Hybrid-integrated devices for mimicking malignant brain tumors ("tumor-on-a-chip") for development of targeted drug delivery and personalized therapy approaches.

Acute and requiring attention problem of oncotheranostics is a necessity for the urgent development of operative and precise diagnostics methods, followed by efficient therapy, to significantly reduce disability and mortality of citizens. A perspective way to achieve efficient personalized treatment is to use methods for operative evaluation of the individual drug load, properties of specific tumors and the effectiveness of selected therapy, and other actual features of pathology. Among the vast diversity of tumor types-brain tumors are the most invasive and malignant in humans with poor survival after diagnosis.

Extracellular GAPDH Promotes Alzheimer Disease Progression by Enhancing Amyloid-β Aggregation and Cytotoxicity.

Neuronal cell death at late stages of Alzheimer's disease (AD) causes the release of cytosolic proteins. One of the most abundant such proteins, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), forms stable aggregates with extracellular amyloid-β (Aβ). We detect these aggregates in cerebrospinal fluid (CSF) from AD patients at levels directly proportional to the progressive stages of AD.

Recent Progress in Animal Studies of the Skin- and Bone-integrated Pylon With Deep Porosity for Bone-Anchored Limb Prosthetics With and Without Neural Interface.

Introduction: The three major unresolved problems in bone-anchored limb prosthetics are stable, infection-free integration of skin with a percutaneous bone implant, robust skeletal fixation between the implant and host bone, and a secure interface of sensory nerves and muscles with a prosthesis for the intuitive bidirectional prosthetic control. Here we review results of our completed work and report on recent progress.

Materials And Methods: Eight female adult cats received skin- and bone-integrated pylon (SBIP) and eight male adult cats received SBIP-peripheral neural interface (PNI) pylon into the right distal tibia.

Urethroplasty with a bilayered poly-D,L-lactide-co-ε-caprolactone scaffold seeded with allogenic mesenchymal stem cells.

Reconstructive surgery for urethral defects employing tissue-engineered scaffolds represents an alternative treatment for urethroplasty. The aim of this study was to compare the therapeutic efficacy of the bilayer poly-D,L-lactide/poly-ε-caprolactone (PL-PC) scaffold seeded with allogenic mesenchymal stem cells (MSCs) for urethra reconstruction in a rabbit model with conventional urethroplasty employing an autologous buccal mucosa graft (BG). The inner layer of the scaffold based on poly-D,L-lactic acid (PL) was seeded with MSCs, while the outer layer, prepared from poly-ε-caprolactone, protected the surrounding tissues from urine.

Enhanced Osseointegrative Properties of Ultra-Fine-Grained Titanium Implants Modified by Chemical Etching and Atomic Layer Deposition.

An integrated approach combining severe plastic deformation (SPD), chemical etching (CE), and atomic layer deposition (ALD) was used to produce titanium implants with enhanced osseointegration. The relationship between morphology, topography, surface composition, and bioactivity of ultra-fine-grained (UFG) titanium modified by CE and ALD was studied in detail. The topography and morphology have been studied by means of atomic force microscopy, scanning electron microscopy, and the spectral ellipsometry.

Improved osseointegration properties of hierarchical microtopographic/nanotopographic coatings fabricated on titanium implants.

Background: Titanium (Ti) implants are extensively used in reconstructive surgery and orthopedics. However, the intrinsic inertness of untreated Ti implants usually results in insufficient osseointegration. In order to improve the osteoconductivity properties of the implants, they are coated with hierarchical microtopographic/nanotopographic coatings employing the method of molecular layering of atomic layer deposition (ML-ALD).

Evaluation of the temporary effect of physical vapor deposition silver coating on resistance to infection in transdermal skin and bone integrated pylon with deep porosity.

Periprosthetic infection via skin-implant interface is a leading cause of failures and revisions in direct skeletal attachment of limb prostheses. Implants with deep porosity fabricated with skin and bone integrated pylons (SBIP) technology allow for skin ingrowth through the implant's structure creating natural barrier against infection. However, until the skin cells remodel in all pores of the implant, additional care is required to prevent from entering bacteria to the still nonoccupied pores.

Application of the allogenic mesenchymal stem cells in the therapy of the bladder tuberculosis.

Urogenital tuberculosis (TB) often leads to contraction of the bladder, a reduction of the urinary reservoir capacity, and, in the latest stage, to real microcystitis up to full obliteration. Bladder TB Stage 4 is unsuitable for conservative therapy, and cystectomy with subsequent enteroplasty is indicated. In this study, using a model of bladder TB in New Zealand rabbits, the therapeutic efficacy of the interstitial injection of autologous bone-derived mesenchymal stem cells (MSCs) combined with standard anti-TB treatment in the restoration of the bladder function was demonstrated.

Experimental bladder regeneration using a poly-l-lactide/silk fibroin scaffold seeded with nanoparticle-labeled allogenic bone marrow stromal cells.

In the present study, a poly-l-lactide/silk fibroin (PL-SF) bilayer scaffold seeded with allogenic bone marrow stromal cells (BMSCs) was investigated as a potential approach for bladder tissue engineering in a model of partial bladder wall cystectomy in rabbits. The inner porous layer of the scaffold produced from silk fibroin was designed to promote cell proliferation and the outer layer produced from poly-l-lactic acid to serve as a waterproof barrier. To compare the feasibility and efficacy of BMSC application in the reconstruction of bladder defects, 12 adult male rabbits were divided into experimental and control groups (six animals each) that received a scaffold seeded with BMSCs or an acellular one, respectively.

The recent development of nanoparticles for brain tumor targeting delivery.

Superparamagnetic iron oxide nanoparticles (SPIONs) have attracted a lot of interest due to their widespread diagnostic and therapeutic applications in neuro-oncology. Functinalization of the particles surface with targeting molecules that recognize tumor receptors might be exploited for the specific brain tumor targeting. Furthermore, multifunctional and/or theranostic SPIONs can be used for simultaneous imaging of cancer and anti-tumor drug delivery.

Properties of substances inhibiting aggregation of oxidized GAPDH: Data on the interaction with the enzyme and the impact on its intracellular content.

This data is related to our paper "Small molecules preventing GAPDH aggregation are therapeutically applicable in cell and rat models of oxidative stress" (Lazarev et al. [1]) where we explore therapeutic properties of small molecules preventing GAPDH aggregation in cell and rat models of oxidative stress. The present article demonstrates a few of additional properties of the chemicals shown to block GAPDH aggregation such as calculated site for targeting the enzyme, effects on GAPDH glycolytic activity, influence on GAPDH intracellular level and anti-aggregate activity of pure polyglutamine exemplifying a denatured protein.

Knock-down of Hdj2/DNAJA1 co-chaperone results in an unexpected burst of tumorigenicity of C6 glioblastoma cells.

The chaperone system based on Hsp70 and proteins of the DnaJ family is known to protect tumor cells from a variety of cytotoxic factors, including anti-tumor therapy. To analyze whether this also functions in a highly malignant brain tumor, we knocked down the expression of Hsp70 (HSPA1A) and its two most abundant co-chaperones, Hdj1 (DNAJB1) and Hdj2 (DNAJA1) in a C6 rat glioblastoma cell line. As expected, tumor depletion of Hsp70 caused a substantial reduction in its growth rate and increased the survival of tumor-bearing animals, whereas the reduction of Hdj1 expression had no effect.

Small molecules preventing GAPDH aggregation are therapeutically applicable in cell and rat models of oxidative stress.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is one of the most abundant targets of the oxidative stress. Oxidation of the enzyme causes its inactivation and the formation of intermolecular disulfide bonds, and leads to the accumulation of GAPDH aggregates and ultimately to cell death. The aim of this work was to reveal the ability of chemicals to break the described above pathologic linkage by inhibiting GAPDH aggregation.

Detection of experimental myocardium infarction in rats by MRI using heat shock protein 70 conjugated superparamagnetic iron oxide nanoparticle.

Unlabelled: Superparamagnetic iron-oxide based contrast agents can provide important diagnostic information regarding the assessment of cardiac inflammatory diseases. The aim of the study was to analyze whether nanoparticles conjugated to recombinant 70-kDa heat shock protein (Hsp70-SPION) can be applied for the detection of acute myocardium infarct by MRI. Cellular experiments demonstrated increased CD40-mediated uptake of Hsp70-SPIONs in comparison to non-conjugated SPIONs.

Phloretin increases the anti-tumor efficacy of intratumorally delivered heat-shock protein 70 kDa (HSP70) in a murine model of melanoma.

Recombinant HSP70 chaperone exerts a profound anticancer effect when administered intratumorally. This action is based on the ability of HSP70 to penetrate tumor cells and extract its endogenous homolog. To enhance the efficacy of HSP70 cycling, we employed phloretin, a flavonoid that enhances the pore-forming activity of the chaperone on artificial membranes.

Ionizing radiation improves glioma-specific targeting of superparamagnetic iron oxide nanoparticles conjugated with cmHsp70.1 monoclonal antibodies (SPION-cmHsp70.1).

The stress-inducible 72 kDa heat shock protein Hsp70 is known to be expressed on the membrane of highly aggressive tumor cells including high-grade gliomas, but not on the corresponding normal cells. Membrane Hsp70 (mHsp70) is rapidly internalized into tumor cells and thus targeting of mHsp70 might provide a promising strategy for theranostics. Superparamagnetic iron oxide nanoparticles (SPIONs) are contrast negative agents that are used for the detection of tumors with MRI.

70-kDa heat shock protein coated magnetic nanocarriers as a nanovaccine for induction of anti-tumor immune response in experimental glioma.

Nanovaccines based on superparamagnetic iron oxide nanoparticles (SPIONs) provide a novel approach to induce the humoral and cell-based immune system to fight cancer. Herein, we increased the immunostimulatory capacity of SPIONs by coating them with recombinant heat shock protein 70 (Hsp70) which is known to chaperone antigenic peptides. After binding, Hsp70-SPIONs deliver immunogenic peptides from tumor lysates to dendritiс cells (DCs) and thus stimulate a tumor-specific, CD8+ cytotoxic T cell response.

Glu-Trp-ONa or its acylated analogue (R-Glu-Trp-ONa) administration enhances the wound healing in the model of chronic skin wounds in rabbits.

The management of chronic skin wounds represents a major therapeutic challenge. The synthesized dipeptide (Glu-Trp-ONa) and its acylated analogue (R-Glu-Trp-ONa) were assessed in the model of nonhealing dermal wounds in rabbits in relation to their healing properties in wound closure. Following wound modeling, the rabbits received a course of intraperitoneal injections of Glu-Trp-ONa or R-Glu-Trp-ONa.

Recombinant interleukin-1 receptor antagonist conjugated to superparamagnetic iron oxide nanoparticles for theranostic targeting of experimental glioblastoma.

Cerebral edema commonly accompanies brain tumors and contributes to neurologic symptoms. The role of the interleukin-1 receptor antagonist conjugated to superparamagnetic iron oxide nanoparticles (SPION-IL-1Ra) was assessed to analyze its anti-edemal effect and its possible application as a negative contrast enhancing agent for magnetic resonance imaging (MRI). Rats with intracranial C6 glioma were intravenously administered at various concentrations of IL-1Ra or SPION-IL-1Ra.

Changes of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) in the model of experimental acute hydrocephalus in rabbits.

Background: To study the integrity of white matter, we investigated the correlation between the changes in neuroradiological and morphological parameters in an animal model of acute obstructive hydrocephalus.

Methods: Hydrocephalus was induced in New Zealand rabbits (n = 10) by stereotactic injection of kaolin into the lateral ventricles. Control animals received saline in place of kaolin (n = 10).

Application of the skin and bone integrated pylon with titanium oxide nanotubes and seeded with dermal fibroblasts.

Background: Direct skeletal attachment of limb prostheses is associated with high rate of transcutaneous infection and loosening of the fixture in the medullary canal prompting for careful assessment of various means for enhancing the skin-device and bone-device interface. The skin and bone integrated pylon system constitutes a technological platform for different modifications being evaluated previously.

Objectives: The current study assessed the combination of nano-treatment skin and bone integrated pylon with its pre-seeding with dermal fibroblasts.

Pilot study of intratumoral injection of recombinant heat shock protein 70 in the treatment of malignant brain tumors in children.

Intratumoral injections of recombinant heat shock protein (Hsp)70 were explored for feasibility in patients with brain tumors. Patients aged 4.5-14 years with untreated newly diagnosed tumors (n=12) were enrolled.

Neurotherapeutic activity of the recombinant heat shock protein Hsp70 in a model of focal cerebral ischemia in rats.

Recombinant 70 kDa heat shock protein (Hsp70) is an antiapoptotic protein that has a cell protective activity in stress stimuli and thus could be a useful therapeutic agent in the management of patients with acute ischemic stroke. The neuroprotective and neurotherapeutic activity of recombinant Hsp70 was explored in a model of experimental stroke in rats. Ischemia was produced by the occlusion of the middle cerebral artery for 45 minutes.

Exogenously delivered heat shock protein 70 displaces its endogenous analogue and sensitizes cancer cells to lymphocytes-mediated cytotoxicity.

Hsp70 chaperone is known to stimulate anti-tumour immunity in a variety of cancer models. Here we demonstrated that the addition of purified recombinant Hsp70 to the culture medium facilitated cancer cell cytolysis by lymphocytes. Importantly, exogenous Hsp70 triggered secretion of the intracellular Hsp70 to a cell surface and extracellular milieu, which played a role in cytolysis because down-regulation of the endogenous Hsp70 reduced both its presence at the cell surface and the lymphocyte-mediated cytolysis.