Angiogenesehemmung in der Neuroonkologie: Eine vielversprechende Therapiestrategie gegen maligne Gliome

Zusammenfassung: Der Einsatz angiogenesehemmender Substanzen in der Hirntumortherapie nimmt zu. Der initialen Euphorie bezüglich der überraschend hohen Ansprechraten bei Hemmstoffen des VEGF ("vascular endothelial growth factor")-Signalwegs ist mittlerweile eine Ernüchterung gefolgt, da die progressionsfreie Zeit und das mediane Überleben langfristig nicht zufriedenstellend sind. Die Tumorprogression kann während/nach antiangiogener Therapie mit rapider klinisch-neurologischer Verschlechterung einhergehen und weist häufig einen gliomatosisähnlichen diffus-infiltrativen Phänotyp auf. Somit bestehen die aktuellen Herausforderungen darin, Kriterien für den individuellen Einsatz von Angiogenesehemmern zu definieren sowie die unter der Therapie auftretenden Resistenzmechanismen zu entschlüssel

Design Considerations for Integral Abutment/ Jointless Bridges in the USA

This paper summarizes results of a major study on jointless bridges sponsored by the U.S. Federal Highway Administration. This study included extensive laboratory and field experiments as well as detailed analytical studies. A set of design recommendations were provided. Jointless bridges have reduced maintenance, improved riding quality, lower impact loads, reduced snowplow damage, and structural continuity for live load and seismic resistance. However, the thermal movements of the bridge and restraint forces from the abutments and piers must be considered and accommodated. The general design philosophy is to build flexibility into the support structures to the extent feasible while providing sufficient strength for restraint forces that cannot be completely eliminated. The experimental phase of the research addressed thermal movements and stresses; creep and shrinkage movements, including the effects of exposure to the outside environment; and pile behavior. The overall analytical program consisted of studies on abutment soil-structure interaction, pier behavior, longitudinal bridge movement, secondary continuity forces, skewed bridge behavior, and construction sequences. In some cases, the research demonstrates that existing design procedures and engineering data can be used to adequately quantify the structural response and design forces for the structure. In other cases, the results of more complex analyses were used to develop simplified design relationships and procedures

Experiment on interaction of abutment, steel H-Pile and soil in integral abutment jointless bridges (IAJBs) under Low-cycle Pseudo-static displacement loads

Soil-abutment or soil-pile interactions under cyclic static loads have been widely studied in integral abutment jointless bridges (IAJBs). However, the IAJB has the combinational interaction of soil-abutment and soil-pile, and the soil-abutment-pile interaction is lack of comprehensively study. Therefore, a reciprocating low-cycle pseudo-static test was carried out under an cyclic horizontal displacement load (DL) to gain insight into the mechanical behavior of the soil-abutment-pile system. Test results indicate that the earth pressure of backfill behind abutment has the ratcheting effect, which induced a large earth pressure. The soil-abutment-pile system has a favorable energy dissipation capacity and seismic behavior with relatively large equivalent viscous damping. The accumulative horizontal deformation in pile will be occurred by the effect of abutment and unbalance soil pressure of backfill. The test shows that the maximum horizontal deformation of pile occurs in the pile depth of 1.0b~3.0b of pile body rather than at the pile head due to the accumulative deformation of pile, which is significantly different from those of previous test results of soil-pile interaction. The time-history curve for abutment is relatively symmetrical and its accumulative deformation is small. However, the time-history curve of pile is asymmetrical and its accumulative deformation is dramatically large. The traditional theory of deformation applies only to the calculation of noncumulative deformation of pile, and the influence of accumulative deformation should be considered in practical engineering. A significant difference of inclinations in the positive and negative directions increases when the displacement load is relatively large. The rotation of abutment when bridge expands is larger than that when bridge contracts due to earth pressure of backfill

APO010, a synthetic hexameric CD95 ligand, induces human glioma cell death in vitro and in vivo

Death receptor targeting has emerged as one of the promising novel approaches of cancer therapy. The activation of one such prototypic death receptor, CD95 (Fas/APO-1), has remained controversial because CD95 agonistic molecules have exhibited either too strong toxicity or too little activity. The natural CD95 ligand (CD95L) is a cytokine, which needs to trimerize to mediate a cell death signal. Mega-Fas-Ligand, now referred to as APO010, is a synthetic hexameric CD95 agonist that exhibits strong antitumor activity in various tumor models. Here, we studied the effects of APO010 in human glioma models in vitro and in vivo. Compared with a cross-linked soluble CD95L or a CD95-agonistic antibody, APO010 exhibited superior activity in glioma cell lines expressing CD95 and triggered caspase-dependent cell death. APO010 reduced glioma cell viability in synergy when combined with temozolomide. The locoregional administration of APO010 induced glioma cell death in vivo and prolonged the survival of tumor-bearing mice. A further exploration of APO010 as a novel antiglioma agent is warranted

MicroRNA-383 located in frequently deleted chromosomal locus 8p22 regulates CD44 in prostate cancer.

A major genomic alteration in prostate cancer (PCa) is frequent loss of chromosome (chr) 8p with a common region of loss of heterozygosity (LOH) at chr8p22 locus. Genomic studies implicate this locus in the initiation of clinically significant PCa and with progression to metastatic disease. However, the genes within this region have not been fully characterized to date. Here we demonstrate for the first time that a microRNA component of this region-miR-383-is frequently downregulated in prostate cancer, has a critical role in determining tumor-initiating potential and is involved in prostate cancer metastasis via direct regulation of CD44, a ubiquitous marker of PCa tumor-initiating cells (TICs)/stem cells. Expression analyses of miR-383 in PCa clinical tissues established that low miR-383 expression is associated with poor prognosis. Functional data suggest that miR-383 regulates PCa tumor-initiating/stem-like cells via CD44 regulation. Ectopic expression of miR-383 inhibited tumor-initiating capacity of CD44+ PCa cells. Also, 'anti-metastatic' effects of ectopic miR-383 expression were observed in a PCa experimental metastasis model. In view of our results, we propose that frequent loss of miR-383 at chr8p22 region leads to tumor initiation and prostate cancer metastasis. Thus, we have identified a novel finding that associates a long observed genomic alteration to PCa stemness and metastasis. Our data suggest that restoration of miR-383 expression may be an effective therapeutic modality against PCa. Importantly, we identified miR-383 as a novel PCa tissue diagnostic biomarker with a potential that outperforms that of serum PSA

Performance of titanium salts compared to conventional FeCl<inf>3</inf> for the removal of algal organic matter (AOM) in synthetic seawater: Coagulation performance, organic fraction removal and floc characteristics

© 2017 Elsevier Ltd During algal bloom periods, operation of seawater reverse osmosis (SWRO) pretreatment processes (e.g. ultrafiltration (UF)) has been hindered due to the high concentration of algal cells and algal organic matter (AOM). The present study evaluated for the first time the performance of titanium salts (i.e. titanium tetrachloride (TiCl4) and polytitanium tetrachloride (PTC)) for the removal of AOM in seawater and results were compared with the conventional FeCl3 coagulant. Previous studies already demonstrated that titanium salts not only provide a cost-effective alternative to conventional coagulants by producing a valuable by-product but also minimise the environmental impact of sludge production. Results from this study showed that both TiCl4 and PTC achieved better performance than FeCl3 in terms of turbidity, UV254 and dissolved organic carbon (DOC) removal at similar coagulant dose. Liquid chromatography – organic carbon detection (LC-OCD) was used to determine the removal of AOM compounds based on their molecular weight (MW). This investigation revealed that both humic substances and low MW organics were preferentially removed (i.e. up to 93% removal) while all three coagulants showed poorer performance for the removal of high MW biopolymers (i.e. less than 50% removal). The detailed characterization of flocs indicated that both titanium coagulants can grow faster, reach larger size and present a more compact structure, which is highly advantageous for the design of smaller and more compact mixing and sedimentation tanks. Both titanium coagulants also presented a higher ability to withstand shear force, which was related to the higher amount of DOC adsorbed with the aggregated flocs. Finally, TiCl4 had a better recovery after breakage suggesting that charge neutralization may be the dominant mechanism for this coagulant, while the lower recovery of both PTC and FeCl3 indicated that sweep flocculation is also a contributing mechanism for the coagulation of AOM

An investigation of the performance of a new Mechanical thrombectomy device using Bond Graph modelling: application to the extraction of blood clots in the middle cerebral artery

A number of thrombectomy devices using a variety of methods have now been developed to facilitate clot removal. We present research involving one such experimental device recently developed in the UK, called a ‘GP’ Thrombus Aspiration Device (GPTAD). This device has the potential to bring about the extraction of a thrombus. Although the device is at a relatively early stage of development, the results look encouraging. In this work, we present an analysis and modeling of the GPTAD by means of the bond graph technique; it seems to be a highly effective method of simulating the device under a variety of conditions. Such modeling is useful in optimizing the GPTAD and predicting the result of clot extraction. The aim of this simulation model is to obtain the minimum pressure necessary to extract the clot and to verify that both the pressure and the time required to complete the clot extraction are realistic for use in clinical situations, and are consistent with any experimentally obtained data. We therefore consider aspects of rheology and mechanics in our modeling

Quantum Dynamics without the Wave Function

When suitably generalized and interpreted, the path-integral offers an alternative to the more familiar quantal formalism based on state-vectors, selfadjoint operators, and external observers. Mathematically one generalizes the path-integral-as-propagator to a {\it quantal measure} $\mu$ on the space $\Omega$ of all ``conceivable worlds'', and this generalized measure expresses the dynamics or law of motion of the theory, much as Wiener measure expresses the dynamics of Brownian motion. Within such ``histories-based'' schemes new, and more ``realistic'' possibilities open up for resolving the philosophical problems of the state-vector formalism. In particular, one can dispense with the need for external agents by locating the predictive content of $\mu$ in its sets of measure zero: such sets are to be ``precluded''. But unrestricted application of this rule engenders contradictions. One possible response would remove the contradictions by circumscribing the application of the preclusion concept. Another response, more in the tradition of ``quantum logic'', would accommodate the contradictions by dualizing $\Omega$ to a space of ``co-events'' and effectively identifying reality with an element of this dual space.Comment: plainTeX, 24 pages, no figures. To appear in a special volume of {\it Journal of Physics A: Mathematical and General} entitled ``The Quantum Universe'' and dedicated to Giancarlo Ghirardi on the occasion of his 70th birthday. Most current version is available at http://www.physics.syr.edu/~sorkin/some.papers/ (or wherever my home-page may be

Causal Sets: Quantum gravity from a fundamentally discrete spacetime

In order to construct a quantum theory of gravity, we may have to abandon certain assumptions we were making. In particular, the concept of spacetime as a continuum substratum is questioned. Causal Sets is an attempt to construct a quantum theory of gravity starting with a fundamentally discrete spacetime. In this contribution we review the whole approach, focusing on some recent developments in the kinematics and dynamics of the approach.Comment: 10 pages, review of causal sets based on talk given at the 1st MCCQG conferenc