RESUMO
Tn is a tumor-associated carbohydrate antigen that constitutes both a diagnostic tool and an immunotherapeutic target. It originates from interruption of the mucin O-glycosylation pathway through defects involving, at least in part, alterations in core-1 synthase activity, which is highly dependent on Cosmc, a folding chaperone. Tn antigen is recognized by the Macrophage Galactose-type Lectin (MGL), a C-type lectin receptor present on dendritic cells and macrophages. Specific interactions between Tn and MGL shape anti-tumoral immune responses by regulating several innate and adaptive immune cell programs. In this work, we generated and characterized a variant of the lung cancer murine cell line LL/2 that expresses Tn by mutation of the Cosmc chaperone gene (Tn+ LL/2). We confirmed Tn expression by lectin glycophenotyping and specific anti-Tn antibodies, verified abrogation of T-synthase activity in these cells, and confirmed its recognition by the murine MGL2 receptor. Interestingly, Tn+ LL/2 cells were more aggressive in vivo, resulting in larger and highly vascularized tumors than those generated from wild type Tn- LL/2 cells. In addition, Tn+ tumors exhibited an increase in CD11c+ F4/80+ cells with high expression of MGL2, together with an augmented expression of IL-10 in infiltrating CD4+ and CD8+ T cells. Importantly, this immunosuppressive microenvironment was dependent on the presence of MGL2+ cells, since depletion of these cells abrogated tumor growth, vascularization and recruitment of IL-10+ T cells. Altogether, our results suggest that expression of Tn in tumor cells and its interaction with MGL2-expressing CD11c+F4/80+ cells promote immunosuppression and angiogenesis, thus favoring tumor progression.
Assuntos
Antígenos Glicosídicos Associados a Tumores/imunologia , Galactose/imunologia , Lectinas Tipo C/imunologia , Neoplasias Pulmonares/imunologia , Macrófagos/imunologia , Neovascularização Patológica/imunologia , Animais , Antígeno CD11c/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Feminino , Terapia de Imunossupressão/métodos , Interleucina-10/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Microambiente Tumoral/imunologiaRESUMO
Hypoxia, angiogenesis, and immunosuppression have been proposed to be interrelated events that fuel tumor progression and impair the clinical effectiveness of anti-tumor therapies. Here we present new mechanistic data highlighting the role of hypoxia in fine-tuning CD8 T cell exhaustion in vitro, in an attempt to reconcile seemingly opposite evidence regarding the impact of hypoxia on functional features of exhausted CD8 T cells. Focusing on the recently characterized terminally-differentiated and progenitor exhausted CD8 T cells, we found that both hypoxia and its regulated mediator, vascular endothelial growth factor (VEGF)-A, promote the differentiation of PD-1+ TIM-3+ CXCR5+ terminally exhausted-like CD8 T cells at the expense of PD-1+ TIM-3- progenitor-like subsets without affecting tumor necrosis factor (TNF)-α and interferon (IFN)-γ production or granzyme B (GZMB) expression by these subpopulations. Interestingly, hypoxia accentuated the proangiogenic secretory profile in exhausted CD8 T cells. VEGF-A was the main factor differentially secreted by exhausted CD8 T cells under hypoxic conditions. In this sense, we found that VEGF-A contributes to generation of terminally exhausted CD8 T cells during in vitro differentiation. Altogether, our findings highlight the reciprocal regulation between hypoxia, angiogenesis, and immunosuppression, providing a rational basis to optimize synergistic combinations of antiangiogenic and immunotherapeutic strategies, with the overarching goal of improving the efficacy of these treatments.
Assuntos
Linfócitos T CD8-Positivos/fisiologia , Diferenciação Celular/imunologia , Hipóxia , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Humanos , Tolerância Imunológica , Camundongos Endogâmicos C57BL , Baço/citologia , Fator A de Crescimento do Endotélio Vascular/imunologia , Fator A de Crescimento do Endotélio Vascular/farmacologiaRESUMO
Galectins, a family of highly conserved ß-galactoside-binding proteins, control tumor progression by modulating different hallmarks of cancer. Galectin-1 (Gal-1), a proto-type member of this family, plays essential roles in tumor angiogenesis and immunosuppression by cross-linking glycosylated receptors on the surface of endothelial and immune cells. Targeted disruption of Gal-1 suppresses tumor growth by counteracting aberrant angiogenesis and reinforcing antitumor immunity in several experimental settings. Given the multiple therapeutic benefits associated with Gal-1 blockade, several Gal-1 inhibitors, including glycan-based competitors, antagonistic peptides, aptamers and neutralizing monoclonal antibodies, have been designed and evaluated in pre-clinical tumor models. Here we report the biochemical and functional characterization of a newly developed neutralizing anti-human Gal-1 monoclonal antibody (Gal-1-mAb3), which specifically recognizes a unique epitope in Gal-1 protein and exerts both angioregulatory and immunomodulatory activities. Blockade of Gal-1 function using Gal-1-mAb3, might be relevant not only in cancer but also in other pathologic conditions characterized by aberrant angiogenesis and uncontrolled immunosuppression.
Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/farmacologia , Galectina 1/imunologia , Fatores Imunológicos/farmacologia , Neovascularização Fisiológica , Animais , Fenômenos Biofísicos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Camundongos Endogâmicos BALB C , Neovascularização Fisiológica/efeitos dos fármacosRESUMO
Pocas situaciones generan mayor angustia en el profesional médico como la de recibir una demanda por mala praxis. Los reclamos medico legales en cáncer de mama están centrados, de acuerdo a la mayor parte de la bibliografía internacional, en el retraso en el diagnóstico de cáncer de mama, si bien existen reclamos legales en el ámbito del tratamiento, estos son menos frecuentes. En EEUU la primera causa de juicios por mala praxis son los daños obstétricos, y la segunda causa es el retraso en el diagnóstico de la patología oncológica, estando en primer lugar el cáncer de mama; el riesgo de reclamo médico legal se calcula en 1/1000 canceres de mama; no hay estadísticas fiables en nuestro país pero extrapolando estos resultados seria esperable unas 20 demandas anuales. El perfil de riesgo es una paciente joven, premenopausica, con una masa autopercibida que es subestimada en la consulta clínica y/o por los estudios por imágenes. Una buena relación médico-paciente y una correcta documentación de la historia clínica es la mejor prevención, trabajando en forma normatizada y de acuerdo a guías nacionales e internacionales. Fomentar el trabajo en equipo y la formación de Unidades de Mastología en las instituciones es una forma de trabajo multidisciplinario que resulta en beneficio tanto de la paciente como de los profesionales.
There are few situations can generate distress for medical professionals like receiving a malpractice lawsuit. Medico legal issues in breast cancer are focused, according to the most international bibliography, on the delay in diagnosis of breast cancer. Even though legal claims exist concerning about treatment, those are less frequent. In USA, obstetric damages are the first cause of malpractice lawsuit and the second one is the delay in diagnosis of oncological pathology being the breast cancer at the first place. The risk of legal medical claim is calculated at 1/1000 breast cancers. There are no reliable statistic in our country but extrapolating these results, it would be expected around 20 demands per year. The risk profile is a young premenopausal patient with a breast mass self-perceived which is underrated by the doctor or imaging studies. A good doctor patient relationship and an accurate report in medical records is the best prevention, working in a standarized way according to international and national guides. We must persuit to encourage teamwork and Mastology Units organisation over all institutions is a multidisciplinary way of working toreach the patients benefit as well as professionals.
Assuntos
Humanos , Feminino , Neoplasias da Mama , Jurisprudência , ImperíciaRESUMO
Quinones are secondary metabolites of higher plants associated with many biological activities, including antiviral effects and cytotoxicity. In this study, the anti-herpetic and anti-dengue evaluation of 27 terpenyl-1,4-naphthoquinone (NQ), 1,4-anthraquinone (AQ) and heterocycle-fused quinone (HetQ) derivatives was done in vitro against Human Herpesvirus (HHV) type 1 and 2, and Dengue virus serotype 2 (DENV-2). The cytotoxicity on HeLa and Jurkat tumor cell lines was also tested. Using plaque forming unit assays, cell viability assays and molecular docking, we found that NQ 4 was the best antiviral compound, while AQ 11 was the most active and selective molecule on the tested tumor cells. NQ 4 showed a fair antiviral activity against Herpesviruses (EC50: <0.4 µg/mL, <1.28 µM) and DENV-2 (1.6 µg/mL, 5.1 µM) on pre-infective stages. Additionally, NQ 4 disrupted the viral attachment of HHV-1 to Vero cells (EC50: 0.12 µg/mL, 0.38 µM) with a very high selectivity index (SI = 1728). The in silico analysis predicted that this quinone could bind to the prefusion form of the E glycoprotein of DENV-2. These findings demonstrate that NQ 4 is a potent and highly selective antiviral compound, while suggesting its ability to prevent Herpes and Dengue infections. Additionally, AQ 11 can be considered of interest as a leader for the design of new anticancer agents.
Assuntos
Antraquinonas/química , Antivirais/química , Antivirais/farmacologia , Naftoquinonas/química , Animais , Linhagem Celular Tumoral , Chlorocebus aethiops , Vírus da Dengue/efeitos dos fármacos , Células HeLa , Herpesviridae/efeitos dos fármacos , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Humanos , Estrutura Molecular , Células VeroRESUMO
ABSTRACT Plants are considered among the main sources of biologically active chemicals. The species Solidago chilensis Meyen, Asteraceae, is native to the southern parts of South America, where the aerial parts of the plant are commonly used for the treatment of inflammatory conditions. However, the effects of S. chilensis on human cancer cells remain to be elucidated. In this study, we evaluated the antiproliferative effects of the hydroalcoholic and dichloromethane extracts of S. chilensis, as well as their chemical constituents quercitrin and solidagenone against the five human tumor cell lines in vitro. The dichloromethane extract showed a promisor antiproliferative effects in vitro, especially against glioma cell line. Besides, the hydroalcoholic extract and quercitrin were inactive. The diterpene solidagenone showed highly potent antiproliferative effects against breast (MCF-7), kidney (786-0), and prostate cancer (PC-3) cells (total growth inhibition: TGI < 6.25 µg/ml). Solidagenone meets the theoretical physico-chemical criteria for bioavailability of drugs, according to the "Rule of Five" and, by theorical studies, the observed biological effects were probably related to the interaction of the molecule with nuclear receptors and as an enzymatic inhibitor. This study contributes to chemical study and to the identification of antiproliferative molecules in S. chilensis.
RESUMO
La estatificación axilar es uno de los más importantes factores pronósticos en pacientes con cáncer de mama. La punción con aguja fina (PAAF) guiada por ecografía de los ganglios axilares es un método técnicamente factible y de baja morbilidad para la evaluación preoperatoria del compromiso axilar, en especial cuando hay sospecha clínica o ecográfica de compromiso a ese nivel. Este procedimiento aún no es parte de la rutina en la práctica general y sus indicaciones no se han establecido claramente. Objetivos: Analizar la utilidad de la punción con aguja fina (PAAF) guiada por ecografía de los ganglios linfáticos axilares en la evaluación preoperatoria de las pacientes con cáncer de mama y sospecha de compromiso axilar clínico o por imágenes; determinar la sensibilidad y especificidad del método;comparar los resultados con la bibliografía. Material y método: Se llevó a cabo un estudio observacional, prospectivo donde se evaluaron 23 pacientes con cáncer de mama a las cuales se les realizó PAAF axilar en el Servicio de Ginecología y el Servicio de Diagnóstico por Imágenes del Hospital Interzonal General de Agudos (HIGA) de Mar del Plata, en el períodonoviembre de 2013 a agosto de 2014. Resultados: La edad promedio de las pacientes fue de 49,4 años. El tamaño tumoral promedio por imágenes fue de 31 mm y por anatomía patológica de 32,5 mm. Se realizaron 25 punciones axilares (dos casos bilaterales) con 14 resultados positivos (56%), 9 negativos (36%) y 2 (8%) insatisfactorios. La sensibilidad del método fue del 82,3% con un 17,7% de falsos negativos; la especificidad fue del 100%, el VPP del 100% y el VPN del 66,6%. No hubo diferencia significativa en la relación del tamaño tumoral con el resultado de la PAAF...
Assuntos
Axila , Neoplasias da Mama , Gânglios , Estadiamento de Neoplasias , PunçõesRESUMO
This paper reports on the syntheses and spectrometric characterisation of eleven novel ent-kaurane diterpenoids, including a complete set of (1)H, (13)C NMR and crystallographic data for two novel ent-kaurane diepoxides. Moreover, the antineoplastic cytotoxicity for kaurenoic acid and the majority of ent-kaurane derivatives were assessed in vitro against a panel of fourteen cancer cell lines, of which allylic alcohols were shown to be the most active compounds. The good in vitro antimalarial activity and the higher selectivity index values observed for some ent-kaurane epoxides against the chloroquine-resistant W2 clone of Plasmodium falciparum indicate that this class of natural products may provide new hits for the development of antimalarial drugs.
Assuntos
Antimaláricos/farmacologia , Antineoplásicos/farmacologia , Diterpenos do Tipo Caurano/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/síntese química , Antimaláricos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diterpenos do Tipo Caurano/síntese química , Diterpenos do Tipo Caurano/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Modelos Moleculares , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-AtividadeRESUMO
Two regioisomeric meroterpenoids, Eugenial A and B, have been isolated from the fruits of Eugenia multiflora and their structures established on the basis of NMR evidences. They possess a phloroglucinol-monoterpene structure similar to the euglobals occurring in the sister genus Eucaliptus. A simple method to distinguish between regioisomeric pairs was pointed.
Assuntos
Floroglucinol/química , Syzygium/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Terpenos/químicaRESUMO
A recent reinvestigation of aerial parts of Wedelia paludosa D.C. is described and reports, for the first time, the isolation of iso-kaurenoic acid from this species.
Assuntos
Diterpenos/isolamento & purificação , Extratos Vegetais/isolamento & purificação , Wedelia/química , Diterpenos/química , Diterpenos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologiaRESUMO
A recent reinvestigation of aerial parts of Wedelia paludosa D.C. is described and reports, for the first time, the isolation of iso-kaurenoic acid from this species.
Uma recente reinvestigação das partes aéreas de Wedelia paludosa D.C. é descrita e relata, pela primeira vez, o isolamento do ácido iso-caurenóico desta espécie.
Assuntos
Diterpenos/isolamento & purificação , Extratos Vegetais/isolamento & purificação , Wedelia/química , Diterpenos/química , Diterpenos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologiaRESUMO
This article presents the development of a versatile hardware platform for brain computer interfaces (BCI). The aim of this work is to produce a small, autonomous and configurable BCI platform adaptable to the user's needs.
Assuntos
Encéfalo/fisiologia , Computadores , Interface Usuário-Computador , Eletroencefalografia , HumanosRESUMO
Prevention methods to avoid transmission of pathogens, including HIV, are crucial in the control of infectious diseases, not only to block epidemic spread but to avoid long-term treatments leading to emergence of resistances and drug associated side effects. Together with vaccine development, the discovery of new virucidal agents represents a research priority in this setting. In the screening of new compounds with antiviral activity, three Guatemalan plant extracts from Justicia reptans, Neurolaena lobata and Pouteria viridis were evaluated with a classic antiviral assay and were found to inhibit HIV replication. This activity was corroborated by an original recombinant virus assay, leading us to perform a deeper study of the virucidal activity. Active fractions were non-toxic in vitro and also inhibited other enveloped viruses. Moreover, these fractions were able to inhibit the transfer of HIV from dendritic cells (DCs) to lymphocytes, that represents the main way of HIV spread in vivo.