Tumour-associated macrophages, TAMs, play a pivotal role in tumour growth and metastasis by promoting tumour angiogenesis. Treatment with clodronate encapsulated in liposomes (clodrolip) efficiently ...depleted these phagocytic cells in the murine F9 teratocarcinoma and human A673 rhabdomyosarcoma mouse tumour models resulting in significant inhibition of tumour growth ranging from 75 to >92%, depending on therapy and schedule. Tumour inhibition was accompanied by a drastic reduction in blood vessel density in the tumour tissue. Vascular endothelial growth factor (VEGF) is one of the major inducers of tumour angiogenesis and is also required for macrophage recruitment. The strongest effects were observed with the combination therapy of clodrolip and a VEGF-neutralising antibody, whereas free clodronate was not significantly active. Immunohistologic evaluation of the tumours showed significant depletion of F4/80+ and MOMA-1+ and a less pronounced depletion of CD11b+ TAMs. Blood vessel staining (CD31) and quantification of the vessels as well as TAMs and tumour-associated dendritic cells (TADCs) in the A673 model showed reduction rates of 85 to >94%, even 9 days after the end of therapy. In addition, CD11c+ TADCs, which have been shown to potentially differentiate into endothelial-like cells upon stimulation by tumour released growth and differentiation factors, were similarly reduced by clodrolip or antibody treatment. These results validate clodrolip therapy in combination with angiogenesis inhibitors as a promising novel strategy for an indirect cancer therapy aimed at the haematopoietic precursor cells that stimulate tumour growth and dissemination and as a tool to study the role of macrophages and dendritic cells in tumorigenesis.
Vascular endothelial growth factors (VEGFs) regulate blood and lymphatic vessel development and homeostasis but also have profound effects on neural cells. VEGFs are predominantly produced by ...endothelial, hematopoietic and stromal cells in response to hypoxia and upon stimulation with growth factors such as transforming growth factors, interleukins or platelet-derived growth factor. VEGFs bind to three variants of type III receptor tyrosine kinases, VEGF receptor 1, 2 and 3. Each VEGF isoform binds to a particular subset of these receptors giving rise to the formation of receptor homo- and heterodimers that activate discrete signaling pathways. Signal specificity of VEGF receptors is further modulated upon recruitment of coreceptors, such as neuropilins, heparan sulfate, integrins or cadherins. Here we summarize the knowledge accumulated since the discovery of these proteins more than 20 years ago with the emphasis on the signaling pathways activated by VEGF receptors in endothelial cells during cell migration, growth and differentiation.
Hydrogels are a class of soft, highly deformable materials formed by swelling a network of polymer chains in water. With mechanical properties that mimic biological materials, hydrogels are often ...proposed for load bearing biomedical or other applications in which their deformation and failure properties will be important. To study the failure of such materials a means for the measurement of deformation fields beyond simple uniaxial tension tests is required. As a non-contact, full-field deformation measurement method, Digital Image Correlation (DIC) is a good candidate for such studies. The application of DIC to hydrogels is studied here with the goal of establishing the accuracy of DIC when applied to hydrogels in the presence of large strains and large strain gradients. Experimental details such as how to form a durable speckle pattern on a material that is 90% water are discussed. DIC is used to measure the strain field in tension loaded samples containing a central hole, a circular edge notch and a sharp crack. Using a nonlinear, large deformation constitutive model, these experiments are modeled using the finite element method (FEM). Excellent agreement between FEM and DIC results for all three geometries shows that the DIC measurements are accurate up to strains of over 10, even in the presence of very high strain gradients near a crack tip. The method is then applied to verify a theoretical prediction that the deformation field in a cracked sample under relaxation loading, i.e. constant applied boundary displacement, is stationary in time even as the stress relaxes by a factor of three.
The impact of 1973–2005 land use–land cover (LULC) changes on near-surface air temperatures during four recent summer extreme heat events (EHEs) are investigated for the arid Phoenix, Arizona, ...metropolitan area using the Weather Research and Forecasting Model (WRF) in conjunction with the Noah Urban Canopy Model. WRF simulations were carried out for each EHE using LULC for the years 1973, 1985, 1998, and 2005. Comparison of measured near-surface air temperatures and wind speeds for 18 surface stations in the region show a good agreement between observed and simulated data for all simulation periods. The results indicate consistent significant contributions of urban development and accompanying LULC changes to extreme temperatures for the four EHEs. Simulations suggest new urban developments caused an intensification and expansion of the area experiencing extreme temperatures but mainly influenced nighttime temperatures with an increase of up to 10 K. Nighttime temperatures in the existing urban core showed changes of up to ∼2 K with the ongoing LULC changes. Daytime temperatures were not significantly affected where urban development replaced desert land (increase by ∼1 K); however, maximum temperatures increased by ∼2–4 K when irrigated agricultural land was converted to suburban development. According to the model simulations, urban landscaping irrigation contributed to cooling by 0.5–1 K in maximum daytime as well as minimum nighttime 2-m air temperatures in most parts of the urban region. Furthermore, urban development led to a reduction of the already relatively weak nighttime winds and therefore a reduction in advection of cooler air into the city.
Background
Little is known about the effect of water content on the mechanical properties of dual cross-linked hydrogels.
Objective
To quantify the changes in the mechanical response and equilibrium ...modulus in a PVA hydrogel as a function of the hydration level.
Methods
A dual cross-linked hydrogel was tested in tension to a stretch of 1.3 at two stretch rates and in a stress relaxation test. The equilibrium modulus was calculated using the final relaxation stress value.
Results
The stiffness of the hydrogel increases significantly as the gel dries.
Conclusions
The equilibrium modulus is found to be linear with the hydration level and approximately 2 × stiffer at 60% hydration relative to 90%.
High nitrogen losses were observed in a rotating biological contactor (RBC) treating ammonium-rich (up to 500 mg${\rm NH}_{4}^{+}\text{-}{\rm N}/{\rm L}$) but organic-carbon-poor leachate from a ...hazardous waste landfill in Kölliken, Switzerland. The composition and spatial structure of the microbial community in the biofilm on the RBC was analyzed with specific attention for the presence of aerobic ammonium and nitrite oxidizing bacteria and anaerobic ammonium oxidizers. Anaerobic ammonium oxidation (anammox) involves the oxidation of ammonium with nitrite to N2. First the diversity of the biofilm community was determined from sequencing cloned PCR-amplified 16S rDNA fragments. This revealed the presence of a number of very unusual 16S rDNA sequences, but very few sequences related to known ammonium or nitrite oxidizing bacteria. From analysis of biofilm samples by fluorescence in situ hybridization with known phylogenetic probes and by dot-blot hybridization of the same probes to total RNA purified from biofilm samples, the main groups of microorganisms constituting the biofilm were found to be ammonium-oxidizing bacteria from the Nitrosomonas europaea/eutropha group, anaerobic ammonium-oxidizing bacteria of the "Candidatus Kuenenia stuttgartiensis" type, filamentous bacteria from the phylum Bacteroidetes, and nitrite-oxidizing bacteria from the genus Nitrospira. Aerobic and anaerobic ammonium-oxidizing bacteria were present in similar amounts of around 20 to 30% of the biomass, whereas members of the CFB phylum were present at around 7%. Nitrite oxidizing bacteria were only present in relatively low amounts (less than 5% determined with fluorescence in situ hybridization). Data from 16S rRNA dot-blot and in situ hybridization were not in all cases congruent. FISH analysis of thin-sliced and fixed biofilm samples clearly showed that the aerobic nitrifiers were located at the top of the biofilm in an extremely high density and in alternating clusters. Anammox bacteria were exclusively present in the lower half of the biofilm, whereas CFB-type filamentous bacteria were present throughout the biofilm. The structure and composition of these biofilms correlated very nicely with the proposed physiological functional separations in ammonium conversion.
Catechols can undergo a variety of chemical reactions. In this review, we particularly focus on complex formations and the redox chemistry of catechols, which play an inportant role in the toxicity ...of catechols. In the presence of heavy metals, such as iron or copper, stable complexes can be formed. In the presence of oxidizing agents, catechols can be oxidized to semiquinone radicals and in a next step to o‐benzoquinones. Heavy metals may catalyse redox reactions in which catechols are involved. Further chemical properties like the acidity constant and the lipophilicity of different catechols are shortly described as well. As a consequence of the chemical properties and the chemical reactions of catechols, many different reactions can occur with biomolecules such as DNA, proteins and membranes, ultimately leading to non‐repairable damage. Reactions with nucleic acids such as adduct formation and strand breaks are discussed among others. Interactions with proteins causing protein and enzyme inactivation are described. The membrane–catechol interactions discussed here are lipid peroxidation and uncoupling. The deleterious effect of the interactions between catechols and the different biomolecules is discussed in the context of the observed toxicities, caused by catechols.
This study provides an insight into the impact of China's international trade of goods and services on its water resources and uses. Virtual water flows associated with China's international trade ...are quantified in an input-output framework. The analysis is scaled down to the sectoral and provincial levels to trace the origins and destinations of virtual water flows associated with the international trade. The results show that China is a net virtual water exporter of 4.8 × 1010 m3 yr−1, accounting for 2.1% of its renewable water resources and 8.6% of the total water use. Water scarce regions tend to have higher percentages of virtual water export relative to their water resources and water uses. In the water scarce Huang-Huai-Hai region, the net virtual water export accounts for 8.0% of the region's water resources and 11.3% of its water uses. For individual sectors, major net virtual water exporters are those where agriculture provides raw materials in the initial process of the production chain. The results suggest that China's economic gains from being a world "manufacture factory" have come at a high cost to its water resources.
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