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Rostov-na-Donu, Russia

Tabernero J.,Autonomous University of Barcelona | Garcia-Carbonero R.,University of Seville | Cassidy J.,Beatson Laboratories | Cassidy J.,Roche Holding AG | And 17 more authors.
Clinical Cancer Research | Year: 2013

Purpose: This randomized, double-blind, placebo-controlled, phase IIb study evaluated adding sorafenib to first-line modified FOLFOX6 (mFOLFOX6) for metastatic colorectal cancer (mCRC). Experimental Design: Patients were randomized to sorafenib (400 mg b.i.d.) or placebo, combined with mFOLFOX6 (oxaliplatin 85 mg/m2; levo-leucovorin 200 mg/m2; fluorouracil 400 mg/m2 bolus and 2400 mg/m2 continuous infusion) every 14 days. Primary endpoint was progression-free survival (PFS). Target sample was 120 events in 180 patients for >85% power (two-sided α = 0.20) to detect an HR = 0.65. Results: Of 198 patients randomized, median PFS for sorafenib plus mFOLFOX6 was 9.1 months versus 8.7 months for placebo plus mFOLFOX6 (HR = 0.88; 95% CI, 0.64-1.23; P = 0.46). There was no difference between treatment arms for overall survival. Subgroup analyses of PFS and overall survival showed no difference between treatment arms by KRAS or BRAF status (mutant and wild type). The most common grade 3/4 adverse events in the sorafenib and placebo arms were neutropenia (48% vs. 22%), peripheral neuropathy (16% vs. 21%), and grade 3 hand-foot skin reaction (20% vs. 0%). Treatment discontinuation because of adverse events was 9% and 6%, respectively. Generally, dose intensity (duration and cumulative doses) was lower in the sorafenib arm than in the placebo arm. Conclusion: This study did not detect a PFS benefit with the addition of sorafenib to first-line mFOLFOX6 for mCRC. KRAS and BRAF status did not seem to impact treatment outcomes but the subgroups were small. These results do not support further development of sorafenib in combination with mFOLFOX6 in molecularly unselected patients with mCRC. ©2013 AACR.

Borodulin V.B.,Saratov State Medical University | Goroshinskaya I.A.,Rostov Research Institute of Oncology | Kachesova P.S.,Rostov Research Institute of Oncology | Babushkina I.V.,Saratov Research and Development Institute of Traumatic and Orthopedic Surgery | And 5 more authors.
Nanotechnologies in Russia | Year: 2015

The biological effect of iron nanoparticles with a size of 20–40nm obtained by the plasmochemical method are studied. An antibacterial effect on antibiotic resistant strains of Pseudomonas aeruginosa and Staphylococcus aureus is found at concentrations of iron nanoparticles in a range of 0.1–10 mg/mL. The toxic effect of iron nanoparticles administered this way is revealed in male mice, which is manifested in a change in biochemical parameters of carbohydrate, lipid, and protein metabolisms. © 2015, Pleiades Publishing, Ltd.

Zhukova G.,Rostov Research Institute of Oncology | Shikhliarova A.,Rostov Research Institute of Oncology | Petrosyan V.,Scientific and Production Firm TELEMAK | Gudzkova T.,Rostov Research Institute of Oncology | And 3 more authors.
European Journal of Cancer, Supplement | Year: 2015

Background: It has previously been shown that additional local electromagnetic impact on the tumor en-hances the systemic antitumor effect of low-intensity electromagnetic radiation (EMR) used in the activation therapy regimes designed by Garkavi L.H. et al. (1990-2008). At the same time the question of the influence of weak EMR, applied to the peritumoral area, on the tumor development has not been studied. The aim of the study was to investigate the changes in the tumor caused by low-intensity microwave electromagnetic radiation of bioeffective frequency that acted on the head and peritumoral zone. Materials and methods: The effects of resonance radiation (RR) with frequency corresponding to that of one of the water-containing medium radiations - 1 GHz ("SPE-effect") - were studied on 53 adult male outbred white rats with transplantable sarcoma 45. Special anticancer agents were not used. The power flux density of RR was less than 1 μW/cm2, surface area of the emitter - 4 cm2, 3-10 min. exposure depending on algorithms of the activation therapy. RR exposure in different groups of animals was localized to the head only, or to the peri-tumoral area only, or successively to the head and peritumoral area ("double" exposure). The course lasted for 4 weeks. The exposure effect was assessed according to the dynamics of the tumor size and results of the light and electron microscopy analysis of tumor changes (JEOL JEM-1011, Japan). Results: The effect of RR in different groups of animals depended on the exposure localization. Central systemic exposure was decisive. The group receiving RR localized to the head showed regression of the tumor or inhibition of its growth in 60% of animals - almost complete tumor regression in 10% and tumor growth inhibition by 70% in the rest cases. RR to the peritumoral area did not show significant influence on the tumor development, while it increased antitumor effect of the central exposure (p < 0.01-0.05). Antitumor effect was registered in 77% of the animals receiving the "double" RR exposure: 30% - morphologically verified complete regression, 24% - partial regression (tumor shrinkage by 2-2.5 times) and tumor growth inhibition by 40% was detected in 23% of animals. Regressing tumor, unlike sarcoma 45 with an active growth, was characterized by significant thickening of the capsule (by 7 times, p < 0.01) and increased intensity of lymphoplasmacytic infiltration (p < 0.01). Immune system cells were present in the capsule, subcapsular zone and as leukocytic barrier in peritumoral area of the conjunctive tissue of up to 170 μm width. Different numbers of lymphocytes and plasma cells were noted in tumor cells. Macrophages were found. Migrating lymphocytes were often noted in the vessels among tumor cells. Electron microscopy showed multiple contacts of lymphocytes with the surface of tumor cells through cytoplasmic excrescences. Such lymphocytes had distinct signs of activation. Simultaneous contacts of lymphocytes and macrophages among themselves and with tumor cells were found. Analysis of ultrastructural characteristics of cells in regressing tumors and detection of collagen in intercellular spaces during histochemical examination of tumor tissues showed the increase in the degree of differentiation of some sarcoma 45 cells. Conclusion: Possibility to increase the systemic antitumor effect of the low-intensity microwave radiation with an additional weak exposure on the peritumoral area was demonstrated for the first time. Damaging effect of RR on tumor was mediated by the changes in composition and activity of elements of the tumor's immune microenvironment and by the increase in the degree of differentiation of some tumor cells, probably under the influence of bioactive factors of leukocytic origin. © 2015.

Mikhailov N.Y.,Russian Academy of Sciences | Garkavi L.H.,Rostov Research Institute of Oncology | Mashchenko N.M.,Rostov Research Institute of Oncology | Zhukova G.V.,Rostov Research Institute of Oncology
Biophysics | Year: 2012

High-frequency oscillations in a pulse wave signal in the range of 1-50 Hz and their relation to differential blood count leucocytes have been investigated. It is shown that the correlation coefficients grow in the frequency range of 1-12.5 Hz between high-frequency oscillations in a pulse wave signal and stab neutrophils, monocytes and segmented granulocytes. The procedure of smoothing the coefficients of harmonic variation has been proposed. © 2012 Pleiades Publishing, Ltd.

Uzdensky A.,Southern Federal University | Demyanenko S.,Southern Federal University | Bibov M.,Southern Federal University | Sharifulina S.,Southern Federal University | And 3 more authors.
Tumor Biology | Year: 2014

Epigenetic processes play a critical role in melanoma development. However, little is known about proteins responsible for epigenetic transformations in melanoma cells. The processes in the peritumoral skin within the excision margin are almost unstudied. We studied the changes in expression of 112 proteins involved in epigenetic regulation of gene expression in the human cutaneous melanoma and its peritumoral zone using “The Proteomic Antibody Microarrays” (GRAA2, Sigma-Aldrich). Dimethylated histone H3 at lysines 4 and 9 as well as proteins involved in the regulation of transcription (histone deacetylases HDAC-1 and HDAC-11, DNA methyl-binding protein Kaiso), cell cycle control (protein kinases Aurora-В and PKR, chromosome protein CENP-E, and phosphorylated and acetylated histone H3), DNA repair (phosphorylated histone H2AX), and nuclear protein import (importins α3 and α5/7) were over-expressed in the melanoma tissue as compared with normal skin. At the same time, HDAC-10 and proliferating cell nuclear antigen PCNA were downregulated. In the peritumoral skin, at the excision margin (1–2 cm from the melanoma edge), we observed similar changes in expression of these proteins and, additionally, over-expression of arginine methyltransferases PRMT5 and NAD-dependent histone deacetylase SIR2. Histone methyltransferase G9a and metastasis-associated protein 2 were downregulated. Therefore, epigenetic regulation that requires histone modifications and expression of some regulatory proteins is of importance for melanoma development and propagation. The observed changes in the peritumoral skin may indicate the epigenetic pre-tuning in this zone possibly involved in malignant transformation. These results can be potentially useful for melanoma diagnostics and targeted therapy. © 2014, International Society of Oncology and BioMarkers (ISOBM).

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