ПРОГНОСТИЧЕСКАЯ МОДЕЛЬ ПРОТИВООПУХОЛЕВОГО ЭФФЕКТА ТАРГЕТНЫХ ПРЕПАРАТОВ ИММУНОТЕРАПИИ

A prognostic model for constructing hypotheses about the relationship of combinations of cytokines with the proliferative activity of cancer cells is proposed. The model is based on the use of inductive inference methods. The methodology takes into account the synergistic interaction of cytokines and uses sequential construction of logical formulas for selecting groups of cytokines, a statistical analysis of contingency tables and logical integration of the obtained estimates. Implementation of the proposed method in the information system of forecasting the effect of targeted anticancer drugs in immunotherapy will greatly accelerate research in this area.На основе использования методов индуктивного вывода предложена прогностическая модель построения гипотез о взаимосвязи комбинации цитокинов с пролиферативной активностью раковых клеток. Модель учитывает синергическое взаимодействие цитокинов и использует последовательное построение логических формул для отбора групп цитокинов, статистический анализ таблиц сопряженности и логическую интеграцию полученных оценок. Реализация предложенной модели в рамках информационной системы прогнозирования противоопухолевого эффекта таргетных препаратов иммунотерапии позволит существенно ускорить научные исследования в этой области

ЛОГИКО-ИНФОРМАЦИОННАЯ МОДЕЛЬ ОЦЕНКИ ВЛИЯНИЯ ПРЕПАРАТОВ ТАРГЕТНОЙ ТЕРАПИИ НА БИОЛОГИЧЕСКУЮ АКТИВНОСТЬ РАКОВЫХ КЛЕТОК

The paper deals with laboratory preclinical studies of the impact of targeted anticancer drugs on the life of A-549 cell cultures of the cancer origin (lung carcinoma). Preclinical studies enable evaluating the effectiveness of targeted therapy drugs, possible contraindications and side effects in order to determine in future the scope of clinical trials and the possibility of performing them. It is proposed to develop information support of preclinical research. In this work the use of functional modeling technology for building a logic-information model in the category of IDEF0 is considered. For detailed elaboration of the model it is necessary to review step-by-step the whole research process. The necessity of creating the information support is connected to the tasks of structuring, storage and processing large amounts of experimental data.В работе рассматриваются лабораторные доклинические исследования воздействия таргетных противоопухолевых препаратов на жизнедеятельность культур клеток ракового происхождения А-549 (карцинома легкого). Доклинические исследования дают возможность оценить эффективность применения таргетных препаратов, возможные противопоказания и побочные эффекты, чтобы в дальнейшем определиться с объемом клинических испытаний и самой возможностью их проведения. Предлагается разработка информационной поддержки доклинических научных исследований. Рассмотрено применение технологии функционально-го моделирования для построения логико-информационных моделей в номинации IDEF0. Детализация модели состоит в поэтапном рассмотрении всего процесса исследования. Необходимость информационной поддержки исследований связана с задачами структуризации, хранения и обработки больших объемов экспериментальных данных

Phenotypes Determined by Cluster Analysis and Their Survival in the Prospective European Scleroderma Trials and Research Cohort of Patients With Systemic Sclerosis

Objective: Systemic sclerosis (SSc) is a heterogeneous connective tissue disease that is typically subdivided into limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) depending on the extent of skin involvement. This subclassification may not capture the entire variability of clinical phenotypes. The European Scleroderma Trials and Research (EUSTAR) database includes data on a prospective cohort of SSc patients from 122 European referral centers. This study was undertaken to perform a cluster analysis of EUSTAR data to distinguish and characterize homogeneous phenotypes without any a priori assumptions, and to examine survival among the clusters obtained. / Methods: A total of 11,318 patients were registered in the EUSTAR database, and 6,927 were included in the study. Twenty‐four clinical and serologic variables were used for clustering. / Results: Clustering analyses provided a first delineation of 2 clusters showing moderate stability. In an exploratory attempt, we further characterized 6 homogeneous groups that differed with regard to their clinical features, autoantibody profile, and mortality. Some groups resembled usual dcSSc or lcSSc prototypes, but others exhibited unique features, such as a majority of lcSSc patients with a high rate of visceral damage and antitopoisomerase antibodies. Prognosis varied among groups and the presence of organ damage markedly impacted survival regardless of cutaneous involvement. / Conclusion: Our findings suggest that restricting subsets of SSc patients to only those based on cutaneous involvement may not capture the complete heterogeneity of the disease. Organ damage and antibody profile should be taken into consideration when individuating homogeneous groups of patients with a distinct prognosis

Rotational dynamics of adenine amino groups in a DNA double helix.

Exocyclic amino groups of the bases undergo conformational fluctuations that affect the recognition and reactivity of nucleic acid molecules. Among these fluctuations, rotation of amino groups around C-N bonds is of special interest. In the present paper, we report the first determination of the rates and energetic parameters for rotation of the N6-amino group of adenine in a DNA double helix. The DNA molecule studied is the dodecamer [d(CGCGAGCTCGCG)]2. The adenine in each A. T basepair of the dodecamer was labeled with 15N at the N6 position, and the NMR resonances of the two protons in the adenine amino group were selectively observed by 15N-editing methods. The rates of rotation of the amino group were obtained from experiments of transfer of magnetization between the two protons in the same group and from lineshape analysis of 15N-edited amino proton NMR resonances. The results show that, over the temperature range from 0 to 70 degrees C, the rates of rotation of adenine amino groups range from 60 to 24,000 s-1. Formation of the activated state during rotation has a standard enthalpy change of 15.3 +/- 0.2 kcal/mol and a standard entropy change of 6.0 +/- 0.7 cal/(mol. K). Analysis of the results suggests that rotation of the amino group occurs in the paired, closed state of the adenine in the A. T basepair of the double-helical DNA structure

Proton exchange and base-pair opening kinetics in 5'-d(CGCGAATTCGCG)-3' and related dodecamers.

We have used nuclear magnetic resonance (NMR) spectroscopy to measure the lifetimes of individual base-pairs in the palindromic DNA oligonucleotide 5'-d(CGCGAATTCGCG)-3' and in three other dodecamers with symmetrical base substitutions in the sites underlined. The resonances of the hydrogen-bonded imino protons in each of the substituted oligomers in the duplex form have been assigned using one dimensional nuclear Overhauser effect (1-D NOE) experiments. The lifetimes have been obtained from the dependence of selective longitudinal relaxation times and linewidths of the imino proton resonances on the concentration of base catalyst (Tris) at 25 degrees C and in the presence of 50 mM NaCl. The lifetimes of the central A.T base-pairs have been found to depend on base sequence. They are greatly increased in the dodecamer 5'-d(CGCAAATTTGCG)-3' which contains an A3T3 tract. The lifetimes of the central A.T base-pairs in 5'-d(CGCGAATTCGCG)-3', 5'-d(CGCTAATTAGCG)-3' and 5'-d(CGCCAATTGGCG)-3' are comparable. In all dodecamers, the lifetime of the A.T base-pair at the 5'-end of the AnTn tract is the shortest. The anomalous opening kinetics of the A.T base-pairs can be correlated to the bending properties of the corresponding sequences

Mathematical analysis of functional properties alterations of mice bone marrow during protracted external irradiation with different dose rate intensity

Using developed mathematical model together with the experimental results concerning protracted continuous irradiation influence in the doses 0.01, 0.03, 0.06, 0.1, 0.25, 0.5 and 0.8 Gy/day (23 h per day), as well as 1, 3, 6 and 10 Gy/day (24 h) on the alterations in colony-forming units (CFU) number of mice bone marrow we defined the mechanism of new steady-state regime of CFU number forming during irradiation; CFU stabilization level is assessed depending on everyday irradiation dose rate. As a result of experiment we have determined parameters characterizing the reaction of hematopoietic system to CFU loss after everyday irradiation with different dose rate intensity. Quantitative indices are established, showing the decrease of CFU income intensity from the sources to bone marrow, when everyday irradiation dose rate increases

Comparative mathematical analysis of the colony-forming ability of bone marrow of mice irradiated in lethal dose with high and low dose rate

Using (1) original mathematical model, (2) new scheme of hematopoiesis and experimental results of γ-irradiation influence in the dose of 8 Gy with 5 and 0.0028 Gy/min dose rate on the number of colony-forming units (CFU) of bone marrow (BM), as well as (3) experimental data concerning the reparation processes of BM CFU, obtained from the scientific publications, we determine parameters characterizing the reaction of hematopoietic system on the different stages of reparation processes of BM CFU number after the termination of ionizing radiation action