Plasma Biomarkers of Brain Atrophy in Alzheimer's Disease

Peripheral biomarkers of Alzheimer's disease (AD) reflecting early neuropathological change are critical to the development of treatments for this condition. The most widely used indicator of AD pathology in life at present is neuroimaging evidence of brain atrophy. We therefore performed a proteomic analysis of plasma to derive biomarkers associated with brain atrophy in AD. Using gel based proteomics we previously identified seven plasma proteins that were significantly associated with hippocampal volume in a combined cohort of subjects with AD (N = 27) and MCI (N = 17). In the current report, we validated this finding in a large independent cohort of AD (N = 79), MCI (N = 88) and control (N = 95) subjects using alternative complementary methods—quantitative immunoassays for protein concentrations and estimation of pathology by whole brain volume. We confirmed that plasma concentrations of five proteins, together with age and sex, explained more than 35% of variance in whole brain volume in AD patients. These proteins are complement components C3 and C3a, complement factor-I, γ-fibrinogen and alpha-1-microglobulin. Our findings suggest that these plasma proteins are strong predictors of in vivo AD pathology. Moreover, these proteins are involved in complement activation and coagulation, providing further evidence for an intrinsic role of these pathways in AD pathogenesis

Automatic synthesis of phosphopeptides on the solid phase

No abstract available

SOURCE: A registry-based prediction model for overall survival in patients with metastatic oesophageal or gastric cancer

Prediction models are only sparsely available for metastatic oesophagogastric cancer. Because treatment in this setting is often preference-based, decision-making with the aid of a prediction model is wanted. The aim of this study is to construct a prediction model, called SOURCE, for the overall survival in patients with metastatic oesophagogastric cancer. Data from patients with metastatic oesophageal (n = 8010) or gastric (n = 4763) cancer diagnosed during 2005⁻2015 were retrieved from the nationwide Netherlands cancer registry. A multivariate Cox regression model was created to predict overall survival for various treatments. Predictor selection was performed via the Akaike Information Criterion and a Delphi consensus among experts in palliative oesophagogastric cancer. Validation was performed according to a temporal internal-external scheme. The predictive quality was assessed with the concordance-index (c-index) and calibration. The model c-indices showed consistent discriminative ability during validation: 0.71 for oesophageal cancer and 0.68 for gastric cancer. The calibration showed an average slope of 1.0 and intercept of 0.0 for both tumour locations, indicating a close agreement between predicted and observed survival. With a fair c-index and good calibration, SOURCE provides a solid foundation for further investigation in clinical practice to determine its added value in shared decision making

SOURCE: A registry-based prediction model for overall survival in patients with metastatic oesophageal or gastric cancer

Prediction models are only sparsely available for metastatic oesophagogastric cancer. Because treatment in this setting is often preference-based, decision-making with the aid of a prediction model is wanted. The aim of this study is to construct a prediction model, called SOURCE, for the overall survival in patients with metastatic oesophagogastric cancer. Data from patients with metastatic oesophageal (n = 8010) or gastric (n = 4763) cancer diagnosed during 2005⁻2015 were retrieved from the nationwide Netherlands cancer registry. A multivariate Cox regression model was created to predict overall survival for various treatments. Predictor selection was performed via the Akaike Information Criterion and a Delphi consensus among experts in palliative oesophagogastric cancer. Validation was performed according to a temporal internal-external scheme. The predictive quality was assessed with the concordance-index (c-index) and calibration. The model c-indices showed consistent discriminative ability during validation: 0.71 for oesophageal cancer and 0.68 for gastric cancer. The calibration showed an average slope of 1.0 and intercept of 0.0 for both tumour locations, indicating a close agreement between predicted and observed survival. With a fair c-index and good calibration, SOURCE provides a solid foundation for further investigation in clinical practice to determine its added value in shared decision making

Probing molecular choreography through single-molecule biochemistry

Single-molecule approaches are having a dramatic impact on views of how proteins work. The ability to observe molecular properties at the single-molecule level allows characterization of subpopulations and acquisition of detailed kinetic information that would otherwise be hidden in the averaging over an ensemble of molecules. In this Perspective, we discuss how such approaches have successfully been applied to in vitro-reconstituted systems of increasing complexity

Nat Methods. 2009 Jul;. Epub 2009 Jun 21

Abstract The use of fluorescently labeled MHC multimers has become an essential technique for the analysis of disease- and therapy-induced T cell immunity. While classical MHC multimer analyses are well-suited for the detection of immune responses against a few epitopes, limitations on patient sample size preclude a comprehensive analysis of T cell immunity. To address this issue, we have developed a combinatorial encoding strategy that allows the parallel detection of a multitude of different T cell populations within a single sample. Detection of antigen-specific T cells from peripheral blood by combinatorial encoding is as efficient as detection with conventional PE labeled multimers, but results in a significantly increased sensitivity, and most importantly, allows comprehensive screens to be performed on patient material. Proof of principle for the feasibility of large-scale screening of patient material was obtained by analysis of HLA-A3 restricted T cell responses against known and potential melanoma-associated antigens in peripheral blood from melanoma patients.

Efficacy of Helicobacter pylori eradication therapies: a single centre observational study

Background: Many Helicobacter pylori eradication regimens have been described. There are little data reporting their efficacy or integration in routine clinical practice. The overall results of eradication therapy in a cohort of patients are described and an algorithm for management outlined. Methods: 469 patients receiving eradication therapy in routine clinical practice were evaluated. The successes of individual regimes as first, second and third line therapy were determined. Results: Overall success after one, two and three courses of therapy were 73% (95% confidence intervals 69–77%), 94% (91–96%) and 98% (97–99%) respectively. 10 different regimens, including many non-recommended ones were used as primary therapy. Ranitidine bismuth citrate-amoxicillin-clarithromycin triple therapy (94.8%, 90–99%) was significantly more effective than any other combination as primary therapy, including all proton pump inhibitor based triple therapies. Quadruple therapy with bismuth chelate-proton pump inhibitor-tetracycline and a nitroimidazole (70%, 52–88%) and ranitidine bismuth citrate-based triple therapy (73%, 56–90%) where more effective second line combinations than proton pump inhibitor-triple therapies (37.5%, 12–58%). Third line therapy directed by the results of sensitivity testing improved eradication compared to further empirical antibiotics. The use of a proton pump inhibitor with clarithromycin and a nitroimidazole as initial therapy was associated with a significantly worse overall eradication rate than other combinations. Conclusions: Helicobacter pylori eradication rates can be maximised by using ranitidine bismuth citrate-clarithromycin-amoxicillin containing triple therapy, followed by bismuth and nitroimidazle containing second-line therapy, with third line combinations directed by sensitivity testing. Proton pump inhibitor-clarithromycin-metronidazole combinations should be avoided