A systematic review and meta-analysis of surgical treatments for malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive disease of the pleural lining with a dismal prognosis. Surgical treatments of MPM with a curative intent include extrapleural pneumonectomy and extended pleurectomy/decortication (P/D). This meta-analysis aimed to compare the perioperative and long-term outcomes of EPP and extended P/D for selected surgical candidates. METHODS: A systematic review of the literature was performed on six electronic databases to identify all relevant data on comparative outcomes of extended P/D and EPP in a multimodality setting. Endpoints included perioperative mortality and morbidity, as well as long-term overall survival. RESULTS: Seven relevant studies with comparative data on EPP (n=632) versus extended P/D (n=513) were identified from the current literature. Comparison of these two groups demonstrated significantly lower perioperative mortality (2.9% vs. 6.8%, p=0.02) and morbidity (27.9% vs. 62.0%, p<0.0001) for patients who underwent extended P/D compared to EPP. Median overall survival ranged between 13-29 months for extended P/D and 12-22 months for EPP, with a trend favouring extended P/D. CONCLUSIONS: Although it must be emphasized that patient selection and treatment strategies differ between EPP and extended P/D, a number of comparative studies have recently been conducted to compare these two surgical techniques for patients with resectable MPM. The present study indicated that selected patients who underwent extended P/D had lower perioperative morbidity and mortality with similar, if not superior, long-term survival compared to EPP, in the context of multi-modality therapy. This may represent an important paradigm shift in the surgical management of MPM.

Systematic review of pleurectomy in the treatment of malignant pleural mesothelioma.

INTRODUCTION: Pleurectomy/decortication (P/D) in the treatment of malignant pleural mesothelioma includes a number of procedures with different clinical indications and therapeutic intents. To unify the nomenclature, IMIG and IASLC recently defined P/D-related procedures according to surgical technique, including 'extended P/D', 'P/D' and 'partial pleurectomy'. The present systematic review aimed to assess the safety and efficacy of these techniques. METHODS: A systematic review of relevant studies was performed by electronic search of five online databases from 1985 to 2012 by two independent reviewers according to predefined selection criteria. RESULTS: Thirty-four studies involving 1916 patients who underwent pleurectomy were included for quantitative analysis. These included 12 studies on 'extended P/D', 8 studies on 'P/D' and 14 studies on 'partial pleurectomy'. Perioperative mortality ranged from 0% to 11% and perioperative morbidity ranged from 13% to 43%. Median overall survival ranged from 7.1 to 31.7 months and disease-free survival ranged from 6 to 16 months. One study reported on quality-of-life outcomes using a standardized questionnaire suggesting superior outcomes for 'extended P/D' compared to extrapleural pneumonectomy. CONCLUSIONS: Results of the present systematic review suggested similar perioperative mortality outcomes between different P/D techniques but a trend towards higher morbidity and length of hospitalization for patients who underwent 'extended P/D'. However, overall and disease-free survival appeared to favour 'extended P/D' compared to less aggressive techniques. Future studies on P/D should adhere to recent definitions to enable accurate analysis of similar procedures. Direct comparisons of pleurectomy to extrapleural pneumonectomy remain challenging, and should be restricted to 'extended P/D' procedures only.

Polyimide/SU-8 catheter-tip MEMS gauge pressure sensor.

This paper describes the development of a polyimide/SU-8 catheter-tip MEMS gauge pressure sensor. Finite element analysis was used to investigate critical parameters, impacting on the device design and sensing characteristics. The sensing element of the device was fabricated by polyimide-based micromachining on a flexible membrane, using embedded thin-film metallic wires as piezoresistive elements. A chamber containing this flexible membrane was sealed using an adapted SU-8 bonding technique. The device was evaluated experimentally and its overall performance compared with a commercial silicon-based pressure sensor. Furthermore, the device use was demonstrated by measuring blood pressure and heart rate in vivo.

Nano-stenciled RGD-gold patterns that inhibit focal contact maturation induce lamellipodia formation in fibroblasts.

Cultured fibroblasts adhere to extracellular substrates by means of cell-matrix adhesions that are assembled in a hierarchical way, thereby gaining in protein complexity and size. Here we asked how restricting the size of cell-matrix adhesions affects cell morphology and behavior. Using a nanostencil technique, culture substrates were patterned with gold squares of a width and spacing between 250 nm and 2 µm. The gold was functionalized with RGD peptide as ligand for cellular integrins, and mouse embryo fibroblasts were plated. Limiting the length of cell-matrix adhesions to 500 nm or less disturbed the maturation of vinculin-positive focal complexes into focal contacts and fibrillar adhesions, as indicated by poor recruitment of α5-integrin. We found that on sub-micrometer patterns, fibroblasts spread extensively, but did not polarize. Instead, they formed excessive numbers of lamellipodia and a fine actin meshwork without stress fibers. Moreover, these cells showed aberrant fibronectin fibrillogenesis, and their speed of directed migration was reduced significantly compared to fibroblasts on 2 µm square patterns. Interference with RhoA/ROCK signaling eliminated the pattern-dependent differences in cell morphology. Our results indicate that manipulating the maturation of cell-matrix adhesions by nanopatterned surfaces allows to influence morphology, actin dynamics, migration and ECM assembly of adhering fibroblasts.

Link between alginate reaction front propagation and general reaction diffusion theory.

We provide a common theoretical framework reuniting specific models for the Ca(2+)-alginate system and general reaction diffusion theory along with experimental validation on a microfluidic chip. As a starting point, we use a set of nonlinear, partial differential equations that are traditionally solved numerically: the Mikkelsen-Elgsaeter model. Applying the traveling-wave hypothesis as a major simplification, we obtain an analytical solution. The solution indicates that the fundamental properties of the alginate reaction front are governed by a single dimensionless parameter λ. For small λ values, a large depletion zone accompanies the reaction front. For large λ values, the alginate reacts before having the time to diffuse significantly. We show that the λ parameter is of general importance beyond the alginate model system, as it can be used to classify known solutions for second-order reaction diffusion schemes, along with the novel solution presented here. For experimental validation, we develop a microchip model system, in which the alginate gel formation can be carried out in a highly controlled, essentially 1D environment. The use of a filter barrier enables us to rapidly renew the CaCl(2) solution, while maintaining flow speeds lower than 1 µm/s for the alginate compartment. This allows one to impose an exactly known bulk CaCl(2) concentration and diffusion resistance. This experimental model system, taken together with the theoretical development, enables the determination of the entire set of physicochemical parameters governing the alginate reaction front in a single experiment.

Fluidic microstructuring of alginate hydrogels for the single cell niche.

Controlling alginate gel formation by diffusion of Ca(2+) ions through a filter barrier, a layer-by-layer deposition technique with resolution on the size scale of a single cell is presented. It offers the possibility of exposing cells under biocompatible conditions to microheterogeneous three-dimensional environments, mimicking the layered structure of extracellular matrix in tissues.

Microcollimator for micrometer-wide stripe irradiation of cells using 20-30 keV X rays.

Abstract Pataky, K., Villanueva, G., Liani, A., Zgheib, O., Jenkins, N., Halazonetis, D. J., Halazonetis, T. D. and Brugger, J. Microcollimator for Micrometer-Wide Stripe Irradiation of Cells Using 20-30 keV X Rays. Radiat. Res. 172, 252-259 (2009). The exposure of subnuclear compartments of cells to ionizing radiation is currently not trivial. We describe here a collimator for micrometer-wide stripe irradiation designed to work with conventional high-voltage X-ray tubes and cells cultured on standard glass cover slips. The microcollimator was fabricated by high-precision silicon micromachining and consists of X-ray absorbing chips with grooves of highly controlled depths, between 0.5-10 microm, along their surfaces. These grooves form X-ray collimating slits when the chips are stacked against each other. The use of this device for radiation biology was examined by irradiating human cells with X rays having energies between 20-30 keV. After irradiation, p53 binding protein 1 (53BP1), a nuclear protein that is recruited at sites of DNA double-strand breaks, clustered in lines corresponding to the irradiated stripes.

An oligomerized 53BP1 tudor domain suffices for recognition of DNA double-strand breaks.

53BP1, the vertebrate ortholog of the budding yeast Rad9 and fission yeast Crb2/Rhp9 checkpoint proteins, is recruited rapidly to sites of DNA double-strand breaks (DSBs). A tandem tudor domain in human 53BP1 that recognizes methylated residues in the histone core is necessary, but not sufficient, for efficient recruitment. By analysis of deletion mutants, we identify here additional elements in 53BP1 that facilitate recognition of DNA DSBs. The first element corresponds to an independently folding oligomerization domain. Replacement of this domain with heterologous tetramerization domains preserves the ability of 53BP1 to recognize DNA DSBs. A second element is only about 15 amino acids long and appears to be a C-terminal extension of the tudor domain, rather than an independently functioning domain. Recruitment of 53BP1 to sites of DNA DSBs is facilitated by histone H2AX phosphorylation and ubiquitination. However, none of the 53BP1 domains/elements important for recruitment are known to bind phosphopeptides or ubiquitin, suggesting that histone phosphorylation and ubiquitination regulate 53BP1 recruitment to sites of DNA DSBs indirectly.

NMR spectroscopy and perfusion of mammalian cells using surface microprobes.

NMR spectra of mammalian cells are taken using surface microprobes that are based on microfabricated planar coils. The surface microprobe resembles a miniaturized Petri dish commonly used in biological research. The diameter of the planar coils is 1 mm. Chinese Hamster Ovaries are immobilized in a uniform layer on the microprobe surface or patterned by an ink-jet printer in the centre of the microcoil, where the rf-field of the planar microcoil is most uniform. The acquired NMR spectra show the prevalent metabolites found in mammalian cells. The volumes of the detected samples range from 25 nL to 1 nL (or 50,000 to 1800 cells). With an extended set-up that provides fluid inlets and outlets to the microprobe, the cells can be perfused within the NMR-magnet while constantly taking NMR spectra. Perfusion of the cells opens the way to increased cell viability for long acquisitions or to analysis of the cells' response to environmental change.