RESUMO
BACKGROUND: The human ATP-dependent SWItch/sucrose nonfermentable (SWI/SNF) complex functions as a primary chromatin remodeler during ontogeny, as well as in adult life. Several components of the complex have been suggested to function as important regulators of tumorigenesis in various cancers. In the current study, we have characterised a possible tumour suppressor role for the largest subunit of the complex, namely the AT-rich interaction domain 1B (ARID1B). METHODS: We performed Azacytidine and Trichostatin A treatments, followed by bisulphite sequencing to determine the possible DNA methylation-induced transcription repression of the gene in pancreatic cancer (PaCa) cell lines. Functional characterisation of effect of ARID1B ectopic expression in MiaPaCa2 PaCa cell line, which harboured ARID1B homozygous deletion, was carried out. Finally, we evaluated ARID1B protein expression in pancreatic tumour samples using immunohistochemistry on a tissue microarray. RESULTS: ARID1B was transcriptionally repressed due to promoter hypermethylation, and ectopic expression severely compromised the ability of MiaPaCa2 cells to form colonies in liquid culture and soft agar. In addition, ARID1B exhibited significantly reduced/loss of expression in PaCa tissue, especially in samples from advanced-stage tumours, when compared with normal pancreas. CONCLUSION: The results therefore suggest a possible tumour-suppressor function for ARID1B in PaCa, thus adding to the growing list of SWI/SNF components with a similar function. Given the urgent need to design efficient targeted therapies for PaCa, our study assumes significance.
Assuntos
Carcinoma Ductal Pancreático/patologia , Proteínas de Ligação a DNA/fisiologia , Neoplasias Pancreáticas/patologia , Fatores de Transcrição/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Proteínas Cromossômicas não Histona/fisiologia , Ilhas de CpG , Metilação de DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transfecção , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
Despite significant advances in preventive, medical, and interventional management, coronary artery disease remains the leading cause of death worldwide. We now know that in the majority of acute coronary syndromes, a thrombotic event is triggered either by the rupture or erosion of the so-called high-risk or 'vulnerable' plaque. However, accurately identifying the individual who is at significant risk of acute event remains the holy grail of preventive cardiology. To better stratify an individual's risk of developing and suffering a cardiovascular event, biomarkers are needed that can accurately predict coronary events and, if possible, monitor disease activity in response to medical or interventional therapies. In order to be able to understand the association of these biomarkers with the morphological substrate of high-risk plaques, intravascular imaging modalities can provide invaluable assistance. Novel imaging tools such as optical coherence tomography (OCT) have not only helped in identifying atherosclerotic plaque characteristics that are unstable but also in estimating global plaque burden. In this study, we provide an overview of our current knowledge of association of various inflammatory markers with atherosclerotic plaque characteristics seen on OCT.
Assuntos
Síndrome Coronariana Aguda , Doença da Artéria Coronariana , Placa Aterosclerótica , Síndrome Coronariana Aguda/diagnóstico por imagem , Biomarcadores , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Humanos , Placa Aterosclerótica/diagnóstico por imagem , Tomografia de Coerência Óptica , Ultrassonografia de IntervençãoRESUMO
AIMS: Microparticles (MPs) are submicron vesicles, released from activated, and apoptotic cells. MPs are elevated in the circulation of patients with coronary artery disease (CAD) and have pro-thrombotic potential. However, limited data exists on MP signature over time following an acute coronary event. METHODS & RESULTS: Circulating total annexin v + (Anv+) MPs of endothelial (EMP), platelet (PMP), monocyte (MMP), neutrophil (NMP) and smooth muscle cell (SMMP) origin were quantified by flow cytometry. 13 patients with acute coronary syndrome (ACS) were prospectively enrolled and 12 patients with stable angina (SA) were included as a comparator group. A panel of MP was measured at baseline, after percutaneous coronary intervention (PCI) and at days 1, 7, 30 and 6 months. Intra & inter group comparison was made between various time points. MP mediated thrombin generation was measured by recording lag phase, velocity index, peak thrombin and endogenous thrombin potential at these time points and compared with healthy controls. The total AnV+ MP levels were similar in ACS and SA groups at baseline, peaked immediately after PCI and were at their lowest on day 1. PMP & EMP levels remained significantly elevated in ACS patients at 6 months when compared to SA. No such difference was noted with NMP, MMP and SMMP. Patients with coronary artery disease showed abnormal thrombograms when compared to controls. Peak thrombin (nano moles) was significantly higher in CAD when compared to controls (254 IQR [226, 239] in ACS, 255 IQR [219, 328] in SA and 132 IQR [57, 252] in controls; p = 0.006). Differences in thrombin generation between ACS and SA were not significant (p = 1). Furthermore, thrombin parameters remained abnormal in ACS & SA patients at 6 months. CONCLUSIONS: Total MP and individual MP phenotypes were significantly elevated after PCI reflecting endothelial injury. Elevated PMP and EMP levels at 6 months in ACS patients is suggestive of on-going inflammation, endothelial injury and may explain on-going pro-thrombogenicity seen up to 6 months after ACS despite dual antiplatelet therapy.
Assuntos
Síndrome Coronariana Aguda , Micropartículas Derivadas de Células , Doença da Artéria Coronariana , Intervenção Coronária Percutânea , Plaquetas , HumanosRESUMO
The management of heart failure has evolved to become a multidisciplinary affair. Constraints of time and resources limit the amount of counselling that is given to heart failure patients in hospital and, with the advent of community heart failure specialist nurses, there is a trend to move more of these services into the community. Most heart failure patients are elderly and may find the information given to them, at the time of diagnosis and later on at home by heart failure nurses, difficult to grasp. In this study, patients' perspectives of a diagnosis of heart failure, their understanding of the diagnosis as well as what being diagnosed with heart failure means to them were recorded. Patients were questioned on whether the news of the heart failure diagnosis was broken to them in a sympathetic manner and how they felt about the information provided at diagnosis.
Assuntos
Conhecimentos, Atitudes e Prática em Saúde , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/psicologia , Educação de Pacientes como Assunto , Adulto , Idoso , Idoso de 80 Anos ou mais , Aconselhamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ambulatório Hospitalar , Equipe de Assistência ao Paciente , Relações Profissional-Paciente , Inquéritos e Questionários , Reino UnidoRESUMO
INTRODUCTION: Platelet Monocyte Complexes (PMCs) are commonly expressed in coronary artery disease but their pathologic significance in ST elevation myocardial infarction (STEMI) is unclear. This study evaluates the relationship between locally activated PMCs and intracoronary inflammation in stable and unstable coronary disease. MATERIAL AND METHODS: Micro catheter aspirated blood samples of 15 STEMI and 7 stable angina patients are collected from the coronary artery (CA), aorta (AO) and right atrium (RA). Samples are labelled with monoclonal antibodies and prepared for flow cytometry. CD 14 and CD 61 double positive cells are identified as PMC. P-selectin expression is identified by additional CD62P positivity and TF expression by additional CD142 positivity. Plasma TNF-alpha and IL-6 are measured using ELISA and CRP is measured in plasma using a high sensitivity automated microparticle enhanced latex turbidimetric immunoassay. RESULTS: No site-specific difference is seen in overall PMC expression in STEMI or stable angina. Surface P-selectin expression in STEMI [median (IQR)] is significantly higher in CA [35.01 (23.15-56.99)] compared with AO [15.99 (10.3-18.85)] or RA [14.02 (10.42-26.08)] (pâ=â0.003). Intracoronary PMC correlates significantly with intracoronary TNF-alpha (râ=â0.87, pâ=â0.001) and intracoronary IL-6 (râ=â0.76, pâ=â0.03). Bound monocytes within P-selectin positive and tissue factor positive complexes correlate positively with intracoronary TNF-alpha (râ=â0.81, pâ=â0.008 & râ=â0.80, pâ=â0.009 respectively) and IL-6 (râ=â0.54, pâ=â0.16 & râ=â0.71, pâ=â0.05 respectively). No such correlation is observed in the peripheral circulation of STEMI and stable angina patients. CONCLUSION: Inflammation is not attributable to PMC formation per se. However, increased intracoronary P-selectin expression by activated platelets and tissue factor expression by activated monocytes within the complexes are determinants of local intracoronary inflammatory burden in STEMI.
Assuntos
Plaquetas/metabolismo , Inflamação/sangue , Monócitos/metabolismo , Infarto do Miocárdio/sangue , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miocárdio/patologiaRESUMO
OBJECTIVE: To assess whether a novel 'direct access pathway' (DAP) for the management of high-risk non-ST-elevation acute coronary syndromes (NSTEACS) is safe, results in 'shorter time to intervention and shorter admission times'. This pathway was developed locally to enable London Ambulance Service to rapidly transfer suspected high-risk NSTEACS from the community to our regional heart attack centre for consideration of early angiography. METHODS: This is a retrospective case-control analysis of 289 patients comparing patients with high-risk NSTEACS admitted via DAP with age-matched controls from the standard pan-London high-risk ACS pathway (PLP) and the conventional pathway (CP). The primary end point of the study was time from admission to coronary angiography/intervention. Secondary end point was total length of hospital stay. RESULTS: Over a period of 43 months, 101 patients were admitted by DAP, 109 matched patients by PLP and 79 matched patients through CP. Median times from admission to coronary angiography for DAP, PLP and CP were 2.8 (1.5-9), 16.6 (6-50) and 60 (33-116)â hours, respectively (p<0.001). Median length of hospital stay for DAP and PLP was similar at 3.0 (2.0-5.0)â days in comparison to 5 (3-7)â days for CP (p<0.001). CONCLUSIONS: DAP resulted in a significant reduction in time to angiography for patients with high-risk NSTEACS when compared to existing pathways.
Assuntos
Síndrome Coronariana Aguda/diagnóstico por imagem , Angiografia Coronária , Procedimentos Clínicos , Serviços Médicos de Emergência/organização & administração , Tempo de Internação/estatística & dados numéricos , Tempo para o Tratamento , Síndrome Coronariana Aguda/mortalidade , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Auxiliares de Emergência , Feminino , Humanos , Londres , Masculino , Pessoa de Meia-Idade , Transferência de Pacientes , Estudos RetrospectivosRESUMO
Life-long oral anticoagulant therapy is recommended to all patients with mechanical heart valves to reduce the incidence of thromboembolic events. However, intracerebral haemorrhage is the fatal complication associated with anticoagulation, with an estimated 6-month mortality of 67%. (1) The incidence of cerebral bleeding while on anticoagulation is 0.3-0.7%/year, with as many as 85% of survivors left with permanent neurological deficits. (2) Difficulties in management arise when anticoagulation is temporarily discontinued as mechanical valves, particularly mitral, are exposed to significant thromboembolic and valve dysfunction risk. The decision on when to appropriately restart anticoagulation needs to be balanced with the risk of precipitating further cerebral haemorrhage. There are currently no guidelines on the optimal time to start anticoagulation. We describe a case of the management approach implemented in a patient with a mechanical valve presenting to the emergency department with an acute intracerebral haemorrhage.
Assuntos
Anticoagulantes/efeitos adversos , Hemorragia Cerebral/induzido quimicamente , Próteses Valvulares Cardíacas , Tromboembolia/prevenção & controle , Varfarina/efeitos adversos , Idoso , Implante de Prótese de Valva Cardíaca , Humanos , Masculino , Prolapso da Valva Mitral/cirurgiaAssuntos
Dor no Peito/diagnóstico , Stents Farmacológicos/efeitos adversos , Neovascularização Patológica/diagnóstico por imagem , Placa Aterosclerótica/diagnóstico por imagem , Tomografia de Coerência Óptica/métodos , Aterosclerose/fisiopatologia , Dor no Peito/diagnóstico por imagem , Dor no Peito/cirurgia , Angiografia Coronária/métodos , Feminino , Humanos , Inflamação/patologia , Pessoa de Meia-Idade , Neovascularização Patológica/complicações , Neovascularização Patológica/fisiopatologia , Placa Aterosclerótica/fisiopatologiaAssuntos
Doença , Marcação de Genes/métodos , Engenharia Genética/métodos , Morfolinos/uso terapêutico , Medicina Preventiva/métodos , Animais , Portadores de Fármacos , Expressão Gênica/efeitos dos fármacos , Humanos , Modelos Genéticos , Morfolinos/administração & dosagem , Morfolinos/efeitos adversos , Morfolinos/farmacologiaRESUMO
A simple but accurate method has been developed for the determination of carbon in uranium carbide powders/pellets as well as in solutions of uranyl nitrates. The methodology involves quantitative conversion of carbon present in the sample to carbon dioxide that is subsequently absorbed in a dilute solution of barium hydroxide. The conductivity shift of the barium hydroxide solution is monitored on-line continuously using a laboratory-built PC-based conductivity measurement system that has been developed in-house based on the direct conversion of conductance to the digital pulse frequency. A new gas absorption cell has been designed to ensure quantitative absorption during the residence time of the gas in the cell. The method is sensitive, accurate and precise to 1-3% at 600-1000 mug of carbon in samples of uranium carbide.