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Treatment options for adenoid cystic carcinoma (ACC) of the salivary gland, a slowly growing tumor with propensity for neuroinvasion and late recurrence, are limited to surgery and radiotherapy. Based on expression analysis performed on clinical specimens of salivary cancers, we identified in ACC expression of the neurotrophin-3 receptor TrkC/NTRK3, neural crest marker SOX10, and other neurologic genes. Here, we characterize TrkC as a novel ACC marker, which was highly expressed in 17 out of 18 ACC primary-tumor specimens, but not in mucoepidermoid salivary carcinomas or head and neck squamous cell carcinoma. Expression of the TrkC ligand NT-3 and Tyr-phosphorylation of TrkC detected in our study suggested the existence of an autocrine signaling loop in ACC with potential therapeutic significance. NT-3 stimulation of U2OS cells with ectopic TrkC expression triggered TrkC phosphorylation and resulted in Ras, Erk 1/2 and Akt activation, as well as VEGFR1 phosphorylation. Without NT-3, TrkC remained unphosphorylated, stimulated accumulation of phospho-p53 and had opposite effects on p-Akt and p-Erk 1/2. NT-3 promoted motility, migration, invasion, soft-agar colony growth and cytoskeleton restructuring in TrkC-expressing U2OS cells. Immunohistochemical analysis demonstrated that TrkC-positive ACC specimens also show high expression of Bcl2, a Trk target regulated via Erk 1/2, in agreement with activation of the TrkC pathway in real tumors. In normal salivary gland tissue, both TrkC and Bcl2 were expressed in myoepithelial cells, suggesting a principal role for this cell lineage in the ACC origin and progression. Sub-micromolar concentrations of a novel potent Trk inhibitor AZD7451 completely blocked TrkC activation and associated tumorigenic behaviors. Pre-clinical studies on ACC tumors engrafted in mice showed efficacy and low toxicity of AZD7451, validating our in vitro data and stimulating more research into its clinical application. In summary, we describe in ACC a previously unrecognized pro-survival neurotrophin signaling pathway and link it with cancer progression.

The approach for the determination of antioxidants of various hydrophilicity using the complex of the iron(III) with bipyridine as a model oxidizing agent and chronoamperometric recording of the analytical signal is proposed. The choice of the oxidant is determined by its solubility in aqueous, organic and aqueous-organic media. The conditions for recording chronoamperograms are selected: the medium is the acetonitrile-acetate buffer solution (pH 3.6) (9 : 1), the electrolyte is the LiClO4, the potential is E = 1.25 V, the current registration time is 80 s. Antioxidants soluble in organic and aqueous-organic media are studied: α-tocopherol, quercetin, catechin, and caffeic acid. The analytical ranges are (0.5−4) × 10 –4 M. The antioxidant capacity ( AOC ) of ethanol extracts from medicinal plant materials is determined. A high correlation is observed between the AOC values obtained by the chronoamperometric and the spectrophotometric approaches, but only for samples whose intrinsic colors do not contribute to the absorbance of the Fe(II)-bipyridine complex. The application of the proposed approach and the potentiometric method using the K 3 [Fe(CN) 6 ]/K 4 [Fe(CN) 6 ] system showed that the values obtained by the potentiometric approach are significantly lower for most of the studied infusions. Thus, it is advisable to analyze multicomponent objects, containing substances of different hydrophilicity, using approaches with oxidizing agents of different solubilities, such as the Fe(III)-bipyridine complex.

The habituation/cross-habituation test (HaXha) is a spontaneous odor discrimination task that has been used for many decades to evaluate olfactory function in animals. Animals are presented repeatedly with the same odorant after which a new odorant is introduced. The time the animal explores the odor object is measured. An animal is considered to cross-habituate during the novel stimulus trial when the exploration time is higher than the prior trial and indicates the degree of olfactory patency. On the other hand, habituation across the repeated trials involves decreased exploration time and is related to memory patency, especially at long intervals. Classically exploration is timed using a stopwatch when the animal is within 2 cm of the object and aimed toward it. These criteria are intuitive, but it is unclear how they relate to olfactory exploration, that is, sniffing. We used video tracking combined with plethysmography to improve accuracy, avoid observer bias, and propose more robust criteria for exploratory scoring when sniff measures are not available. We also demonstrate that sniff rate combined with proximity is the most direct measure of odorant exploration and provide a robust and sensitive criterion.

Sodium salt of 3-nitro-4-hydroxy-7-methylthio-4H-[1,2,4]triazolo[5,1- c ][1,2,4]triazinide mono-hydrate (compound ( 1 )) is one of promising compounds exhibited potential antiviral activity against the Coxsackie B3 virus. Using cyclic voltammetry, it was found that the electrochemical activity of compound 1 on a glassy carbon electrode in a Britton–Robbinson buffer solution ( BRB ) is due to the electroreduction of the nitro group. A method for determining compound 1 using direct cathodic square-wave voltammetry is developed. The linearity range of the calibration curve using the developed method in a BRB solution (pH 2.0 ± 0.1) is 10–300 mg/L ( R 2 = 0.999) with the limits of detection and determination being 1.27 and 4.11 mg/L, respectively.

We assessed the effect of the matrix and the studied antioxidants on the results of determining antioxidant capacity by a potentiometric method. An approach is proposed on an example of a hexacyanoferrate redox system, which takes into account the impact of these factors on the establishment of an equilibrium potential in the system with reducing any result distortion. The procedure involves introducing a series of additions of the oxidized component of the redox system after its interaction with a test sample. The approach results in constructing a calibration graph against the background of the sample matrix after the completion of the reaction of the antioxidant with an oxidant with determining the value of the prelogarithmic coefficient under the experimental conditions. The procedure was tested in the determination of individual antioxidants and in the analysis of samples of complex composition (extracts of plant raw materials) using both the redox system and its oxidized component.

DEC1/STRA13 is a bHLH type transcriptional regulator involved with immune regulation, hypoxia response and carcinogenesis. We recently demonstrated that STRA13 interacts with STAT3 in the transcriptional activation of STAT-dependent promoters. Here, we pursue STRA13 involvement in the JAK/STAT pathway by studying its role in STAT1 expression. First, we showed that VHL deficiency or HIF-1 activation resulted in the repression of endogenous STAT1 mediated by STRA13. We then characterized the STAT1 proximal promoter to assess its response to STRA13 by transient coexpression in a luciferase reporter assay. Using sequential truncation and site-directed mutagenesis of the STAT1 promoter with STRA13 deletion constructs, we showed that the STRA13 C-terminal trans -activation domain, which is known to bind HDAC1, mostly determines the repressive activity. Involvement of HDAC activity in STAT1 regulation was validated by TSA inhibition and chromatin immunoprecipitation (ChIP) assay. Thus, we demonstrate that STRA13-mediated repression of STAT1 transcription utilizes an HDAC1-dependent mechanism. Furthermore, we show that targets of unphosphorylated STAT1, such as antigen presenting genes and CASP1, are also repressed by hypoxia possibly through the same STRA13-mediated mechanism. Thus, the newly discovered link between HIF-1 and STAT1 reveals a previously unknown role of STRA13 in hypoxia and carcinogenesis.

6-Nitro-7-(4'-nitrophenyl)-5-ethyl-4,7-dihydropyrazolo[1,5- a ]pyrimidine-3-carboxylate (1) is one of promising antitumor compounds exhibiting biological activity against type 2 casein kinase, which is currently considered as a promising target in chemotherapy. Using the method of cyclic voltammetry, it was shown that the electrochemical activity of compound 1 in a mixed solution of Tris-HCl and ethanol (1 : 1) at pH 7.5 on a glassy-carbon electrode is due to the electrochemical reduction of the nitro group conjugated with the phenyl ring. A method was developed for the determination of compound 1 by direct cathodic square-wave voltammetry. The linearity region of the corresponding calibration curve obtained in a solution of a mixture of Tris-HCl and ethanol (1 : 1) at pH 7.5 is 5–500 mg/L ( R 2 = 0.988), the limit of detection is 0.8 mg/L, the limit of quantification is 2.4 mg/L. The accuracy of the developed procedure is close to 100%, the relative standard deviation is 1.4%.

The sodium salt of 7-ethylthio-3-nitro-1,2,4-triazolo[5,1- c ]-1,2,4-triazin-4-one dihydrate ( 1 ) is one of promising antiviral compounds that have shown a pronounced biological activity against influenza virus subtype H5N1, West Nile, and SARS (severe acute respiratory syndrome). Using cyclic voltammetry, it was shown that the electrochemical activity of compound 1 in a Britton–Robinson buffer solution (BRB) of pH 2.0 on a glassy carbon electrode is due to the electrochemical reduction of the nitro group conjugated with the heterocyclic system. A method was developed for the determination of compound 1 by direct cathodic square-wave voltammetry. The linearity region of the calibration curve in a BRB solution of pH 7.0 is 10–300 mg/L ( R 2 = 0.999), the limit of detection is 1.5 mg/L, and the limit of quantification is 4.5 mg/L. The accuracy of the developed procedure is close to 100%, the relative standard deviation is 3.6%.

The preparation and study of the biological properties of the pVAKS-GPVM DNA immunogen containing a gene encoding Marburgvirus glycoprotein are described. The specificity of blood serum antibodies of guinea pigs immunized with DNA immunogen was analyzed by ELISA. Inactivated viral preparation, recombinant glycoprotein (GP) obtained in the prokaryotic system and virus-like particles based on the recombinant vesicular stomatitis virus exhibiting Marburgvirus GP were used as the antigens. The neutralizing activity of antibodies of immunized animals was tested in vitro using a pseudovirus system. It was demonstrated that the developed immunogen administered to guinea pigs induced the production of specific antibodies that neutralize virus-like particles and Marburgvirus in cultured Vero cells.

Mechanism of radiosensitivity of normal tissues, a key factor in determining the toxic side effects of cancer radiotherapy, is not fully understood. We recently demonstrated that deficiency of mitochondrial tumor suppressor, Fus1, increases radiosensitivity at the organismal, tissue and cellular levels. Since Fus1-deficient mice and cells exhibit high levels of oxidative stress, we hypothesized that dysregulation of cellular antioxidant defenses may contribute to the increased radiosensitivity. To address this potential mechanism, we treated the Fus1 KO mice with an inhibitor of pathogenic oxidative reactions, pyridoxamine (PM). Treatment with PM ameliorated IR-induced damage to GI epithelium of Fus1 KO mice and significantly increased the survival of irradiated mice. In cultured Fus1 KO epithelial cells, IR-induced oxidative stress was enhanced because of inadequate cellular antioxidant defenses, such as low levels and/or activities of cytochrome C, Sod 2 and STAT3. This resulted in dysregulation of IR-induced DNA-damage response and DNA synthesis. Treatment of Fus1 KO cells with PM or Sod 2 mimetic Tempol normalized the oxidative stress response, thus compensating to a significant degree for inadequate antioxidant response. Our findings using Fus1 KO radiosensitive mice suggest that radiosensitivity is mediated via dysregulation of antioxidant response and defective redox homeostasis.