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Palecek E.,Academy of Sciences of the Czech Republic | Tkac J.,Slovak Academy of Sciences | Bartosik M.,Masaryk Memorial Cancer Institute | Bertok T.,Slovak Academy of Sciences | And 2 more authors.
Chemical Reviews | Year: 2015

Significant progress has been done in the electrochemical (EC) analysis of practically all proteins, based on the electroactivity of amino acid (aa) residues in proteins. From a transducer point of view, it can be anticipated that many different ways of how nanomaterials can be integrated into the EC detection platform of detection will be developed. This can be done by direct modification of electroactive surfaces by nanomaterials or by advanced patterning protocol and by using nanomaterials as amplification tags, helping to produce lectin biosensors/biochips working in an ultrasensitive and selective way. Further, it can be anticipated that EC-based biosensors will compete in a future with instrumental techniques or lectin microarrays only if such devices are integrated into a biochip format offering multiplexed glycan measurements. Moreover, it has been shown that some glucosamine-containing poly- and oligosaccharides are electroactive under conditions close to physiological and that most polysaccharides and glycans can be transformed into electrochemically active substances by a simple chemical modification. Usually 4-10 biomarkers have to be detected to obtain good specificity and selectivity of detection. EC detection appears particularly advantageous for the preparation of low-density chips with this number of biomarkers. Source


Pastorek J.,Slovak Academy of Sciences | Pastorekova S.,Slovak Academy of Sciences | Pastorekova S.,Masaryk Memorial Cancer Institute
Seminars in Cancer Biology | Year: 2015

The tumor microenvironment includes a complicated network of physiological gradients contributing to plasticity of tumor cells and heterogeneity of tumor tissue. Hypoxia is a key component generating intratumoral oxygen gradients, which affect the cellular expression program and lead to therapy resistance and increased metastatic propensity of weakly oxygenated cell subpopulations. One of the adaptive responses of tumor cells to hypoxia involves the increased expression and functional activation of carbonic anhydrase IX (CA IX), a cancer-related cell surface enzyme catalyzing the reversible conversion of carbon dioxide to bicarbonate ion and proton. Via its catalytic activity, CA IX participates in regulation of intracellular and extracellular pH perturbations that result from hypoxia-induced changes in cellular metabolism producing excess of acid. Through the ability to regulate pH, CA IX also facilitates cell migration and invasion. In addition, CA IX has non-catalytic function in cell adhesion and spreading. Thus, CA IX endows tumor cells with survival advantages in hypoxia/acidosis and confers an increased ability to migrate, invade and metastasize. Accordingly, CA IX is expressed in a broad range of tumors, where it is associated with prognosis and therapy outcome. Its expression pattern and functional implications in tumor biology make CA IX a promising therapeutic target, which can be hit either by immunotherapy with monoclonal antibodies or with compounds inhibiting its enzyme activity. The first strategy has already reached the clinical trials, whereas the second one is still in preclinical testing. Both strategies indicate that CA IX can become a clinically useful anticancer target, but urge further efforts toward better selection of patients for immunotherapy and deeper understanding of tumor types, clinical situations and synthetic lethality interactions with other treatment approaches. © 2014. Source


Fraser J.A.,University of Edinburgh | Vojtesek B.,Masaryk Memorial Cancer Institute | Hupp T.R.,University of Edinburgh
Journal of Biological Chemistry | Year: 2010

p53 is a thermodynamically unstable protein containing a conformationally flexible multiprotein docking site within the DNA-binding domain. A combinatorial peptide chip used to identify the novel kinase consensus site RXSΦ(K/D) led to the discovery of a homologous phosphorylation site in the S10 β-strand of p53 at Ser269. Overlapping peptide libraries confirmed that Ser269 was a phosphoacceptor site in vitro, and immunochemical approaches evaluated whether p53 is phosphorylated in vivo at Ser269. Mutation or phosphorylation of p53 at Ser269 attenuates binding of the p53-specific monoclonal antibody DO-12, identifying an assay for measuring Ser269 phosphorylation of p53 in vivo. The mAb DO-12 epitope of p53 is masked via phosphorylation in a range of human tumor cells with WT p53 status, as defined by increased mAb DO-12 binding to endogenous p53 after phosphatase treatment. Phospho-Ser269-specific monoclonal antibodies were generated and used to demonstrate that p53 phosphorylation is induced at Ser269 after irradiation with kinetics similar to those of p53 protein induction. Phosphomimetic mutation at Ser 269 inactivated the transcription activation function and clonogenic suppressor activity of p53. These data suggest that the dynamic equilibrium between native and unfolded states of WT p53 can be modulated by phosphorylation of the conformationally flexible multiprotein binding site in the p53 DNA-binding domain. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc. Source


Temporal arteries are typically below detectable levels of PET scanners, which repeatedly showed to be limiting in finding increased F-FDG accumulation even in histologically proven cases of giant cell arteritis. In 2010, Gaemperli and coworkers showed metabolic active inflammation in temporal arteries in an experimental study using PET with [C]-PK11195 combined with CT angiography. Herein, we present the case where an increased accumulation of routinely used tracer F-FDG can be identified directly in temporal and occipital arteries and even in smaller branches using a common hybrid PET/CT scanner if a brain acquisition protocol is applied. Source


Bartosik M.,Masaryk Memorial Cancer Institute
Chemicke Listy | Year: 2014

Electrochemistry could be a valuable tool in nucleic acids research by offering relatively inexpensive instrumentation, short assay times and high sensitivity. Interesting applications can be found in the literature, including detection of oncogenes or tumor suppressor genes, analysis of point mutations in DNA, or determination of viruses and bacteria. Moreover, new strategies are being developed for detection of microRNAs, or for analysis of DNA methylation, both important in carcinogenesis. These novel approaches usually involve the use of various electroactive labels, nanomaterials, enzymes or magnetic particles, rendering them more sensitive, selective and efficient. In addition, electrochemistry was applied also in studies of DNA damage and interactions with other molecules. Numerous chemicals damage DNA in such a way that they alters electrochemical properties of DNA itself, such as oxygen radicals, aromatic hydrocarbons, alkylating agents and pesticides. DNA-modified electrodes could thus serve as simple biosensors for detection of environmental pollutants as well as potential antitumor drugs. Source

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