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1.
Eur J Med Chem ; 201: 112443, 2020 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-32599324

RESUMO

CDK8 is a cyclin-dependent kinase that forms part of the mediator complex, and modulates the transcriptional output from distinct transcription factors involved in oncogenic control. Overexpression of CDK8 has been observed in various cancers, representing a potential target for developing novel CDK8 inhibitors in cancer therapeutics. In the course of our investigations to discover new CDK8 inhibitors, we designed and synthesized tricyclic pyrido[2,3-b][1,5]benzoxazepin-5(6H)-one derivatives, by introduction of chemical complexity in the multi-kinase inhibitor Sorafenib taking into account the flexibility of the P-loop motif of CDK8 protein observed after analysis of structural information of co-crystallized CDK8 inhibitors. In vitro evaluation of the inhibitory activity of the prepared compounds against CDK8 led us to identify compound 2 as the most potent inhibitor of the series (IC50 = 8.25 nM). Co-crystal studies and the remarkable selectivity profile of compound 2 are presented. Compound 2 showed moderate reduction of phosphorylation of CDK8 substrate STAT1 in cells, in line with other reported Type II CDK8 inhibitors. We propose herein an alternative to find a potential therapeutic use for this chemical series.

2.
Sci Rep ; 10(1): 7741, 2020 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385335

RESUMO

This study evaluates the impact of breast cancer (BC) in health related quality of life (HRQL) and in psychological distress (PD) during the initial phases of the disease and looks for contributing factors. A multicentric case-control study, EpiGEICAM, was carried out. Incident BC cases and age- and residence- matched controls were included. Clinical, epidemiological, HRQL (SF-36) and PD information (GHQ-28) was collected. We used multivariable logistic regression models to estimate OR of low HRQL and of PD in cases compared to controls, and to identify factors associated with low HRQL and with PD. Among 896 BC cases and 890 control women, cases had poorer scores than both, the reference population and the control group, in all SF-36 scales. BC women with lower education, younger, active workers, never smokers, those with comorbidities, in stage IV and with surgical treatment had lower physical HRQL; factors associated with low mental HRQL were dissatisfaction with social support, being current smoker and having children. Cases had a fivefold increased odds of PD compared to controls. Managing comorbidities and trying to promote social support, especially in younger and less educated women, could improve well-being of BC patients.

4.
Gut Microbes ; 11(4): 962-978, 2020 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-32167021

RESUMO

Nutrition during pregnancy plays an important role in maternal-neonatal health. However, the impact of specific dietary components during pregnancy on maternal gut microbiota and the potential effects on neonatal microbiota and infant health outcomes in the short term are still limited. A total of 86 mother-neonate pairs were enrolled in this study. Gut microbiota profiling on maternal-neonatal stool samples at birth was carried out by 16S rRNA gene sequencing using Illumina. Maternal dietary information and maternal-neonatal clinical and anthropometric data were recorded during the first 18 months. Longitudinal Body Mass Index (BMI) and Weight-For-Length (WFL) z-score trajectories using the World Health Organization (WHO) curves were obtained. The maternal microbiota was grouped into two distinct microbial clusters characterized by Prevotella (Cluster I) and by the Ruminococcus genus (Cluster II). Higher intakes of total dietary fiber, omega-3 fatty acids, and polyphenols were observed in Cluster II compared to Cluster I. Higher intakes of plant-derived components were associated with a higher presence of the Christensellaceae family, Dehalobacterium and Eubacterium, and lower amounts of the Dialister and Campylobacter species. Maternal microbial clusters were also linked to neonatal microbiota and infant growth in a birth-dependent manner. C-section neonates from Cluster I showed the highest BMI z-score at age 18 months, along with a higher risk of overweight. Longitudinal BMI and WL z-score trajectories from birth to 18 months were shaped by maternal microbial cluster, diet, and birth mode. Diet was an important perinatal factor in early life that may impact maternal microbiota; in particular, fiber, lipids and proteins, and exert a significant effect on the neonatal microbiome and contribute to infant development during the first months of life. ABBREVIATIONS: NCDs: Non-Communicable Diseases, C-section: Cesarean Section, BMI: Body Mass Index; WL: Weight for length; EPA: Eicosapentanoic Acid; DHA: Docosahexaenoic Acid; DPA: Docosapentaenoic Acid; SCFA: Short Chain Fatty Acids; MD: Mediterranean Diet; FFQ: Food Frequency Questionnaire; CHI: Calinski Harabasz Index.

7.
Microbiome ; 7(1): 100, 2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-31272480

RESUMO

BACKGROUND: The microbial populations of the human intestinal tract and their relationship to specific diseases have been extensively studied during the last decade. However, the characterization of the human bile microbiota as a whole has been hampered by difficulties in accessing biological samples and the lack of adequate methodologies to assess molecular studies. Although a few reports have described the biliary microbiota in some hepatobiliary diseases, the bile microbiota of healthy individuals has not been described. With this in mind, the goal of the present study was to generate fundamental knowledge on the composition and activity of the human bile microbiota, as well as establishing its potential relationship with human bile-related disorders. RESULTS: Human bile samples from the gallbladder of individuals from a control group, without any record of hepatobiliary disorder, were obtained from liver donors during liver transplantation surgery. A bile DNA extraction method was optimized together with a quantitative PCR (qPCR) assay for determining the bacterial load. This allows the selection of samples to perform functional metagenomic analysis. Bile samples from the gallbladder of individuals suffering from lithiasis were collected during gallbladder resection and the microbial profiles assessed, using a 16S rRNA gene-based sequencing analysis, and compared with those of the control group. Additionally, the metabolic profile of the samples was analyzed by nuclear magnetic resonance (NMR). We detected, for the first time, bacterial communities in gallbladder samples of individuals without any hepatobiliary pathology. In the biliary microecosystem, the main bacterial phyla were represented by Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria. Significant differences in the relative abundance of different taxa of both groups were found. Sequences belonging to the family Propionibacteriaceae were more abundant in bile samples from control subjects; meanwhile, in patients with cholelithiasis members of the families Bacteroidaceae, Prevotellaceae, Porphyromonadaceae, and Veillonellaceae were more frequently detected. Furthermore, the metabolomics analysis showed that the two study groups have different metabolic profiles. CONCLUSIONS: Our results indicate that the gallbladder of human individuals, without diagnosed hepatobiliary pathology, harbors a microbial ecosystem that is described for the first time in this study. Its bacterial representatives and metabolites are different from those detected in people suffering from cholelithiasis. In this regard, since liver donors have been subjected to the specific conditions of the hospital's intensive care unit, including an antibiotic treatment, we must be cautious in stating that their bile samples contain a physiologically normal biliary microbiome. In any case, our results open up new possibilities to discover bacterial functions in a microbial ecosystem that has not previously been explored.


Assuntos
Bile/metabolismo , Bile/microbiologia , Vesícula Biliar/microbiologia , Vesícula Biliar/fisiologia , Microbiota , Adulto , Idoso , Bactérias/classificação , Feminino , Humanos , Litíase/microbiologia , Masculino , Metabolômica , Metagenoma , Pessoa de Meia-Idade , RNA Ribossômico 16S/genética , RNA Ribossômico 18S/genética
8.
Int J Mol Sci ; 20(8)2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31027304

RESUMO

The colonic epithelium is exposed to a mixture of compounds through diet, among which some are procarcinogens, whereas others have a protective effect. Therefore, the net impact of these compounds on human health depends on the overall balance between all factors involved. Strong scientific evidence has demonstrated the relationship between nitrosamines (NA), heterocyclic amines (HCAs), and polycyclic aromatic hydrocarbons (PAHs), which are the major genotoxins derived from cooking and food processing, and cancer. The mechanisms of the relationship between dietary toxic xenobiotics and cancer risk are not yet well understood, but it has been suggested that differences in dietary habits affect the colonic environment by increasing or decreasing the exposure to mutagens directly and indirectly through changes in the composition and activity of the gut microbiota. Several changes in the proportions of specific microbial groups have been proposed as risk factors for the development of neoplastic lesions and the enrichment of enterotoxigenic microbial strains in stool. In addition, changes in the gut microbiota composition and activity promoted by diet may modify the faecal genotoxicity/cytotoxicity, which can be associated with a higher or lower risk of developing cancer. Therefore, the interaction between dietary components and intestinal bacteria may be a modifiable factor for the development of colorectal cancer in humans and deserves more attention in the near future.


Assuntos
Neoplasias Colorretais/metabolismo , Manipulação de Alimentos , Microbioma Gastrointestinal , Xenobióticos/metabolismo , Animais , Humanos
9.
Eur J Med Chem ; 168: 87-109, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30802730

RESUMO

PIM kinase family (PIM-1, PIM-2 and PIM-3) is an appealing target for the discovery and development of selective inhibitors, useful in various disease conditions in which these proteins are highly expressed, such as cancer. The significant effort put, in the recent years, towards the development of small molecules exhibiting inhibitory activity against this protein family has ended up with several molecules entering clinical trials. As part of our ongoing exploration for potential drug candidates that exhibit affinity towards this protein family, we have generated a novel chemical series of triazolo[4,3-b]pyridazine based tricycles by applying a scaffold hopping strategy over our previously reported potent pan-PIM inhibitor ETP-47453 (compound 2). The structure-activity relationship studies presented herein demonstrate a rather selective PIM-1/PIM-3 biochemical profile for this novel series of tricycles, although pan-PIM and PIM-1 inhibitors have also been identified. Selected examples show significant inhibition of the phosphorylation of BAD protein in a cell-based assay. Moreover, optimized and highly selective compounds, such as 42, did not show significant hERG inhibition at 20 µM concentration, and proved its antiproliferative activity and utility in combination with particular antitumoral agents in several tumor cell lines.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Piridazinas/farmacologia , Quinolinas/farmacologia , Triazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Piridazinas/síntese química , Piridazinas/química , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
10.
Nutrients ; 10(9)2018 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-30223526

RESUMO

Recent dietary habits and lifestyle could explain the shaping of the gut microbiota composition and, in consequence, the increasing prevalence of certain pathologies. However, little attention has been paid to the influence of diet on microbiotas, other than the gut microbiota. This is important in cholelithiasis, given that changes in the production of bile acids may affect gallbladder microbial communities. Our aim was to assess the association between regular dietary intake and gallbladder microbial composition. Fourteen adults with cholelithiasis and 14 controls, sex‒age-matched and without gastrointestinal pathology, were included. Diet was assessed through a food frequency questionnaire and quantification of gallbladder microbiota sequences by Illumina 16S rRNA gene-based analysis. The cholelithiasic patients showed greater intake of potatoes and lower consumption of vegetables, non-alcoholic drinks, and sauces, which resulted in a lower intake of energy, lipids, digestible polysaccharides, folate, calcium, magnesium, vitamin C, and some phenolic compounds. Regarding the altered bile microorganisms in cholelithiasic patients, dairy product intake was negatively associated with the proportions of Bacteroidaceae and Bacteroides, and several types of fiber, phenolics, and fatty acids were linked to the abundance of Bacteroidaceae, Chitinophagaceae, Propionibacteraceae, Bacteroides, and Escherichia‒Shigella. These results support a link between diet, biliary microbiota, and cholelithiasis.


Assuntos
Bactérias/classificação , Bile/microbiologia , Colelitíase/microbiologia , Dieta/efeitos adversos , Comportamento Alimentar , Vesícula Biliar/microbiologia , Adulto , Idoso , Bactérias/isolamento & purificação , Estudos de Casos e Controles , Colelitíase/diagnóstico , Disbiose , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Nutritivo , Fatores de Risco
11.
J Agric Food Chem ; 66(40): 10438-10446, 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30227707

RESUMO

Although most of the health effects attributed to polyphenols may be linked to their phenolic-derived metabolites, the role of the intestinal derived-phenolics in human health is still far from being well understood. We determined the profile of fecal phenolic-derived metabolites, microbiota, biomarkers of oxidative stress and inflammation, and daily intake of bioactive compounds in 71 elderly volunteers. Phenylacetic and phenylpropionic acids were the main phenolic metabolites present in feces. From them, phenylacetic acid was related with a more pro-oxidant and immune stimulated status, and both were negatively associated with fecal propionate, whereas phenylpropionic acid was directly related with the fecal concentration of acetate. Moreover, phenylacetic acid was negatively associated with the Bacteroides group and Clostridium cluster XIVa and positively with Lactobacillus. These results provide a rationale to explore the potential of fecal microbial phenolic-derived metabolites as possible biomarkers of health status in future studies focused on the elderly population.


Assuntos
Biomarcadores/análise , Fezes/química , Fenilacetatos/análise , Fenilpropionatos/análise , Idoso , Idoso de 80 Anos ou mais , Bactérias/classificação , Bactérias/isolamento & purificação , Bactérias/metabolismo , Biomarcadores/metabolismo , Dieta , Feminino , Microbioma Gastrointestinal , Nível de Saúde , Humanos , Mucosa Intestinal/metabolismo , Intestinos/microbiologia , Masculino , Estresse Oxidativo , Fenilacetatos/metabolismo , Fenilpropionatos/metabolismo
12.
Oncogene ; 37(50): 6425-6441, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30065298

RESUMO

Membrane type 1-matrix metalloproteinase (MT1-MMP), a membrane-tethered protease, is key for matrix breakdown during cancer invasion and metastasis. Assembly of branched actin networks by the Arp2/3 complex is required for MT1-MMP traffic and formation of matrix-degradative invadopodia. Contrasting with the well-established role of actin filament branching factor cortactin in invadopodia function during cancer cell invasion, the contribution of coronin-family debranching factors to invadopodia-based matrix remodeling is not known. Here, we investigated the contribution of coronin 1C to the invasive potential of breast cancer cells. We report that expression of coronin 1C is elevated in invasive human breast cancers, correlates positively with MT1-MMP expression in relation with increased metastatic risk and is a new independent prognostic factor in breast cancer. We provide evidence that, akin to cortactin, coronin 1C is required for invadopodia formation and matrix degradation by breast cancer cells lines and for 3D collagen invasion by multicellular spheroids. Using intravital imaging of orthotopic human breast tumor xenografts, we find that coronin 1C accumulates in structures forming in association with collagen fibrils in the tumor microenvironment. Moreover, we establish the role of coronin 1C in the regulation of positioning and trafficking of MT1-MMP-positive endolysosomes. These results identify coronin 1C as a novel player of the multi-faceted mechanism responsible for invadopodia formation, MT1-MMP surface exposure and invasiveness in breast cancer cells.


Assuntos
Metaloproteinase 14 da Matriz/metabolismo , Proteínas dos Microfilamentos/metabolismo , Podossomos/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Animais , Linhagem Celular Tumoral , Feminino , Xenoenxertos , Humanos , Camundongos , Invasividade Neoplásica/patologia , Podossomos/patologia , Transporte Proteico/fisiologia , Esferoides Celulares , Neoplasias de Mama Triplo Negativas/metabolismo
13.
Nat Commun ; 9(1): 2443, 2018 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-29934494

RESUMO

Cancer cells' ability to migrate through constricting pores in the tissue matrix is limited by nuclear stiffness. MT1-MMP contributes to metastasis by widening matrix pores, facilitating confined migration. Here, we show that modulation of matrix pore size or of lamin A expression known to modulate nuclear stiffness directly impinges on levels of MT1-MMP-mediated pericellular collagenolysis by cancer cells. A component of this adaptive response is the centrosome-centered distribution of MT1-MMP intracellular storage compartments ahead of the nucleus. We further show that this response, including invadopodia formation in association with confining matrix fibrils, requires an intact connection between the nucleus and the centrosome via the linker of nucleoskeleton and cytoskeleton (LINC) complex protein nesprin-2 and dynein adaptor Lis1. Our results uncover a digest-on-demand strategy for nuclear translocation through constricted spaces whereby confined migration triggers polarization of MT1-MMP storage compartments and matrix proteolysis in front of the nucleus depending on nucleus-microtubule linkage.


Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/metabolismo , Movimento Celular , Metaloproteinase 14 da Matriz/metabolismo , Proteínas dos Microfilamentos/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Neoplasias/patologia , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Centrossomo/metabolismo , Humanos , Lamina Tipo A/metabolismo , Invasividade Neoplásica/patologia , Podossomos/metabolismo , Proteólise
15.
Eur J Nutr ; 57(2): 487-497, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27744545

RESUMO

PURPOSE: Short-chain fatty acids (SCFAs) formation by intestinal bacteria is regulated by many different factors, among which dietary fibre is currently receiving most attention. However, since fibre-rich foods are usually good dietary sources of phenolic compounds, which are also known to affect the microbiota, authors hypothesize that the regular intake of these bioactive compounds could be associated with a modulation of faecal SCFA production by the intestinal microbiota. METHODS: In this work, food intake was recorded by means of a validated Food Frequency Questionnaire. Fibres were determined using Marlett food composition tables, and phenolic compounds were obtained from Phenol-Explorer Database. Analysis of SCFA was performed by gas chromatography-flame ionization/mass spectrometry and quantification of microbial populations in faeces by quantitative PCR. RESULTS: Klason lignin and its food contributors, as predictors of faecal butyrate production, were directly associated with Bacteroides and Bifidobacterium levels, as well as lignans with Bacteroides. Also, anthocyanidins, provided by strawberries, were associated with faecal propionate and inversely related to Lactobacillus group. CONCLUSIONS: These results support the hypothesis we put forward regarding the association between some vegetable foods (strawberries, pasta, lentils, lettuce and olive oil) and faecal SCFA. More studies are needed in order to elucidate whether these associations have been mediated by the bacterial modulatory effect of the bioactive compounds, anthocyanins, lignans or Klason lignin, present in foodstuffs.


Assuntos
Bacteroides/metabolismo , Bifidobacterium/metabolismo , Dieta Saudável , Fibras na Dieta/uso terapêutico , Disbiose/prevenção & controle , Microbioma Gastrointestinal , Cooperação do Paciente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bacteroides/classificação , Bacteroides/crescimento & desenvolvimento , Bacteroides/isolamento & purificação , Bifidobacterium/classificação , Bifidobacterium/crescimento & desenvolvimento , Bifidobacterium/isolamento & purificação , Estudos Transversais , Dieta/efeitos adversos , Dieta/etnologia , Dieta Saudável/etnologia , Fibras na Dieta/metabolismo , Disbiose/etnologia , Disbiose/etiologia , Disbiose/microbiologia , Ácidos Graxos Voláteis/análise , Ácidos Graxos Voláteis/metabolismo , Fezes/química , Fezes/microbiologia , Feminino , Fermentação , Humanos , Masculino , Pessoa de Meia-Idade , Tipagem Molecular , Avaliação Nutricional , Inquéritos Nutricionais , Cooperação do Paciente/etnologia , Espanha , Adulto Jovem
16.
Nutr Hosp ; 34(4): 934-941, 2017 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-29095019

RESUMO

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic infl ammatory disease of autoimmune nature, in which oxidative stress is implicated. AIM: Compare the concentrations of dietary and blood antioxidants, as well as gut microbiota, with serum malondialdehyde (MDA) and C reactive protein (CRP) in 21 subjects suffering from non-active systemic lupus erythematosus (SLE) and 21 age and gender-matched controls. METHODS: General biochemical parameters and CRP were determined by enzymatic methods: copper, zinc and selenium by inductively coupled plasma mass spectrometry (ICP-MS), MDA and total antioxidant capacity (TAC) by spectrophotometric methods, gut microbiota by metagenomic analyses and dietary intake by means of food frequency questionnaire. RESULTS: No significant differences were found in diet between lupus patients and the control group, with the exception of trans fatty acids intake, which was higher in patients. In addition, higher concentration of serum copper and lower of zinc in SLE were found. Serum copper was positively associated with CRP and also, this protein with the proportion of Lentisphaerae, ProteobacteriaandVerrucomicrobiain feces. Moreover, MDA levels displayed inverse correlations with the Cyanobacteriaand Firmicutesgroups, while Actinobacteria showed a positive association. The lupus subjects with presence of anti-SSA/Ro were related to higher levels of serum zinc. CONCLUSION: These results could be useful in the future to go deeper into the understanding of this complex disease.


Assuntos
Antioxidantes/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Lúpus Eritematoso Sistêmico/microbiologia , Microbiota , Adulto , Dieta , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo
17.
Bioorg Med Chem Lett ; 27(21): 4794-4799, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29017786

RESUMO

A scaffold hopping strategy, including intellectual property availability assessment, was successfully applied for the discovery of novel PI3K inhibitors. Compounds were designed based on the chemical structure of the lead compound ETP-46321, a potent PI3K inhibitor, previously reported by our group. The new generated compounds showed good in vitro potency and selectivity, proved to inhibit potently the phosphorylation of AKTSer473 in cells and demonstrated to be orally bioavailable, thus becoming potential back-up candidates for ETP-46321.


Assuntos
Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/metabolismo , Administração Oral , Animais , Química Farmacêutica , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Imidazóis/química , Imidazóis/metabolismo , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos BALB C , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirazinas/química , Pirazinas/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo
18.
Cell Rep ; 21(1): 181-194, 2017 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-28978472

RESUMO

Adenomatous polyposis coli (APC) is a polarity regulator and tumor suppressor associated with familial adenomatous polyposis and colorectal cancer development. Although extensively studied in epithelial transformation, the effect of APC on T lymphocyte activation remains poorly defined. We found that APC ensures T cell receptor-triggered activation through Nuclear Factor of Activated T cells (NFAT), since APC is necessary for NFAT's nuclear localization in a microtubule-dependent fashion and for NFAT-driven transcription leading to cytokine gene expression. Interestingly, NFAT forms clusters juxtaposed with microtubules. Ultimately, mouse Apc deficiency reduces the presence of NFAT in the nucleus of intestinal regulatory T cells (Tregs) and impairs Treg differentiation and the acquisition of a suppressive phenotype, which is characterized by the production of the anti-inflammatory cytokine IL-10. These findings suggest a dual role for APC mutations in colorectal cancer development, where mutations drive the initiation of epithelial neoplasms and also reduce Treg-mediated suppression of the detrimental inflammation that enhances cancer growth.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/genética , Regulação Neoplásica da Expressão Gênica , Microtúbulos/imunologia , Fatores de Transcrição NFATC/genética , Linfócitos T Reguladores/imunologia , Polipose Adenomatosa do Colo/imunologia , Polipose Adenomatosa do Colo/patologia , Proteína da Polipose Adenomatosa do Colo/antagonistas & inibidores , Proteína da Polipose Adenomatosa do Colo/imunologia , Animais , Diferenciação Celular , Linhagem Celular Tumoral , Células HCT116 , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Células Jurkat , Linfonodos/imunologia , Linfonodos/patologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microtúbulos/ultraestrutura , Fatores de Transcrição NFATC/imunologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Linfócitos T Reguladores/patologia
19.
PLoS One ; 12(10): e0184181, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28985233

RESUMO

PURPOSE: To determine the frequency of breast cancer (BC) patients with hereditary risk features in a wide retrospective cohort of patients in Spain. METHODS: a retrospective analysis was conducted from 10,638 BC patients diagnosed between 1998 and 2001 in the GEICAM registry "El Álamo III", dividing them into four groups according to modified ESMO and SEOM hereditary cancer risk criteria: Sporadic breast cancer group (R0); Individual risk group (IR); Familial risk group (FR); Individual and familial risk group (IFR) with both individual and familial risk criteria. RESULTS: 7,641 patients were evaluable. Of them, 2,252 patients (29.5%) had at least one hereditary risk criteria, being subclassified in: FR 1.105 (14.5%), IR 970 (12.7%), IFR 177 (2.3%). There was a higher frequency of newly diagnosed metastatic patients in the IR group (5.1% vs 3.2%, p = 0.02). In contrast, in RO were lower proportion of big tumors (> T2) (43.8% vs 47.4%, p = 0.023), nodal involvement (43.4% vs 48.1%, p = 0.004) and lower histological grades (20.9% G3 for the R0 vs 29.8%) when compared to patients with any risk criteria. CONCLUSIONS: Almost three out of ten BC patients have at least one hereditary risk cancer feature that would warrant further genetic counseling. Patients with hereditary cancer risk seems to be diagnosed with worse prognosis factors.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Adulto , Neoplasias da Mama/epidemiologia , Feminino , Aconselhamento Genético , Humanos , Pessoa de Meia-Idade , Prevalência , Prognóstico , Sistema de Registros , Estudos Retrospectivos , Espanha/epidemiologia
20.
J Eval Clin Pract ; 23(6): 1408-1414, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28971579

RESUMO

RATIONALE AND OBJECTIVES: Late diagnosis of HIV infection is a public health problem. Framed by the international guidelines for improving HIV testing, in 2014, the Spanish Ministry of Health published a guide of recommendations to promote early diagnosis of HIV in health care settings. In the Community of Madrid, in order to implement these recommendations, we defined 3 new HIV testing strategies in primary health care. The objectives of this study were to know the interest of professionals and the acceptability for patients towards these strategies. METHODS: We performed a quasi-experimental study to assess the feasibility of the implementation of new strategies (indicator condition, risk based, and universal offer) to promote early detection of HIV infection in the framework of the ESTVIH project. The centres participating in this project were randomly chosen among centres located in the health areas with the highest incidence of HIV infection. The feasibility was assessed in 6 centres. We considered outcomes by strategy in relation to the participation of professionals (family physician and nursing) and patients. RESULTS: Overall, 56.9% of eligible professionals agreed to take part in the study; however, the percentage of professionals who recruited patients was 25.9%. This percentage was higher in the indicator condition strategy (47.2%, versus 18.5% in the universal offer and 14.3% in the risk-based strategy, P-value < 0.05). The test uptake percentage was greater than 80%, and there were no statistically significant differences between strategies. CONCLUSION: Different strategies promoting HIV testing in primary care had different acceptability among professionals and similar among patients. At the end of the ESTVIH project, these results will be complemented with others related to the contribution of each strategy to improving the early diagnosis of HIV infection.


Assuntos
Infecções por HIV/diagnóstico , Pessoal de Saúde/psicologia , Promoção da Saúde/organização & administração , Programas de Rastreamento/organização & administração , Atenção Primária à Saúde/organização & administração , Enfermagem Familiar , Estudos de Viabilidade , Feminino , Humanos , Masculino , Aceitação pelo Paciente de Cuidados de Saúde , Médicos de Família , Fatores Socioeconômicos , Espanha
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