[Xenobiotic toxicity prediction combined with xenobiotic metabolism prediction in the human body]. / Komp'iuternaia otsenka toksichnosti ksenobiotikov s uchetom ikh metabolizma v organizme cheloveka.

The majority of xenobiotics undergo a number of chemical reactions known as biotransformation in human body. The biological activity, toxicity, and other properties of the metabolites may significantly differ from those of the parent compound. Not only xenobiotic itself and its final metabolites produced in large quantities, but the intermediate and final metabolites that are formed in trace quantities, can cause undesirable effects. We have developed a freely available web resource MetaTox (http://www.way2drug.com/mg/) for integral assessment of xenobiotics toxicity taking into account their metabolism in the humans. The generation of the metabolite structures is based on the reaction fragments. The estimates of the probability of the reaction of a certain class and the probability of site of biotransformation are used at the generation of the xenobiotic metabolism pathways. The web resource MetaTox allows researchers to assess the metabolism of compounds in the humans and to obtain assessment of their acute, chronic toxicity, and adverse effects.

[Primary multiple malignant lung tumors. References and a clinical observation].

The problem of primary multiple tumors is relevant to current clinical oncology because of increasing of number of patients with multiple malignant tumors and unsolved issues of treatment. Primary multiple malignant lung tumors is a common oncological situation requires an individualized, differentiated approach to treatment. The results of treatment are associated with the prevalence of the process, stages of tumor development, spare capacity of patients. There is presented clinical example of a patient with metachronous primary multiple malignant tumors of one lung.

[SPECT/CT radiation in treatment of bone metastases of osteosarcoma].

The aim of this study was to demonstrate the diagnostic ca- pabilities to control effects of radiotherapy treatment in patient with osteosarcoma bone metastases by SPECT-CT method. There was conducted SPECT/CT treatment monitoring of the patient with bone metastases of osteosarcoma after external radiotherapy and cyber knife. There were detected changes in the SPECT/CT-pictures of treated bones osteosarcoma metasta- ses. The SPECT/CT has proven as a reliable method of dynam- ic control at radiotherapy. Treatment effect all of these methods was to reduce or to get absent accumulation of bone-tropic radiopharmaceutical labeled with 99mTc-technetium. SPECT/ CT study was a demonstrative method for early determination of pathological metabolism degree in bone metastases of os- teosarcoma. SPECT/CT was an effective method of treatment monitoring of bone metastases after radiotherapy.

[Computer search for molecular mechanisms of ulcerogenic action of nonsteroidal antiinflammatory drugs].

"Peptic ulcers" is the most frequent side effect of non-steroidal anti-inflammatory drugs (NSAIDs). Experimental data indicate that pathogenesis of peptic ulcers cannot be explained only by the inhibition of cyclooxygenases. The knowledge about other molecular mechanisms of action of drugs related with development of peptic ulcers could be useful for design of new safe NSAIDs. However, considerable time and material resources are needed for corresponding experimental research. For simplification of experimental search, we have developed an approach for in silico identification of probable molecular mechanisms of action of drugs related with its side effects. We have created the set of NSAIDs containing 85 substances with data about structures and side effects. The computer program PASS (Prediction of Activity Spectra for Substances) predicting more than 3000 molecular mechanisms of action based on structural formula of substances was used to estimate unknown molecular mechanisms of action for these set of NSAIDs. Statistically significant relationships between predicted molecular mechanisms of action and development of peptic ulcers have been established. We have discovered twenty-six molecular mechanisms of action (two known previously and twenty-four new) which probably related with development of peptic ulcers. By analyzing of Gene Ontology data, signal and metabolic pathways, publications in Medline, we formulated hypotheses about the role of ten molecular mechanisms of action in pathogenesis of peptic ulcer.

[Novel method for activation of the locomotor circuitry in human].

We examine the possibility for activation of the involuntary locomotion of the lower limbs by spinal electromagnetic stimulation (ES). The subject laid on the left side. The legs are supported in a gravity-neutral position by special mounting that to provide horizontal rotation in the hip, knee and ankle. ES (3 Hz and 1.56 Tesla) at the T11,-T12 vertebrae induced involuntary locomotor-like movements in the legs. The latency from the initiation of ES to the first EMG burst compoused 0.68 +/- 1.0 s and it shortened at increasing of the frequency ES from 3 Hz to 20 Hz. Thus, the spinal ES can unduce the activation of the locomotor movements in human.

In silico method for identification of promising anticancer drug targets.

In recent years, the accumulation of the genomics, proteomics, transcriptomics data for topological and functional organization of regulatory networks in a cell has provided the possibility of identifying the potential targets involved in pathological processes and of selecting the most promising targets for future drug development. We propose an approach for anticancer drug target identification, which, using microarray data, allows discrete modelling of regulatory network behaviour. The effect of drugs inhibiting a particular protein or a combination of proteins in a regulatory network is analysed by simulation of a blockade of single nodes or their combinations. The method was applied to the four groups of breast cancer, HER2/neu-positive breast carcinomas, ductal carcinoma, invasive ductal carcinoma and/or a nodal metastasis, and to generalized breast cancer. As a result, some promising specific molecular targets and their combinations were identified. Inhibitors of some identified targets are known as potential drugs for therapy of malignant diseases; for some other targets we identified hits in the commercially available sample databases.

[Effectiveness of treatment of single cerebral metastasis depending on prognostic groups (RPA RTOG)].

Our investigation was aimed at establishing a relationship between single metastases in the brain and a set of prognostic factors. It involved 278 patients treated at the Center in 1983-2003. The whole brain was irradiated in 273 while 159 of them (58.2%) received additional local irradiation of the brain. Single dosage of 2-2.5 Gy was administered to 158 (57.9%), 115--3Gy and more (42.1%). Mean total dosage was 36 Gy per metastasis for the whole brain and 46 Gy--for total plus local exposure. Among patients with favorable prognosis (RPA) were those aged up to 65, Karnofsky's index > or = 70%, with cured or controllable tumor and without extracranial metastases; poor prognosis--Karnofsky's index < or = 70%, irrespective of any other prognosticators, and intermediate prognosis--the remaining cases. The following four treatment modalities were used: 1) surgery --> radio- or radiochemotherapy (40); 2) chemotherapy > or = radiotherapy --> chemotherapy successively (56); (3) radiotherapy alone (110) and (4) simultaneous radiochemotherapy (72).

Effect of mixing on reaction-diffusion kinetics for protein hydrogel-based microchips.

Protein hydrogel-based microchips are being developed for high-throughput evaluation of the concentrations and activities of various proteins. To shorten the time of analysis, the reaction-diffusion kinetics on gel microchips should be accelerated. Here we present the results of the experimental and theoretical analysis of the reaction-diffusion kinetics enforced by mixing with peristaltic pump. The experiments were carried out on gel-based protein microchips with immobilized antibodies under the conditions utilized for on-chip immunoassay. The dependence of fluorescence signals at saturation and corresponding saturation times on the concentrations of immobilized antibodies and antigen in solution proved to be in good agreement with theoretical predictions. It is shown that the enhancement of transport with peristaltic pump results in more than five-fold acceleration of binding kinetics. Our results suggest useful criteria for the optimal conditions for assays on gel microchips to balance high sensitivity and rapid fluorescence saturation kinetics.

[Thermoradiotherapy as a component of desmoid tumor management: 10-year experience].

Data on radio- and thermoradiotherapy of 83 patients with extra-abdominal desmoid tumors are discussed. In a group of 57 patients followed up for 10 years or less, the relapse-free survival rates, in thermoradiotherapy-treated cases, were significantly higher (74.4% and 28.6%) than in those receiving radiotherapy (9.3% and 57.1%). Monitoring tumor temperature during local hyperthermia is a factor of relapse-free survival of vital importance.

[Thermoradiochemotherapy of inoperable soft-tissue sarcoma].

Three groups of patients with inoperable soft-tissue sarcoma received preoperative radiotherapy (57), thermoradiotherapy (102) and thermoradiochemotherapy (16) (n=175). Five year recurrence-free survival in group 1 was 37+/-7%, group 2 48+/-6%, and group 3 - 56+/-1,7%. Patients survived 5 years and more in group 3 (60+/-2%), group 2 - 50+/-7%, and group I 44+/-8% (p>0.05). Local hyperthermia used in conjunction with radio- and chemoradiotherapy was followed by a significant rise in the rate of complete and partial tumor regression.

[Radiotherapy as a component of treatment for Ewing's sarcoma].

The main stages of development of such conservative modalities as radio- and chemoradiotherapy for localized Ewing's sarcoma are discussed. Factors affecting five-year overall and recurrence-free survival of patients treated with chemoradiotherapy are presented.

[Results of repeat large-scale dissection of soft-tissue sarcoma following non-radical removal].

The reports deals with the data on repeat large-scale dissection of soft-tissue sarcoma following non-radical removal in 23 patients (13 males and 10 females , aged 14-75; mean age 42+/-30.2 yrs). Repeat surgery was carried out 3-6 weeks after primary one. Tumor progression was registered in 8 (34.8%): local recurrences which required radical intervention 4 (17.4%), distant metastases - 6 (26.1%) (lung - 3; liver - 1; lung and mediastinal lymph nodes - 1; lung and lumbar vertebra - 1). During the study, 5 patients died of tumor progression; all of them revealed distant metastases while 2 had local recurrences. Overall 5-year survival in 23 patients was 78%; whereas disease-free one - 65%.

Hydrogel-based protein microchips: manufacturing, properties, and applications.

Here a simple, reproducible, and versatile method is described for manufacturing protein and ligand chips. The photo-induced copolymerization of acrylamide-based gel monomers with different probes (oligonucleotides, DNA, proteins, and low-molecular ligands) modified by the introduction of methacrylic groups takes place in drops on a glass or silicone surface. All probes are uniformly and chemically fixed with a high yield within the whole volume of hydrogel semispherical chip elements that are chemically attached to the surface. Purified enzymes, antibodies, antigens, and other proteins, as well as complex protein mixtures such as cell lysates, were immobilized on a chip. Avidin- and oligohistidine-tagged proteins can be immobilized within biotin- and Ni-nitrilotriacetic acid-modified gel elements. Most gel-immobilized proteins maintain their biological properties for at least six months. Fluorescence and chemiluminescence microscopy were used as efficient methods for the quantitative analysis of the microchips. Direct on-chip matrix-assisted laser desorption ionization-time of flight mass spectrometry was used for the qualitative identification of interacting molecules and to analyze tryptic peptides after the digestion of proteins in individual gel elements. We also demonstrate other useful properties of protein microchips and their application to proteomics and diagnostics.