Absence of progression as assessed by response evaluation criteria in solid tumors predicts survival in advanced GI stromal tumors treated with imatinib mesylate: the intergroup EORTC-ISG-AGITG phase III trial.

PURPOSE: From February 2001 to February 2002, 946 patients with advanced GI stromal tumors (GISTs) treated with imatinib were included in a controlled EORTC/ISG/AGITG (European Organisation for Research and Treatment of Cancer/Italian Sarcoma Group/Australasian Gastro-Intestinal Trials Group) trial. This analysis investigates whether the response classification assessed by RECIST (Response Evaluation Criteria in Solid Tumors), predicts for time to progression (TTP) and overall survival (OS). PATIENTS AND METHODS: Per protocol, the first three disease assessments were done at 2, 4, and 6 months. For the purpose of the analysis (landmark method), disease response was subclassified in six categories: partial response (PR; > 30% size reduction), minor response (MR; 10% to 30% reduction), no change (NC) as either NC- (0% to 10% reduction) or NC+ (0% to 20% size increase), progressive disease (PD; > 20% increase/new lesions), and subjective PD (clinical progression). RESULTS: A total of 906 patients had measurable disease at entry. At all measurement time points, complete response (CR), PR, and MR resulted in similar TTP and OS; this was also true for NC- and NC+, and for PD and subjective PD. Patients were subsequently classified as responders (CR/PR/MR), NC (NC+/NC-), or PD. This three-class response categorization was found to be highly predictive of further progression or survival for the first two measurement points. After 6 months of imatinib, responders (CR/PR/MR) had the same survival prognosis as patients classified as NC. CONCLUSION: RECIST perfectly enables early discrimination between patients who benefited long term from imatinib and those who did not. After 6 months of imatinib, if the patient is not experiencing PD, the pattern of radiologic response by tumor size criteria has no prognostic value for further outcome. Imatinib needs to be continued as long as there is no progression according to RECIST.

Identifying and Implementing Effective Training for Hispanic Craft Workers, American Supervisors, and DOT Inspectors: Phase III of the Hispanic Workforce Research Project, May 2006

The number of Hispanic workers in the U.S. construction industry has been steadily increasing, and language and cultural barriers have sometimes arisen on the jobsite. Due in part to these barriers, the number of fatalities among Hispanics at construction sites in 2001 jumped 24%, while construction fatalities overall dropped 3%. This study, which constitutes Phase III of the Hispanic Workforce Research Project, addresses these language and cultural barriers by investigating the most effective way to deliver training material developed in Phases I and II to Hispanic workers, American supervisors, and department of transportation (DOT) inspectors. The research methodology consisted of assessing the needs and interests of potential and current course participants in terms of exploring innovative ways to deliver the training. The training courses were then adapted and delivered to fit the specific needs of each audience. During Phase III of this project, the research team delivered the courses described in the Phase I and II reports to eight highway construction companies and two DOT groups. The courses developed in Phases I and II consist of four construction-focused language training courses that can be part of an effective training program to facilitate integration among U.S. and Hispanic workers, increase productivity and motivation at the jobsite, and decrease the existing high mortality rate for Hispanic workers. Moreover, the research team developed a course for the construction season called Toolbox Integration Course for Hispanic workers and American supervisors (TICHA), which consists of nine 45-minute modules delivered to one construction company over 11 weeks in the summer of 2005.

Spatially-resolved eigenmode decomposition of red blood cells membrane fluctuations questions the role of ATP in flickering.

Red blood cells (RBCs) present unique reversible shape deformability, essential for both function and survival, resulting notably in cell membrane fluctuations (CMF). These CMF have been subject of many studies in order to obtain a better understanding of these remarkable biomechanical membrane properties altered in some pathological states including blood diseases. In particular the discussion over the thermal or metabolic origin of the CMF has led in the past to a large number of investigations and modeling. However, the origin of the CMF is still debated. In this article, we present an analysis of the CMF of RBCs by combining digital holographic microscopy (DHM) with an orthogonal subspace decomposition of the imaging data. These subspace components can be reliably identified and quantified as the eigenmode basis of CMF that minimizes the deformation energy of the RBC structure. By fitting the observed fluctuation modes with a theoretical dynamic model, we find that the CMF are mainly governed by the bending elasticity of the membrane and that shear and tension elasticities have only a marginal influence on the membrane fluctations of the discocyte RBC. Further, our experiments show that the role of ATP as a driving force of CMF is questionable. ATP, however, seems to be required to maintain the unique biomechanical properties of the RBC membrane that lead to thermally excited CMF.

Petrus Aureoli, in librum III Sentenciarum.

Fonds non déterminé.

Evaluation of Composite Pavement Unbonded Overlays: Phase III, August 2006

In recent years, thin whitetopping has evolved as a viable rehabilitation technique for deteriorated asphalt cement concrete (ACC) pavements. Numerous projects have been constructed and tested, allowing researchers to identify the important elements contributing to the projects’ successes. These elements include surface preparation, overlay thickness, synthetic fiber reinforcement usage, joint spacing, and joint sealing. Although the main factors affecting thin whitetopping performance have been identified by previous research, questions still existed as to the optimum design incorporating these variables. The objective of this research is to investigate the interaction between these variables over time. Laboratory testing and field testing were conducted to achieve the research objectives. Laboratory testing involved shear testing of the bond between the portland cement concrete (PCC) overlay and the ACC surface. Field testing involved falling weight deflectometer deflection responses, measurement of joint faulting and joint opening, and visual distress surveys on the 9.6-mile project. The project was located on Iowa Highway 13 extending north from the city of Manchester, Iowa, to Iowa Highway 3 in Delaware County. Variables investigated include ACC surface preparation, PCC thickness, slab size, synthetic fiber reinforcement usage, and joint spacing. This report documents the planning, construction, and performance of each variable in the time period from summer 2002 through spring 2006. The project has performed well with only minor distress identification since its construction.

Antitumor activities of ATP-competitive inhibitors of mTOR in colon cancer cells.

BACKGROUND: The mammalian target of rapamycin (mTOR) is frequently activated in colon cancers due to mutations in the phosphatidylinositol 3-kinase (PI3K) pathway. Targeting mTOR with allosteric inhibitors of mTOR such as rapamycin reduces colon cancer progression in several experimental models. Recently, a new class of mTOR inhibitors that act as ATP-competitive inhibitors of mTOR, has been developed. The effectiveness of these drugs in colon cancer cells has however not been fully characterized. METHODS: LS174T, SW480 and DLD-1 colon cancer cell lines were treated with PP242 an ATP-competitive inhibitor of mTOR, NVP-BEZ235, a dual PI3K/mTOR inhibitor or rapamycin. Tumor cell growth, proliferation and survival were assessed by MTS assay, 5-bromo-2'-deoxyuridine (BrDU) incorporation or by quantification of DNA fragmentation respectively. In vivo, the anticancer activity of mTOR inhibitors was evaluated on nude mice bearing colon cancer xenografts. RESULTS: PP242 and NVP-BEZ235 reduced the growth, proliferation and survival of LS174T and DLD-1 colon cancer cells more efficiently than rapamycin. Similarly, PP242 and NVP-BEZ235 also decreased significantly the proliferation and survival of SW480 cells which were resistant to the effects of rapamycin. In vivo, PP242 and NVP-BEZ235 reduced the growth of xenografts generated from LS174T and SW480 cells. Finally, we also observed that the efficacy of ATP-competitive inhibitors of mTOR was enhanced by U0126, a MEK inhibitor. CONCLUSIONS: Taken together, these results show that ATP-competitive inhibitors of mTOR are effective in blocking colon cancer cell growth in vitro and in vivo and thus represent a therapeutic option in colon cancer either alone or in combination with MEK inhibitors.