Características dos agentes de mudança

Há duas linhas básicas ao longo deste trabalho que podem sumariá-lo. Uma é a dependência comum, entre diversos autores, do trabalho de Lippitt e outros (13) para definir o agente de mudança. A outra reflete o esforço deliberado de vários estudiosos no sentido de ir além do simples conhecimento do que é um agente de mudança, mediante o desempenho de seu papel, ou simplesmente sendo um deles. Dos cinco exemplos vistos sobre esforços para definir os agentes de mudança, E. Rogers (24) na área de desenvolvimento intercultural, Tichy (27) na área de transformação social, Beckhard (1) na área de desenvolvimento organizacional, Gross e outros (7) no setor de instituições educacionais, e Pincus e Minahan (19) no campo de serviço social, todos baseiam-se nos conceitos originais de Lippitt e outros

Detecting tumour responses to treatment using metabolic imaging with hyperpolarised [1-13C]pyruvate and 2-([18F]fluoro)-2-deoxy-D-glucose

Earlier detection of tumour responses to treatment would facilitate modification of treatment regimens and reduce unnecessary side effects and the costs of ineffective therapy. Anatomical changes following treatment are often slow to manifest and are occasionally misleading. Molecular imaging targeting dysregulated metabolic pathways in tumours can facilitate earlier detection of treatment response. The aim of this study was to directly compare two metabolic imaging techniques that measure different parts of glycolysis, 2-([18F]fluoro)-2-deoxy-D-glucose positron emission tomography ([18F]FDG-PET) and hyperpolarised [1-13C]pyruvate magnetic resonance imaging), for the purpose of detecting early responses to treatment in mouse models of cancer. Two mouse models of lymphoma, subcutaneous EL4 tumours and Eμ-Myc transgenic mice, were treated with etoposide and cyclophosphamide, respectively. In EL4 tumours 24 h after treatment there was a significant reduction in [18F]FDG uptake with no significant change in the hyperpolarised [1-13C]lactate/[1-13]Cpyruvate ratio. While treatment resulted in significant decreases in glucose transporter expression, there were variable amounts of cell death before and after treatment, potentially explaining this discrepancy. In Eμ-Myc mice, reductions of both [18F]FDG uptake and the [1-13C]lactate/[1-13C]pyruvate ratio were observed after treatment. However, the decreases in [18F]FDG uptake in cervical tumours were partially masked by high uptake in surrounding tissues demonstrating the benefit of improved specificity of hyperpolarised [1-13C]pyruvate for detecting the Warburg effect. In two xenograft models of human colorectal and breast adenocarcinoma, a large reduction in hyperpolarised [1-13C]lactate/[1-13C]pyruvate ratio was observed in all tumours 24 hours after treatment with a TRAIL agonist. However, despite treatment inducing widespread apoptosis and long-term remission, [18F]FDG-PET largely failed to detect a response. Measurements of [18F]FDG uptake in disaggregated tumour cells that had been sorted by fluorescence-activated cell sorting demonstrated that inflammatory infiltration or activation was not responsible for failure to detect a response to treatment with [18F]FDG. Furthermore, [1,6 13C2]glucose infusions into tumour bearing mice demonstrated that tumour uptake of [18F]FDG after treatment was not reflective of overall glycolytic flux.CRU

Magnetic resonance imaging of cancer metabolism with hyperpolarized 13C- labeled cell metabolites

Hyperpolarization of 13C-labeled substrates can increase their 13C NMR signal by more than 10,000-fold, which has allowed magnetic resonance imaging (MRI) of metabolic reactions in vivo. This has already provided a unique insight into the dysregulated metabolic pathways and microenvironment of tumors. Perhaps the best known of the cancer-associated metabolic abberations is the Warburg effect, which has been imaged in patients using hyperpolarized [1-13C]pyruvate. In clinical oncology there is a requirement to diagnose tumors earlier, better determine their aggressiveness and prognosis, identify novel treatment targets and detect response to treatment earlier. Here we consider some of the hyperpolarized substrates that have been developed and have the potential to meet these requirements and become the precision imaging tools of the future.KMB's lab is supported by a Cancer Research UK Programme grant (17242) and by the CRUK-EPSRC Imaging Centre in Cambridge and Manchester (16465)

Radiomics and circulating tumor cells: personalized care in hepatocellular carcinoma?

Personalized care in oncology is expected to significantly improve morbidity and mortality, facilitated by our increasing understanding of the molecular mechanisms driving tumors and the ability to target those drivers. Hepatocellular carcinoma has a very high mortality to incidence ratio despite localized disease being curable, emphasizing the importance of early diagnosis. Radiomics, the use of imaging technology to extrapolate molecular tumor data, and the detection of circulating tumor cells (CTCs) are two new technologies that could be incorporated into the clinical setting with relative ease. Here we discuss the molecular mechanisms leading to the development of hepatocellular carcinoma focusing on the latest developments in liver magnetic resonance imaging, CTC, and radiomic technology and their potential to improve diagnosis, staging, and therapy

The national security key indicators as a part of economic development in the conditions of digitization

International audienceMethylglyoxal is a faulty metabolite. It is a ubiquitous by-product of glucose and amino acid metabolism that spontaneously reacts with proximal amino groups in proteins and nucleic acids, leading to impairment of their function. The glyoxalase pathway evolved early in phylogeny to bring about rapid catabolism of methylglyoxal, and an understanding of the role of methylglyoxal and the glyoxalases in many diseases is beginning to emerge. Metabolic processing of methylglyoxal is very rapid in vivo and thus notoriously difficult to detect and quantify. Here we show that C-13 nuclei in labeled methylglyoxal can be hyperpolarized using dynamic nuclear polarization, providing C-13 nuclear magnetic resonance signal enhancements in the solution state close to 5,000-fold. We demonstrate the applications of this probe of metabolism for kinetic characterization of the glyoxalase system in isolated cells as well as mouse brain, liver and lymphoma in vivo

Glyoxalase activity in human erythrocytes and mouse lymphoma, liver and brain probed with hyperpolarized C-13-methylglyoxal

Methylglyoxal is a faulty metabolite. It is a ubiquitous by-product of glucose and amino acid metabolism that spontaneously reacts with proximal amino groups in proteins and nucleic acids, leading to impairment of their function. The glyoxalase pathway evolved early in phylogeny to bring about rapid catabolism of methylglyoxal, and an understanding of the role of methylglyoxal and the glyoxalases in many diseases is beginning to emerge. Metabolic processing of methylglyoxal is very rapid in vivo and thus notoriously difficult to detect and quantify. Here we show that 13C nuclei in labeled methylglyoxal can be hyperpolarized using dynamic nuclear polarization, providing 13C nuclear magnetic resonance signal enhancements in the solution state close to 5,000-fold. We demonstrate the applications of this probe of metabolism for kinetic characterization of the glyoxalase system in isolated cells as well as mouse brain, liver and lymphoma in vivo

Magnetic Resonance Imaging Is More Sensitive Than PET for Detecting Treatment-Induced Cell Death-Dependent Changes in Glycolysis.

Metabolic imaging has been widely used to measure the early responses of tumors to treatment. Here, we assess the abilities of PET measurement of [18F]FDG uptake and MRI measurement of hyperpolarized [1-13C]pyruvate metabolism to detect early changes in glycolysis following treatment-induced cell death in human colorectal (Colo205) and breast adenocarcinoma (MDA-MB-231) xenografts in mice. A TRAIL agonist that binds to human but not mouse cells induced tumor-selective cell death. Tumor glycolysis was assessed by injecting [1,6-13C2]glucose and measuring 13C-labeled metabolites in tumor extracts. Injection of hyperpolarized [1-13C]pyruvate induced rapid reduction in lactate labeling. This decrease, which correlated with an increase in histologic markers of cell death and preceded decrease in tumor volume, reflected reduced flux from glucose to lactate and decreased lactate concentration. However, [18F]FDG uptake and phosphorylation were maintained following treatment, which has been attributed previously to increased [18F]FDG uptake by infiltrating immune cells. Quantification of [18F]FDG uptake in flow-sorted tumor and immune cells from disaggregated tumors identified CD11b+/CD45+ macrophages as the most [18F]FDG-avid cell type present, yet they represented <5% of the cells present in the tumors and could not explain the failure of [18F]FDG-PET to detect treatment response. MRI measurement of hyperpolarized [1-13C]pyruvate metabolism is therefore a more sensitive marker of the early decreases in glycolytic flux that occur following cell death than PET measurements of [18F]FDG uptake. SIGNIFICANCE: These findings demonstrate superior sensitivity of MRI measurement of hyperpolarized [1-13C]pyruvate metabolism versus PET measurement of 18F-FDG uptake for detecting early changes in glycolysis following treatment-induced tumor cell death