásicas/citologia , Aldeído Desidrogenase/metabolismo , Antígenos CD/biossíntese , Antígenos CD34/biossíntese , Receptores de Hialuronatos/biossíntese , Diferenciação Celular , Glicoproteínas/biossíntese , Oncologia/métodos , Transdução de Sinais
13.
Actas dermo-sifiliogr. (Ed. impr.) ; 100(2): 142-146, mar. 2009. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-128307

RESUMO

Los procesos linfoproliferativos asociados a metotrexato son un grupo heterogéneo de proliferaciones linfoides o linfomas que se desarrollan en pacientes con enfermedades autoinmunes tratados con metotrexato. Con frecuencia, se asocian a infección por el virus de Epstein-Barr (VEB) y, ocasionalmente, involucionan al suspender el metotrexato. Se presenta un caso de proceso linfoproliferativo tipo linfoma B difuso de célula grande, con una presentación clínica inusual de úlceras orales, afectando a una paciente de 79 años, con artritis reumatoide de larga evolución en tratamiento con metotrexato. Se detectó positividad para LMP-1 (proteína latente de membrana-1) y EBER (Epstein-Barr encoded RNA) por inmunohistoquímica e hibridación in situ cromogénica, respectivamente. Se confirmó la clonalidad del infiltrado por inmunohistoquímica (restricción de cadenas ligeras), PCR (reordenamiento monoclonal del gen IgH) y electroforesis capilar (GeneScan). El estudio de extensión fue negativo. La suspensión del metotrexato condujo a la remisión completa en 6 semanas. Dieciocho meses después del diagnóstico la paciente continúa libre de enfermedad. Los procesos linfoproliferativos asociados a metotrexato raramente afectan primariamente a la cavidad oral y, sólo excepcionalmente, se manifiestan en forma de úlceras. Se revisa la literatura relativa a procesos linfoproliferativos asociados a metotrexato con presentación clínica de úlceras orales (AU)


Methotrexate-associated lymphoproliferative disorders are a heterogeneous group of lymphoid proliferations or lymphomas that develop in patients with autoimmune diseases treated using methotrexate. These lymphoproliferative disorders are often associated with Epstein-Barr virus infection and occasionally regress after the withdrawal of methotrexate therapy. The lymphoproliferative disorder in this case was diffuse large B-cell lymphoma, unusually presenting as oral ulcers in a 79-year-old woman on treatment with methotrexate for longstanding rheumatoid arthritis. Latent membrane protein 1 positivity was detected by immunohistochemistry and Epstein-Barr-virus encoded small RNA positivity by chromogenic in situ hybridization. Clonality was confirmed by immunohistochemistry (K light-chain restriction), polymerase chain reaction (monoclonal immunoglobulin H gene rearrangement), and capillary electrophoresis (GeneScan). Staging procedures were negative. Withdrawal of methotrexate therapy led to complete remission within 6 weeks, and the patient is alive and disease-free 18 months after the diagnosis was made. The oral cavity is not often involved in the initial presentation of methotrexate-associated lymphoproliferative disorders, and presentation with intraoral ulcers is very rare. We have performed a review of the literature on methotrexate-associated lymphoproliferative disorders presenting as ulcers in the oral cavity (AU)


Assuntos
Humanos , Feminino , Idoso , Artrite/complicações , Artrite/tratamento farmacológico , Imunossupressores/efeitos adversos , Linfoma Difuso de Grandes Células B/etiologia , Metotrexato/efeitos adversos , Úlceras Orais/etiologia , Úlceras Orais/patologia , Herpesvirus Humano 4/isolamento & purificação , Indução de Remissão , Antígenos CD/análise , Antígenos de Neoplasias/análise , Infecções por Vírus Epstein-Barr/complicações , Linfoma Difuso de Grandes Células B/química , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/virologia , Rearranjo Gênico de Cadeia Pesada de Linfócito B , Hospedeiro Imunocomprometido , Cadeias kappa de Imunoglobulina/análise , Biomarcadores Tumorais/análise
15.
Clin. transl. oncol. (Print) ; 10(5): 262-267, mayo 2008. ilus
Artigo em Inglês | IBECS | ID: ibc-123445

RESUMO

Besides the role of normal stem cells in organogenesis, cancer stem cells are thought to be crucial for tumorigenesis. Most current research on human tumors is focused on molecular and cellular analysis of the bulk tumor mass. However, evidence in leukemia and, more recently, in solid tumors suggests that the tumor cell population is heterogeneous. In recent years, several groups have described the existence of a cancer stem cell population in different brain tumors. These neural cancer stem cells (NCSC) can be isolated by cell sorting of dissociated suspensions of tumor cells for the neural stem cell marker CD133. These CD133+ cells -which also express nestin, an intermediate filament that is another neural stem cell marker- represent a small fraction of the entire brain tumor population. The stem-like cancer cells appear to be solely responsible for propagating the disease in laboratory models. A promising new approach to treating glioblastoma proposes targeting cancer stem cells. Here, we summarize progress in delineating NCSC and the implications of the discovery of this cell population in human brain tumors (AU)


No disponible


Assuntos
Humanos , Masculino , Feminino , Neoplasias Encefálicas/patologia , Gliossarcoma/patologia , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/fisiologia , Antígenos CD/metabolismo , Neoplasias Encefálicas/metabolismo , Gliossarcoma/metabolismo , Glicoproteínas/metabolismo , Peptídeos/metabolismo
16.
Rev. esp. patol ; 41(1): 57-63, ene.-mar. 2008. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-68289

RESUMO

Introducción: El carcinoma metaplásico de mama se caracteriza por la transición directa de un carcinoma ductal infiltrante a elementos metaplásicos y/o sarcomatoides. El componente epitelial puede ser escaso o estar ausente y entonces su diferenciación frente a otros tumores de hábito sarcomatoide resulta difícil. La utilización de marcadores inmunohistoquímicos como el p63 y CD99 puede ser eficaz. Estudiamos la expresión de estos marcadores en un caso de carcinoma metaplásico variante productor de matriz (CMPM), haciendo una descripción detallada del componente epitelial y metaplásico. Material y método: Presentamos el caso de una mujer de 85 años que presenta una gran masa de 4,7 cm en localización retroareolar. Macroscópicamente, se trata de una masa blanquecina, de aspecto gelatinoso, blando de contorno lobulado, que corresponde a un tumor con múltiples patrones celulares. Muestra varios focos de carcinoma ductal infiltrante, aunque el componente más abundante es de células pequeñas redondeadas con tendencia a la formación de hileras o cordones inmersos en un estroma basófilo y mixoide. Resultados: El estudio inmunohistoquímico muestra que la totalidad del tumor expresa queratina AE1/AE3, p63, CD99, EGFR, EMA, S-100 y progesterona. El componente epitelial expresa además CAM 5.2 y e-caderina. El componente metaplásico resulta positivo para queratina 5/6, queratina 14, queratina de alto peso (34‚E12), actina y vimentina. Los receptores de estrógeno y Her2/neu son negativos. Se trata de un carcinoma metaplásico variante «productor de matriz» (CMPM). Conclusiones: El CMPM resulta positivo para CD99, y es el único subtipo de carcinoma de mama que lo expresa. Por ello se constituye en un marcador útil para su diagnóstico tanto en el tumor primario como en las metástasis. La expresión de p63 en nuestro caso, resulta útil para su diferenciación frente a otros sarcomas o tumores mixtos de mama (fillodes). Este CMPM muestra un fenotipo mioepitelial o basal en el componente metaplásico, y exhibe diferencias de expresión inmunohistoquímica con el componente epitelial. La confirmación de una diferenciación mioepitelial o basal para el CMPM tiene importantes implicaciones clínicas y terapéuticas


Introduction: Metaplastic breast carcinoma is characterized by the direct transition from an invasive duct carcinoma to metaplastic or/and sarcomatoid elements. As the epithelial component can be minimal or even absent, it may be difficult to differentiate it from sarcomatoid tumours. In these cases, immunohistochemical markers such as p63 and CD99 can be useful. We study the expression of these markers in a case of metaplastic carcinoma of matrix producing variant and make a thorough immunohistochemical characterization of the epithelial and metaplastic component.Material and method: The case of an 85-year-old woman with a 4,7-cm retroareolar mass is presented. Grossly, the specimen revealed a soft, whitish, lobulated mass of gelatinous appearance which microscopically exhibited multiple cellular patterns. Several foci of invasive duct carcinoma were observed although the tumour was composed predominantly of fascicles and chords of small round cells dispersed in a basophilic and myxoid stroma. Results: Immunohistochemical study revealed that the entire tumour stained positively with keratin AE1/AE3, p63, CD99, EGFR, EMA S-100 and progesterone. In addition, the epithelial component exhibited keratin CAM 5.2 and e-cadherine. The metaplastic component was positive with keratin 5/6, keratin 14, high molecular weight keratin (34‚E12), actin and vimentin. Oestrogen receptors and Her2/neu were negative. It is a metaplastic carcinoma of matrix producing variant. Discussion: The metaplastic carcinoma of matrix producing variant is positive for CD99 and it is the only subtype which expresses it. Therefore, it can be diagnostically useful, both in primary tumours and metastases. In this case, p63 expression is valuable in the differential diagnosis with other sarcomas and mixed tumours of the breast (fillodes tumour). This matrix-producing carcinoma shows a myoepithelial or basal phenotype in the metaplastic component and exhibits immunohistochemical differences from the epithelial component. The confirmation of a myoepithelial or basal component in the metaplastic carcinoma of matrix producing variant has important clinical and therapeutic implications (AU)


Assuntos
Humanos , Feminino , Idoso , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Metaplasia/patologia , Antígenos CD/análise , Mioepitelioma/patologia , Biomarcadores Tumorais/análise
17.
Inmunología (1987) ; 26(2): 65-72, abr.-jun. 2007. ilus
Artigo em Inglês | IBECS | ID: ibc-62522

RESUMO

Las tetraspaninas son moléculas de la superficie celular de ampliadistribución en los organismos eucarióticos. Poseen como característicaestructural peculiar cuatro dominios transmembranales, regionesN- y C-terminales intracitoplásmicas, y dos lazos extracelularesde distinto tamaño. También poseen un motivo de secuencia CCGen el lazo extracelular mayor, así como residuos polares conservadosen los dominios transmembranales. Las células sanguíneas delos mamíferos expresan combinaciones peculiares de distintas tetraspaninas,incluyendo los antígenos de diferenciación CD9, CD37,CD53, CD81/TAPA-1, CD82, CD151/PETA-3 y CD231/TALLA1.En este trabajo se resumen la estructura y las interacciones desus regiones citoplásmicas con proteínas del citoesqueleto y señalizadoras,como la proteína cinasa C (PKC) o la Fosfatidil-Inositol 4-cinasa (PI4-K). Sus interacciones específicas con otras tetraspaninas,con integrinas, antígenos de histocompatibilidad, y miembros dela superfamilia de las inmunoglobulinas son también revisadas.Las tetraspaninas son proteínas “adaptadoras” o “facilitadoras”.Al formar parte de complejos moleculares, modulan funcionescelulares clave que incluyen la fusión celular, la adhesión, lamigración, la diferenciación y la transducción de señales. Las tetraspaninasse organizan en una red con distintos niveles de asociación,determinados por su resistencia a la solubilización por detergentes.En concreto, se analizan las tetraspaninas como reguladorasdel Sistema Inmunitario gracias a sus interacciones con los receptoresde antígeno de los linfocitos T y B, las moléculas de histocompatibilidadde clase I y clase II, y los co-receptores CD2, CD4,CD5, CD8 y CD19. Por último, se revisa detalladamente el papelde la tetraspanina CD9 en la función de las células linfoides y mieloides,su relevancia en infecciones como el HIV, y la importanciade su asociación con integrinas en la progresión cancerosa


Tetraspanins are cell surface proteins widely distributed ineukaryotic organisms. They characteristically span four times theplasma membrane, have intracellular N and C terminal regions,and two extracellular loops of unequal size. Tetraspanins also possessa CCG motif in the large extracellular loop, and conservedpolar residues in the transmembrane domains. Mammalian bloodcells express different sets of tetraspanins including the differentiationantigens CD9, CD37, CD53, CD81/TAPA-1, CD82,CD151/PETA-3 and CD231/TALLA1.Here, tetraspanin structure and their cytoplasmic tail interactionswith cytoskeletal and signalling proteins like Protein kinaseC (PKC) or Phosphatidyl Inositol 4-kinase (PI4-K) are brieflysummarized. The specific interactions with other cell surface proteins,forming complexes with other tetraspanins and membersof the integrin family, MHC histocompatibility antigens, or membersof the immunoglobulin superfamily are also reviewed.Tetraspanins are considered as “adapter” or “facilitating” proteinsand, through their participation in complexes, they modulatekey cellular functions like cell fusion, adhesion, migration,differentiation and signal transduction. The organization of thetetraspanin web, based on different association levels determinedby their resistance to detergent solubilization, is described. In particular,tetraspanins participating in the regulation of the ImmuneSystem through interactions with the B- and T-cell receptors,the class I and class II MHC antigens, and co-receptors such asCD2, CD4, CD5, CD8, or CD19 are analyzed. At last, the role ofCD9 in myeloid and lymphoid cell function, its relevance to HIVinfection, and the importance of tetraspanin association with integrinsto cancer progression are described in detail


Assuntos
Humanos , Proteínas de Membrana/análise , Antígenos CD/análise , Sistema Imunitário/fisiologia , Citoplasma , Integrinas , Infecções por HIV/imunologia , Neoplasias/imunologia , Linfócitos/imunologia , Células Mieloides/imunologia , Infecções/imunologia
18.
Allergol. immunopatol ; 34(4): 131-135, jul. 2006. tab
Artigo em Inglês | IBECS | ID: ibc-049225

RESUMO

Background. Common variable immunodeficiency (CVID) is a very heterogeneous syndrome defined by impaired immunoglobulin production. The primary defect remains unknown, but many reports describe peripheral blood T and B lymphocyte dysfunctions in a substantial proportion of CVID patients. Immunophenotypic alterations on memory B lymphocytes correlate with clinical findings. A B-cell-oriented classification principle of the patients has been proposed. Methods and results. We investigated the expression of activation surface molecules on CD4 and CD8 T-cells from 14 patients with CVID, 6 non-CVID hypogammaglobulinemic patients with recurrent infections, 47 asymptomatic HIV-positive patients without AIDS defining conditions and 23 healthy subjects. Lymphocyte subsets were analysed by three-colour flow cytometry. Monoclonal panel: CD38-FITC/HLADR-PE/CD4 or CD8-PerCP. In CVID patients serum levels of CD4 T-cells co-expressing the activation marker HLA-DR [CD4+DR+ (34 %), CD4+CD38+DR+ (18 %)] were significantly elevated compared with controls. Significant increases in CD8+DR+ (54 %), CD8+ CD38+ (43 %) and CD8+CD38+DR+ (29 %) T-cells were observed in comparison with healthy controls. CVID patients with splenomegaly, lower pre-infusion IgG levels (< 600 mg/dl), autoimmune or lymphoproliferative conditions demonstrated even higher levels of CD4+CD38+DR+T cells (22, 22, 21 and 21 % respectively) compared with other CVID patients (13, 13, 15 and 15 % respectively). Conclusion. These findings indicate a state of ongoing T lymphocyte activation which is associated with clinical findings frequently observed in CVID


Fundamento. La inmunodeficiencia variable común (IDVC) es una enfermedad caracterizada por una deficiencia en la formación de anticuerpos. El defecto primario sigue sin conocerse, pero los pacientes exhiben alteraciones funcionales de los linfocitos T y B. Recientemente se ha demostrado que las alteraciones inmunofenotípicas de los linfocitos B se correlacionan con características clínicas de la enfermedad, habiéndose propuesto clasificaciones de los pacientes sobre la base de las alteraciones inmunofenotípicas. Métodos y resultados. Mediante un estudio descriptivo transversal, comparamos la expresión de marcadores de activación linfocitaria sobre células T CD4+ y CD8+ de 14 pacientes con IDVC, 6 pacientes con hipogammaglobulinemia (sin criterio de IDVC), 47 pacientes con infección VIH sin criterio clínico de SIDA y 23 controles sanos. Las subpoblaciones linfocitarias se estudiaron mediante citometría de flujo de tres colores. Panel de anticuerpos monoclonales: CD38-FITC/HLADR-PE/CD4 o CD8-PerCP. El porcentaje medio de linfocitos T CD4+DR+ (34%), CD4+CD38+DR+ (18%) en los pacientes con IDVC era mayor que en los controles. Los pacientes con IDVC tenían valores más altos de células T CD8+DR+ (54%), CD8+CD38+ (43%) y CD8+CD38+DR+ (29%) que los controles sanos. Los pacientes con IDVC que tenían esplenomegalia, niveles más bajos de IgG pre-infusión de GGIV (<600 mg/dl), enfermedad autoinmune o condiciones linfoproliferativas, mostraron valores mayores de linfocitos T CD4+CD38+DR+ (22%, 22%, 21% y 21%, respectivamente) en comparación con pacientes con IDVC sin estas condiciones clínicas (13%, 13%, 15% y 15%, respectivamente). Conclusiones. Valores mayores de activación linfocitaria de células T CD4+ se asocian con ciertas características clínicas en pacientes con IDVC


Assuntos
Adulto , Idoso , Pessoa de Meia-Idade , Humanos , Contagem de Linfócito CD4 , T-Linfocitopenia Idiopática CD4-Positiva/imunologia , Imunodeficiência de Variável Comum/imunologia , Ativação Linfocitária , Agamaglobulinemia/sangue , Agamaglobulinemia/imunologia , Antígenos CD/análise , Doenças Autoimunes/etiologia , Linfócitos B/química , Linfócitos B/imunologia , T-Linfocitopenia Idiopática CD4-Positiva/tratamento farmacológico , Linfócitos T CD8-Positivos/química , Linfócitos T CD8-Positivos/imunologia , Citometria de Fluxo , Infecções por HIV/sangue , Infecções por HIV/imunologia , Esplenomegalia/etiologia
19.
An. sist. sanit. Navar ; 29(1): 77-96, ene.-abr. 2006. ilus
Artigo em Espanhol | IBECS | ID: ibc-044766

RESUMO

La manipulación farmacológica del sistema inmunitario para conseguir respuestas linfocitarias de mayor intensidad tiene aplicación potencial en inmunoterapia tumoral y en el tratamiento de enfermedades virales crónicas. Los anticuerpos monoclonales inmunoestimuladores se definen como una familia de fármacos que aumentan la respuesta inmunitaria al interaccionar como ligandos artificiales con proteínas funcionales del sistema inmunitario, activando o inhibiendo su función. Hay anticuerpos monoclonales humanizados dirigidos frente al receptor inhibidor linfocitario CD152 (CTLA-4) que se están probando en ensayos clínicos con evidencia de actividad antitumoral, aunque con la contrapartida de producir reacciones autoinmunitarias severas. Los anticuerpos anti-CD137 tienen la capacidad de inducir potentes respuestas inmunitarias, mediadas principalmente por linfocitos T citotóxicos, con el resultado de erradicar tumores transplantables de ratón de forma comparativamente superior a los anticuerpos frente a CD152. CD137 (4-1BB) es un antígeno de diferenciación expresado selectivamente en la superficie de linfocitos T y NK activados y sobre células dendríticas. Los anticuerpos monoclonales que actúan como ligandos artificiales estimuladores de este receptor (anticuerpos monoclonales agonistas anti-CD137) potencian la inmunidad celular antitumoral y antiviral en modelos experimentales murinos. Paradójicamente, estos mismos anticuerpos previenen o mejoran el curso de enfermedades autoinmunitarias establecidas en ratones como modelo. A la luz de estos datos experimentales, varios grupos de investigación han procedido a la humanización de anticuerpos dirigidos frente a CD137 humano y se plantea la inminente realización de los primeros ensayos clínicos


Pharmacological intervention on the immune system to achieve more intense lymphocyte responses has potential application in tumour immunology and in the treatment of chronic viral diseases. Immunostimulating monoclonal antibodies are defined as a new family of drugs that augment cellular immune responses. They interact as artificial ligands with functional proteins of the immune system, either activating or inhibiting their functions. There are humanized monoclonal antibodies directed to the inhibitory receptor CD152 (CTLA-4) that are being tested in clinical trials with evidence of antitumoural activity. As a drawback, anti-CTLA-4 monoclonal antibodies induce severe autoimmunity reactions in a fraction of the patients. Anti-CD137 monoclonal antibodies have the ability to induce potent immune responses mainly mediated by cytotoxic lymphocytes with the result of frequent complete tumour eradications in mice. Comparative studies in experimental models indicate that the antitumour activity of anti-CD137 monoclonal antibodies is superior to that of anti-CD152. CD137 (4-1BB) is a leukocyte differentiation antigen selectively expressed on the surface of activated T and NK lymphocytes, as well as on dendritic cells. Monoclonal antibodies acting as artificial stimulatory ligands of this receptor (anti-CD137 agonist antibodies) enhance cellular antitumoural and antiviral immunity in a variety of mouse models. Paradoxically, anti-CD137 monoclonal antibodies are therapeutic or preventive in the course of model autoimmune diseases in mice. In light of these experimental results, a number of research groups have humanized antibodies against human CD137 and early clinical trials are about to start


Assuntos
Animais , Humanos , Camundongos , Anticorpos Monoclonais/uso terapêutico , Antígenos CD/imunologia , Antígenos de Diferenciação/imunologia , Antineoplásicos/uso terapêutico , Imunoterapia , Receptores de Fator de Crescimento Neural/imunologia , Viroses/terapia , Receptores do Fator de Necrose Tumoral/imunologia , Autoimunidade , Vacinas Anticâncer/uso terapêutico , Doença Crônica , Ensaios Clínicos como Assunto , Citocinas/imunologia , Camundongos Transgênicos , Transplante Homólogo , Células Tumorais Cultivadas , Vacinas Virais/uso terapêutico , Transplante de Medula Óssea/imunologia , Neoplasias/imunologia , Neoplasias Experimentais/imunologia
20.
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