Biosensor incorporating cell barrier architectures on ion selective electrodes for early screening of cancer

Angiogenesis occurs during the early phase of cancer. Recruitment of new blood vessels by existing cancer cells leads to the release of higher concentrations of cytokines as compared to cells in healthy individuals. Some of the common cytokines observed at higher concentrations, such as vascular endothelial growth factor, basic fibroblast growth factor, hepatocyte growth factor and tumor necrosis factor-alpha, are also known to induce increased permeability across an endothelial cell monolayer. A whole-cell-based biosensor has been developed that can detect the presence of small quantities of the abovementioned cytokines individually and in different combinations. It was observed that the biosensor could differentiate between the cytokine concentrations observed in the sera of healthy individuals and cancer patients. The biosensor was also evaluated by exposing it to actual serum. These results demonstrated that the sensor can distinguish between healthy individuals and cancer patients and that the corresponding biosensor responses correlate with the stages of cancer.     

Modeling of anisotropic wound healing

Biological soft tissues exhibit non-linear complex properties, the quantification of which presents a challenge. Nevertheless, these properties, such as skin anisotropy, highly influence different processes that occur in soft tissues, for instance wound healing, and thus its correct identification and quantification is crucial to understand them. Experimental and computational works are required in order to find the most precise model to replicate the tissues' properties. In this work, we present a wound healing model focused on the proliferative stage that includes angiogenesis and wound contraction in three dimensions and which relies on the accurate representation of the mechanical behavior of the skin. Thus, an anisotropic hyperelastic model has been considered to analyze the effect of collagen fibers on the healing evolution of an ellipsoidal wound. The implemented model accounts for the contribution of the ground matrix and two mechanically equivalent families of fibers. Simulation results show the evolution of the cellular and chemical species in the wound and the wound volume evolution. Moreover, the local strain directions depend on the relative wound orientation with respect to the fibers.     

Development of CE methods to analyze potential components of the angiogenic glycoprotein vascular endothelial growth factor 165

The vascular endothelial growth factor 165 (VEGF₁₆₅) is the predominant form of the complex VEGF family. This glycoprotein has, among others, an angiogenic effect in many physiological and pathological events. For this reason, its roles as a biomarker and as a therapeutic drug have been considered. However, very little is known about the existence of different forms of VEGF₁₆₅ arising from glycosylation and other potential PTMs. This aspect is crucial because it is known that for other glycoproteins the ratio between these isoforms actually acts as a biomarker for certain diseases and other physiological states. In addition, for therapeutic use of glycoproteins it is known that the biological activity may differ for the various isoforms. In this work CE methods to separate up to seven peaks without baseline resolution containing various forms of VEGF₁₆₅ are developed. Using a computer program previously developed in‐house peak assignment could be performed with accuracy close to 100%. In this way, comparison between recombinant human VEGF₁₆₅ expressed in insect cells, which is a glycosylating system, and in Escherichia coli cells, which are unable of performing glycosylation of proteins, has been possible. The methods developed, besides providing information about the existence of several forms of VEGF₁₆₅, mean a starting point that permits the study of the role of VEGF₁₆₅ as a potential biomarker of different diseases and physiological processes and to perform quality control of the recombinant drug during manufacturing. To the best of our knowledge this is the first time that CE methods for VEGF₁₆₅ have been developed.     

Design and chemical synthesis of [1,2,4]triazol[1,5-c]pyrimidin-5-yl amines, a novel class of VEGFR-2 kinase inhibitors

The Letter describes a facile approach to 7,8-dihydro[1,2,4]triazol[1,5-c]pyrimidin-5-yl amines, a novel class of potent inhibitors of vascular endothelial growth factor receptor II (VEGFR-2). The synthetic sequence is centered around preparation of the key 3(5)-cyanomethyl-1,2,4-triazole intermediates and their Knoevenagel condensation with aromatic aldehydes. A subsequent three-step conversion of Knoevenagel adducts involving a reduction of vinyl nitriles followed by the reaction of the resulting amines with aryl isothiocyanates and cyclization of the respective thioureas yielded targeted heterocycles as a 1:1 mixture of tautomers. A representative molecule featured sound activity against VEGFR-2 in both enzymatic and cellular assays.     

An angiogenesis model with nonlinear chemotactic response and flux at the tumor boundary

In this paper we consider a parabolic problem as well as its stationary counterpart of a model arising in angiogenesis. The problem includes a chemotaxis type term and a nonlinear boundary condition at the tumor boundary. We show that the parabolic problem admits a unique positive global in time solution. Moreover, by bifurcation methods, we show the existence of coexistence states and also we study the local stability of the semi-trivial states.     

Isoindolones from Lasiosphaera fenzlii Reich. and Their Bioactivities

Two new, 1 and 2 , along with one known isoindolone, 3 , were isolated from the AcOEt extract of Lasiosphaera fenzlii Reich . The structures of these compounds were determined as 4,6‐dihydroxy‐1H‐isoindole‐1,3(2H)‐dione ( 1 ), 4,6‐dihydroxy‐2,3‐dihydro‐1H‐isoindol‐1‐one ( 2 ), and clitocybin A ( 3 ) on the basis of chemical and spectroscopic evidences. The bioactivity assays revealed that all of them were devoid of significant cytotoxicities against tumor cells, whereas 1 exhibited potent antiangiogenic activity by inhibiting the secretion of vascular endothelial growth factor (VEGF) in A549 cells.     

A parabolic–hyperbolic system modeling the tumor growth with angiogenesis

In this paper, we study the parabolic–hyperbolic system about the growth of a tumor. The model is a coupled system of PDEs with Robin boundary, which involves nutrient density, extracellular matrix and matrix degrading enzyme. By transforming the free boundary into a fixed boundary and using strict mathematical analysis, we can prove the existence and uniqueness of the radially symmetric stationary solution. By the fixed point theorem, we obtain the existence and uniqueness of the radially symmetric solution globally in time.     

6,7‐Dimethoxy‐Quinazolin‐4‐yl‐Amino‐Nicotinamide Derivatives as Potent Inhibitors of VEGF Receptor II

The sprouting of new blood vessels, or angiogenesis, is necessary for any solid tumor to grow large enough to cause life‐threatening disease. Vascular endothelial growth factor (VEGF) is one of the key promoters of tumor‐induced angiogenesis. Inhibition of the VEGF signaling pathway has emerged as one of the most promising new approaches for cancer therapy. A series of 6,7‐dimethoxy‐quinazolin‐4‐yl‐amino‐nicotinamides were synthesized and evaluated as antagonists of VEGF receptor II (VEGFR‐2). Many compounds display VEGFR‐2 inhibitory activity, and compound 7a was found to be a potent inhibitor of VEGFR‐2 in an homogeneous time‐resolved fluorescence enzymatic assay with an IC₅₀ as low as 48 nM (comparable activity to ZD‐6474).     

A bioreducible polypeptide for efficient gene transfection both in vitro and in vivo

A disulfide bond containing polypeptide,PolyK 6-R 8,was designed and prepared by oxidative polymerization between terminal cysteinyl thiol groups of CHK 6 HC and CR 8 C.The molar ratio between CHK 6 HC and CR 8 C within obtained PolyK 6-R 8 was 9:1,and PolyK 6-R 8 could combine DNA compactly when weight ratio reached 5.Through in vitro investigation,it was found that PolyK 6-R 8 was an efficient gene vector with low cytotoxicity for delivering DNA in both COS-7 and HeLa cells.Cellular uptake of DNA mediated by PolyK 6-R 8 /DNA complexes was promoted after incubation for 4 h.Moreover,by examining the histological sections of hindlimb ischemia rats through immunohistochemistry,PolyK 6 R 8 /VEGF complexes were proved to be effective in both VEGF protein expression and succeeding vessel formation.The results indicated that polypeptide-based PolyK 6-R 8 is a promising gene vector for the limb ischemia treatment.     

Efficient total synthesis of bastadin 6, an anti-angiogenic brominated tyrosine-derived metabolite from marine sponge

An efficient total synthesis of bastadin 6 (1), a cyclic tetramer of brominated tyrosine derivatives from the marine sponge, Ianthella basta, with selective anti-angiogenic activity, was accomplished. We developed a novel Ce(IV)-mediated oxidative coupling reaction of 2,6-dibromophenols to give the diaryl ether derivatives, the characteristic segment of 1. Condensation of two segments and subsequent intramolecular macrocyclization gave bastadin 6 (1) in nine steps, 26% overall yield.