923 resultados para INERTIAL-FUSION
Resumo:
Despite the well-established antitumor activity of CD1d-restricted invariant natural killer T lymphocytes (iNKT), their use for cancer therapy has remained challenging. This appears to be due to their strong but short-lived activation followed by long-term anergy after a single administration of the CD1d agonist ligand alpha-galactosylceramide (αGC). As a promising alternative, we obtained sustained mouse iNKT cell responses associated with prolonged antitumor effects through repeated administrations of tumor-targeted recombinant sCD1d-antitumor scFv fusion proteins loaded with αGC. Here, we demonstrate that CD1d fusion proteins bound to tumor cells via the antibody fragment specific for a tumor-associated antigen, efficiently activate human iNKT cell lines leading to potent tumor cell lysis. The importance of CD1d tumor targeting was confirmed in tumor-bearing mice in which only the specific tumor-targeted CD1d fusion protein resulted in tumor inhibition of well-established aggressive tumor grafts. The therapeutic efficacy correlated with the repeated activation of iNKT and natural killer cells marked by their release of TH1 cytokines, despite the up-regulation of the co-inhibitory receptor PD-1. Our results demonstrate the superiority of providing the superagonist αGC loaded on recombinant CD1d proteins and support the use of αGC/sCD1d-antitumor fusion proteins to secure a sustained human and mouse iNKT cell activation, while targeting their cytotoxic activity and cytokine release to the tumor site.
Resumo:
In order to prevent adjacent segment degeneration following spinal fusion new techniques are being used. Lumbar disc arthroplasty yields mid term results equivalent to those of spinal fusion. Cervical disc arthroplasty is indicated in the treatment of cervicobrachialgia with encouraging initial results. The ability of arthroplasty to prevent adjacent segment degeneration has yet to be proven. Although dynamic stabilization had not been proven effective in treating chronic low back pain, it might be useful following decompression of lumbar spinal stenosis in degenerative spondylolisthesis. Interspinal devices are useful in mild lumbar spinal stenosis but their efficacy in treating low back pain is yet to be proven. Confronted with a growing number of new technologies clinicians should remain critical while awaiting long term results.
Resumo:
OBJECTIVE: Interleukin-1 (IL-1) mediates ischemia-reperfusion injury and graft inflammation after heart transplantation. IL-1 affects target cells through two distinct types of transmembrane receptors, type-1 receptor (IL-1R1), which transduces the signal, and the non-signaling type-2 receptor (IL-1R2), which acts as a ligand sink that subtracts IL-1beta from IL-1R1. We analyzed the efficacy of adenovirus (Ad)-mediated gene transfer of a soluble IL-1R2-Ig fusion protein in delaying cardiac allograft rejection and the mechanisms underlying the protective effect. METHODS: IL-1 inhibition by IL-1R2-Ig was tested using an in vitro functional assay whereby endothelial cells preincubated with AdIL-1R2-Ig or control virus were stimulated with recombinant IL-1beta or tumor necrosis factor-alpha (TNF-alpha), and urokinase-type plasminogen activator (u-PA) induction was measured by zymography. AdIL-1R2-Ig was delivered to F344 rat donor hearts ex vivo, which were placed in the abdominal position in LEW hosts. Intragraft inflammatory cell infiltrates and proinflammatory cytokine expression were analyzed by immunohistochemistry and real-time reverse transcriptase-polymerase chain reaction (RT-PCR), respectively. RESULTS: IL-1R2-Ig specifically inhibited IL-1beta-induced u-PA responses in vitro. IL-1R2-Ig gene transfer reduced intragraft monocytes/macrophages and CD4(+) cell infiltrates (p<0.05), TNF-alpha and transforming growth factor-beta (TGF-beta) expression (p<0.05), and prolonged graft survival (15.6+/-5.7 vs 10.3+/-2.5 days with control vector and 10.1+/-2.1 days with buffer alone; p<0.01). AdIL-1R2-Ig combined with a subtherapeutic regimen of cyclosporin A (CsA) was superior to CsA alone (19.4+/-3.0 vs 15.9+/-1.8 days; p<0.05). CONCLUSIONS: Soluble IL-1 type-2 receptor gene transfer attenuates cardiac allograft rejection in a rat model. IL-1 inhibition may be useful as an adjuvant therapy in heart transplantation.
Resumo:
PURPOSE: To improve the risk stratification of patients with rhabdomyosarcoma (RMS) through the use of clinical and molecular biologic data. PATIENTS AND METHODS: Two independent data sets of gene-expression profiling for 124 and 101 patients with RMS were used to derive prognostic gene signatures by using a meta-analysis. These and a previously published metagene signature were evaluated by using cross validation analyses. A combined clinical and molecular risk-stratification scheme that incorporated the PAX3/FOXO1 fusion gene status was derived from 287 patients with RMS and evaluated. RESULTS: We showed that our prognostic gene-expression signature and the one previously published performed well with reproducible and significant effects. However, their effect was reduced when cross validated or tested in independent data and did not add new prognostic information over the fusion gene status, which is simpler to assay. Among nonmetastatic patients, patients who were PAX3/FOXO1 positive had a significantly poorer outcome compared with both alveolar-negative and PAX7/FOXO1-positive patients. Furthermore, a new clinicomolecular risk score that incorporated fusion gene status (negative and PAX3/FOXO1 and PAX7/FOXO1 positive), Intergroup Rhabdomyosarcoma Study TNM stage, and age showed a significant increase in performance over the current risk-stratification scheme. CONCLUSION: Gene signatures can improve current stratification of patients with RMS but will require complex assays to be developed and extensive validation before clinical application. A significant majority of their prognostic value was encapsulated by the fusion gene status. A continuous risk score derived from the combination of clinical parameters with the presence or absence of PAX3/FOXO1 represents a robust approach to improving current risk-adapted therapy for RMS.
Resumo:
Cell-cell fusion is essential for fertilization. For fusion of walled cells, the cell wall must be degraded at a precise location but maintained in surrounding regions to protect against lysis. In fission yeast cells, the formin Fus1, which nucleates linear actin filaments, is essential for this process. In this paper, we show that this formin organizes a specific actin structure-the actin fusion focus. Structured illumination microscopy and live-cell imaging of Fus1, actin, and type V myosins revealed an aster of actin filaments whose barbed ends are focalized near the plasma membrane. Focalization requires Fus1 and type V myosins and happens asynchronously always in the M cell first. Type V myosins are essential for fusion and concentrate cell wall hydrolases, but not cell wall synthases, at the fusion focus. Thus, the fusion focus focalizes cell wall dissolution within a broader cell wall synthesis zone to shift from cell growth to cell fusion.
Resumo:
The synthesis of a membrane-bound MalE ,B-galactosidase hybrid protein, when induced by growth of Escherichia coli on maltose, leads to inhibition of cell division and eventually a reduced rate of mass increase. In addition, the relative rate of synthesis of outer membrane proteins, but not that of inner membrane proteins, was reduced by about 50%o. Kinetic experiments demonstrated that this reduction coincided with the period of maximum synthesis of the hybrid protein (and another maltose-inducible protein, LamB). The accumulation of this abnormal protein in the envelope therefore appeared specifically to inhibit the synthesis, the assembly of outer membrane proteins, or both, indicating that the hybrid protein blocks some export site or causes the sequestration of some limiting factor(s) involved in the export process. Since the MalE protein is normally located in the periplasm, the results also suggest that the synthesis of periplasmic and outer membrane proteins may involve some steps in common. The reduced rate of synthesis of outer membrane proteins was also accompanied by the accumulation in the envelope of at least one outer membrane protein and at least two inner membrane proteins as higher-molecular-weight forms, indicating that processing (removal of the N-terminal signal sequence) was also disrupted by the presence of the hybrid protein. These results may indicate that the assembly of these membrane proteins is blocked at a relatively late step rather than at the level of primary recognition of some site by the signal sequence. In addition, the results suggest that some step common to the biogenesis of quite different kinds of envelope protein is blocked by the presence of the hybrid protein.
Resumo:
CONTEXT: The current standard for diagnosing prostate cancer in men at risk relies on a transrectal ultrasound-guided biopsy test that is blind to the location of the cancer. To increase the accuracy of this diagnostic pathway, a software-based magnetic resonance imaging-ultrasound (MRI-US) fusion targeted biopsy approach has been proposed. OBJECTIVE: Our main objective was to compare the detection rate of clinically significant prostate cancer with software-based MRI-US fusion targeted biopsy against standard biopsy. The two strategies were also compared in terms of detection of all cancers, sampling utility and efficiency, and rate of serious adverse events. The outcomes of different targeted approaches were also compared. EVIDENCE ACQUISITION: We performed a systematic review of PubMed/Medline, Embase (via Ovid), and Cochrane Review databases in December 2013 following the Preferred Reported Items for Systematic reviews and Meta-analysis statement. The risk of bias was evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. EVIDENCE SYNTHESIS: Fourteen papers reporting the outcomes of 15 studies (n=2293; range: 13-582) were included. We found that MRI-US fusion targeted biopsies detect more clinically significant cancers (median: 33.3% vs 23.6%; range: 13.2-50% vs 4.8-52%) using fewer cores (median: 9.2 vs 37.1) compared with standard biopsy techniques, respectively. Some studies showed a lower detection rate of all cancer (median: 50.5% vs 43.4%; range: 23.7-82.1% vs 14.3-59%). MRI-US fusion targeted biopsy was able to detect some clinically significant cancers that would have been missed by using only standard biopsy (median: 9.1%; range: 5-16.2%). It was not possible to determine which of the two biopsy approaches led most to serious adverse events because standard and targeted biopsies were performed in the same session. Software-based MRI-US fusion targeted biopsy detected more clinically significant disease than visual targeted biopsy in the only study reporting on this outcome (20.3% vs 15.1%). CONCLUSIONS: Software-based MRI-US fusion targeted biopsy seems to detect more clinically significant cancers deploying fewer cores than standard biopsy. Because there was significant study heterogeneity in patient inclusion, definition of significant cancer, and the protocol used to conduct the standard biopsy, these findings need to be confirmed by further large multicentre validating studies. PATIENT SUMMARY: We compared the ability of standard biopsy to diagnose prostate cancer against a novel approach using software to overlay the images from magnetic resonance imaging and ultrasound to guide biopsies towards the suspicious areas of the prostate. We found consistent findings showing the superiority of this novel targeted approach, although further high-quality evidence is needed to change current practice.
Resumo:
We present a brief résumé of the history of solidification research and key factors affecting the solidification of fusion welds. There is a general agreement of the basic solidification theory, albeit differing - even confusing - nomenclatures do exist, and Cases 2 and 3 (the Chalmers' basic boundary conditions for solidification, categorized by Savage as Cases) are variably emphasized. Model Frame, a tool helping to model the continuum of fusion weld solidification from start to end, is proposed. It incorporates the general solidification models, of which the pertinent ones are selected for the actual modeling. The basic models are the main solidification Cases 1…4. These discrete Cases are joined with Sub-Cases: models of Pfann, Flemings and others, bringing needed Sub-Case variables into the model. Model Frame depicts a grain growing from the weld interface to its centerline. Besides modeling, the Model Frame supports education and academic debate. The new mathematical modeling techniques will extend its use into multi-dimensional modeling, introducing new variables and increasing the modeling accuracy. We propose a model: melting/solidification-model (M/S-model) - predicting the solute profile at the start of the solidification of a fusion weld. This Case 3-based Sub-Case takes into account the melting stage, the solute back-diffusion in the solid, and the growth rate acceleration typical to fusion welds. We propose - based on works of Rutter & Chalmers, David & Vitek and our experimental results on copper - that NEGS-EGS-transition is not associated only with cellular-dendritic-transition. Solidification is studied experimentally on pure and doped copper with welding speed range from 0 to 200 cm/min, with one test at 3000 cm/min. Found were only planar and cellular structures, no dendrites - columnar or equiaxed. Cell sub structures: rows of cubic elements we call "cubelettes", "cell-bands" and "micro-cells", as well as an anomalous crack morphology "crack-eye", were detected, as well as microscopic hot crack nucleus we call "grain-lag cracks", caused by a grain slightly lagging behind its neighbors in arrival to the weld centerline. Varestraint test and R-test revealed a change of crack morphologies from centerline cracks to grainand cell boundary cracks with an increasing welding speed. High speed made the cracks invisible to bare eye and hardly detectable with light microscope, while electron microscope often revealed networks of fine micro-cracks.
Resumo:
The present study proposes a method based on ski fixed inertial sensors to automatically compute spatio-temporal parameters (phase durations, cycle speed and cycle length) for the diagonal stride in classical cross-country skiing. The proposed system was validated against a marker-based motion capture system during indoor treadmill skiing. Skiing movement of 10 junior to world-cup athletes was measured for four different conditions. The accuracy (i.e. median error) and precision (i.e. interquartile range of error) of the system was below 6ms for cycle duration and ski thrust duration and below 35ms for pole push duration. Cycle speed precision (accuracy) was below 0.1m/s (0.005m/s) and cycle length precision (accuracy) was below 0.15m (0.005m). The system was sensitive to changes of conditions and was accurate enough to detect significant differences reported in previous studies. Since capture volume is not limited and setup is simple, the system would be well suited for outdoor measurements on snow.
Resumo:
The advent of multiparametric MRI has made it possible to change the way in which prostate biopsy is done, allowing to direct biopsies to suspicious lesions rather than randomly. The subject of this review relates to a computer-assisted strategy, the MRI/US fusion software-based targeted biopsy, and to its performance compared to the other sampling methods. Different devices with different methods to register MR images to live TRUS are currently in use to allow software-based targeted biopsy. Main clinical indications of MRI/US fusion software-based targeted biopsy are re-biopsy in men with persistent suspicious of prostate cancer after first negative standard biopsy and the follow-up of patients under active surveillance. Some studies have compared MRI/US fusion software-based targeted versus standard biopsy. In men at risk with MRI-suspicious lesion, targeted biopsy consistently detects more men with clinically significant disease as compared to standard biopsy; some studies have also shown decreased detection of insignificant disease. Only two studies directly compared MRI/US fusion software-based targeted biopsy with MRI/US fusion visual targeted biopsy, and the diagnostic ability seems to be in favor of the software approach. To date, no study comparing software-based targeted biopsy against in-bore MRI biopsy is available. The new software-based targeted approach seems to have the characteristics to be added in the standard pathway for achieving accurate risk stratification. Once reproducibility and cost-effectiveness will be verified, the actual issue will be to determine whether MRI/TRUS fusion software-based targeted biopsy represents anadd-on test or a replacement to standard TRUS biopsy.