Ejc Supplements最新文献_第10页

P119 P119

Ejc Supplements Pub Date : 2015-11-01 Epub Date: 2015-11-23 DOI: 10.1016/j.ejcsup.2015.08.028

R. Fadeev , M. Solovieva , S. Zakharov , I. Fadeeva , A. Senotov , A. Golenkov , V. Akatov

{"title":"P119","authors":"R. Fadeev , M. Solovieva , S. Zakharov , I. Fadeeva , A. Senotov , A. Golenkov , V. Akatov","doi":"10.1016/j.ejcsup.2015.08.028","DOIUrl":"10.1016/j.ejcsup.2015.08.028","url":null,"abstract":"<div><p>Acute myelomonocytic leukemia (FAB M4) is one of the most common forms of acute myeloid leukemia (AML). This AML form is characterized by rapid accumulation transformed myeloblasts and monoblasts in bone marrow, with the rapid suppression of normal hematopoiesis. Bone marrow microenvironment is one of the main factors determining drug resistance of leukemic cells. It is known that the adhesion of leukemic cells to mesenchymal stem cell and bone marrow extracellular matrix (laminin, collagen) enhances their drug resistance. However, it remains unknown whether the emergence of drug resistance when cell–cell contacts are formed only between leukemia cells, without the involvement of bone marrow stromal elements. We studied the role of cell aggregation in drug resistance of leukemic cells. We used the bone marrow mononuclear cells (BMMC) isolated from the patients with acute myelomonocytic leukemia. For the formation of multicellular aggregates, BMMC were cultivated in 96-well plates coated with 1.5% agarose. We showed that resistance of BMMC to bortezomib, doxorubicin and fludarabine in multicellular aggregates was increased. In three-dimensional multicellular aggregates of BMMC index IC50 for bortezomib, doxorubicin and fludarabine was 7±1ng/ml, 1±0.4mkM and 0.8±0.05mkM, respectively. In control condition, index IC50 bortezomib, doxorubicin and fludarabine was significantly lower, 2±0.5ng/ml, 0.3±0.05mkM and 0.07±0.001mkM, respectively. In multicellular aggregates of BMMC number of mitotic cells and expression of Ki-67 protein were not significantly different from the control. It has also been shown that cells in multicellular aggregates increased expression antiapoptotic protein Bcl-2. Suppression of BMMC aggregation by culturing the cells in medium containing 0.9% methylcellulose resulted in decreased IC50 index for bortezomib, doxorubicin and fludarabine, 2±0.7ng/ml, 0.12±0.004mkM and 0.04±0.005mkM, respectively. Expression of the Bcl-2 protein was also decreased. This work demonstrates the involvement of cell aggregation in the formation of drug resistance phenotype in leukemic cells.</p><p>The work was supported by the <span>Russian Foundation for Basic Research</span> (Russia) (No. <span>14-04-32183</span>, <span>14- 04-32191</span>), the scholarship of the <span>President of the Russian Federation</span> (Russia) (No. <span>SP-6867.2013.4</span>, <span>SP-1519.2015.4</span>), and by the <span>Government of the Russian Federation</span> (Russia) (No.<span>14.Z50.31.0028</span>).</p></div>","PeriodicalId":11675,"journal":{"name":"Ejc Supplements","volume":"13 1","pages":"Page 16"},"PeriodicalIF":0.0,"publicationDate":"2015-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ejcsup.2015.08.028","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54309031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

P82 P82

Ejc Supplements Pub Date : 2015-11-01 Epub Date: 2015-11-23 DOI: 10.1016/j.ejcsup.2015.08.092

S. Shevchenko , L, Mostovich , G. Logacheva , S. Svyatchenko , L. Gulyaeva

{"title":"P82","authors":"S. Shevchenko , L, Mostovich , G. Logacheva , S. Svyatchenko , L. Gulyaeva","doi":"10.1016/j.ejcsup.2015.08.092","DOIUrl":"10.1016/j.ejcsup.2015.08.092","url":null,"abstract":"<div><p>Papillary thyroid cancer (PTC) is the most common malignancy of the endocrine system. The most frequent genetic alteration in PTC is the BRAF V600E mutation, which affects the activation of several intracellular signaling pathways. As a result, changes in the expression levels of cell membrane integrin receptors and their ligands – extracellular matrix proteins – osteopontin (OPN) and thrombospondin -1 (TSP1) are observed. This process increases the metastatic potential of tumor cells. Thus, integrin receptors and their ligands are potential biomarkers of an aggressive PTC phenotype.</p><p>The aim of our study was to compare the gene expression profile of integrins ITGA2, ITGA3, ITGAV, ITGA6, ITGA9, ITGB1, ITGB3 and their ligands OPNa, OPNb, and TSP1 in PTC with different BRAF V600E mutation status.</p><p>Intraoperative thyroid tissue samples from 41 patients diagnosed with PTC (<em>n</em>  =10) and follicular adenoma (<em>n</em>  =0.014), ITGAV (1.9-fold, <em>p</em>  =0.026), OPNb (2.5-fold, <em>p</em>  =0.017) was identified in the PTC tissues, and a high gene expression level of OPNb (5.9-fold, <em>p</em>  =0.005) was identified in the tissue samples of lymph node metastases compared to the conventionally normal tissue.</p><p>In the samples with advanced cancer (T3, T4, TNM) the expression levels of ITGA3, ITGA6 and ITGA9 were higher compared to the T1 samples. MRNA levels of ITGA3 and ITGAV were significantly higher in the PTC BRAF V600E positive samples than in the BRAF V600E negative samples.</p><p>Elevated levels of OPNa (11.4-fold, <em>p</em>  =0.0216) and TSP1 (33.5-fold, <em>p</em>  =0.","PeriodicalId":11675,"journal":{"name":"Ejc Supplements","volume":"13 1","pages":"Pages 51-52"},"PeriodicalIF":0.0,"publicationDate":"2015-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ejcsup.2015.08.092","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54310089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

T9 T9

Ejc Supplements Pub Date : 2015-11-01 Epub Date: 2015-11-23 DOI: 10.1016/j.ejcsup.2015.08.090

O. Shatova, D. Kaplun, I. Zinkovych

{"title":"T9","authors":"O. Shatova, D. Kaplun, I. Zinkovych","doi":"10.1016/j.ejcsup.2015.08.090","DOIUrl":"10.1016/j.ejcsup.2015.08.090","url":null,"abstract":"<div><h3>Background</h3><p>Metformin is a antidiabetic drug with anticancer properties. However, the mechanism action by which metformin affects various cancer cells still unknown. It is known that tumor growth is accompanied by changes in the metabolic cascade that includes overproduction of lactate and adenosine. The adenosine is released into the extracellular environment and regulates differentiation, proliferation, and angiogenesis of tumor mass. We found that lactate is activator of key enzyme of adenosine metabolism – adenosine deaminase (ADA).</p></div><div><h3>Aim</h3><p>The aim of our study was to investigate the catabolism of adenosine in the tumor while taking metformin.</p></div><div><h3>Materials and methods</h3><p>In this study we investigated the level of adenosine, inosine, hypoxanthine and ADA activity in 15 women aged 46–76years, with breast cancer (BC) T2-4N1M0 (cancer tissues) during treatment with metformin, 1000mg per day for 3 months. Control group – 15 women aged 46–76years, with stage T2-4N1M0 breast cancer (cancer tissues) without metformin therapy.</p><p>Statistical analysis was performed using the license package StatSoft. Statistica 12.0.</p></div><div><h3>Results</h3><p>ADA activity during treatment with metformin was 2-fold increased: 12.1±2.49nmol/min*mg in comparison with 4.77±0.943nmol/min*mg. Concentration of catabolic products of adenosine degradation was increased before metformin therapy. Inosine level was 0.121±0.041micromol/g tissue (BC tissues from women without metformin 0.042±0.015micromol/g tissue). Hypoxanthine 2.45±0.428micromol/g tissue (in comparison with 0.711±0.269micromol/g tissue). Whereas, adenosine level in BC after metformin therapy was 0.226±0.148micromol/g tissue (in comparison with 0.186±0.056micromol/g tissue), that were not significantly different.</p></div><div><h3>Conclusion</h3><p>Thus, we have found that metformin significantly increases the rate of catabolism of adenosine, and this in turn reduces the inhibitory effect on the tumor microenvironment cytotoxic cells. Therefore, our data for the first time provide novel evidence for a mechanism that the anticancer activities of metformin are due to adenosine metabolism regulation.</p></div>","PeriodicalId":11675,"journal":{"name":"Ejc Supplements","volume":"13 1","pages":"Pages 50-51"},"PeriodicalIF":0.0,"publicationDate":"2015-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ejcsup.2015.08.090","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54310060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

P96 P96

Ejc Supplements Pub Date : 2015-11-01 Epub Date: 2015-11-23 DOI: 10.1016/j.ejcsup.2015.08.070

T. Nikitenko , O. Rymar , S. Malyutina , L. Shcherbakova , E. Veryovkin , S. Kurilovich , Yu. Ragino , M. Voevoda

{"title":"P96","authors":"T. Nikitenko , O. Rymar , S. Malyutina , L. Shcherbakova , E. Veryovkin , S. Kurilovich , Yu. Ragino , M. Voevoda","doi":"10.1016/j.ejcsup.2015.08.070","DOIUrl":"10.1016/j.ejcsup.2015.08.070","url":null,"abstract":"<div><p>Obesity, associated with metabolic syndrome, is considered a significant risk factor for colorectal cancer (CRC).</p></div><div><h3>Purpose</h3><p>To compare the levels of metabolic syndrome (MS) components in persons with CRC and control in the frame of nested “case-control” design.</p></div><div><h3>Materials and Methods</h3><p>The study was carried out on the basis of a comparison of databases from epidemiological study The HAPIEE project and CRC register. The patients examined in the HAPIEE project, who had developed CRC during 10-year follow-up period according to the register of cancer (<em>n</em>     =184, men-96, women-88, mean age 60.7+6.8years). We used MS criteria’s according to NCEP ATP – III (2001). The data was processed using statistical program SPSS 13.0.</p></div><div><h3>Results</h3><p>Body mass index (BMI) and waist circumference (WC) had no significant differences in the studied groups, the average BMI value in CRC group was 28.6+5.3kg/m<sup>2</sup> vs 28.4+5.6kg/m<sup>2</sup> in control (<em>p</em>        =0.90). The percentage of patients with abdominal obesity was 41.3% in patients with CRC vs 42.9% in the control group (<em>p</em>        =0.27). The average level of HDL cholesterol in CRC group was within normal limits and also did not differ from control (<em>p</em>        =0.07). The average level of glucose did not differ in patients with CRC and in control: 5.9+1,2mmol/l vs 6.1+2.1mmol/L (<em>p</em>        =0.005). The level of diastolic blood pressure was slightly lower than in the control group compared to CRC (88.9+11.2mmHg vs91.","PeriodicalId":11675,"journal":{"name":"Ejc Supplements","volume":"13 1","pages":"Pages 39-40"},"PeriodicalIF":0.0,"publicationDate":"2015-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ejcsup.2015.08.070","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54309808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

P97 P97

Ejc Supplements Pub Date : 2015-11-01 Epub Date: 2015-11-23 DOI: 10.1016/j.ejcsup.2015.08.088

Y. Shapovalova , D. Lytkina , L. Rasskazova , A. Gudima , V. Ryabov , A. Filimoshkin , I. Kurzina , J. Kzhyshkowska

{"title":"P97","authors":"Y. Shapovalova , D. Lytkina , L. Rasskazova , A. Gudima , V. Ryabov , A. Filimoshkin , I. Kurzina , J. Kzhyshkowska","doi":"10.1016/j.ejcsup.2015.08.088","DOIUrl":"10.1016/j.ejcsup.2015.08.088","url":null,"abstract":"<div><p>Orthopedic oncologic prostheses are essential in postoperative therapy and improvement of life quality of oncological patients. However, construction and composition of implants has to be improved for better biocompatibility and reduction of inflammatory responses. The materials based on polylactic acid (PLA) and hydroxyapatite (HA) have been suggested as promising solution for implant coating in order to improve reconstruction of bone defects, to reduce risk of inflammation and implant rejection.</p></div><div><h3>Objective</h3><p>To obtain the bioresorbable composites using biocompatible poly-L-lactide (PLA) with HA and to evaluate its effect on bone remodeling rate.</p></div><div><h3>Materials and methods</h3><p>After dissolution of PLA<sup>∗</sup> in chloroform the powder-like HA (<em>d</em>      =0.1– 0.5μm, of more than 2mm length) were formed. The PLA/HA composite fibers were air-dried; they consisted of HA nanoparticles homogeneously distributed in the PLA matrix. The composites ability to participate in bone remodeling was estimated by determination of the polymer matrix dissolution rate and by formation of the CPL on the surface of the composites.</p></div><div><h3>Results</h3><p>The degradation rate of the polymer matrix was calculated by measuring concentration of lactic acid (by HPLC method), being released from PLA macromolecules as the result of the hydrolysis in the physiologic solution (pH 7, <em>ω</em>(NaCl)=0.9%). The PLA degradation rate during the first 4 days of soaking of the substrates (<em>d</em>   =190mm<sup>2</sup>, <em>m</em>         <!-->°C, over 28 days period. The total concentration of Ca2+ and Mg2+ ions in the SBF-solution was determined by daily trilonometry in the ammonia buffer with eriochrome black T as indicator. This investigation clearly shows that the substrates both of HA and PLA/HA promote the CLP formation on their surfaces. On day 14 of the substrates soaking in the SBF solution the ","PeriodicalId":11675,"journal":{"name":"Ejc Supplements","volume":"13 1","pages":"Pages 49-50"},"PeriodicalIF":0.0,"publicationDate":"2015-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ejcsup.2015.08.088","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54310032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 4

P38 P38

Ejc Supplements Pub Date : 2015-11-01 Epub Date: 2015-11-23 DOI: 10.1016/j.ejcsup.2015.08.087

S. Semina, M. Krasil’nikov

{"title":"P38","authors":"S. Semina, M. Krasil’nikov","doi":"10.1016/j.ejcsup.2015.08.087","DOIUrl":"10.1016/j.ejcsup.2015.08.087","url":null,"abstract":"<div><p>The efficiency of endocrine therapy for tumors is limited by the development of hormone resistance and progression of tumor cells to hormone-independent phenotype. Among these tumors – breast cancers, for which hormone therapy is one of the most common and effective methods of treatment, but only in cases, when the tumors retain their hormonal dependence. The mechanism of hormonal independence was found to be based on the fundamental properties of cancer cell including both downregulation of specific hormone receptors, and affecting of intracellular signalling, particularly – estrogen-independent growth signaling pathways. However, the role of the intercellular interactions in the progression of hormonal resistance is still unclear.</p><p>We hypothesize, that the formation of the clone of the hormone-resistant cells in the tumor, and the subsequent common growth of the hormone-resistant and sensitive cells may lead to spread the hormonal resistance to the sensitive cells – as a result of the secretion of the specific factors acting in the paracrine manner or via the direct cell–cell contacts. Here, using the estrogen-dependent breast cancer cells MCF-7 and the resistant subline MCF-7/T developed by long-term cultivation of MCF-7 cells in the presence of antiestrogen tamoxifen, we investigated the possible changes in the hormonal sensitivity of these cells caused by the co-cultivation in vitro. For this purpose MCF-7/T cells were transfected with the plasmid containing the gene of the green fluorescent protein (GFP), and GFP-positive hormone-resistant subline MCF-7/T/GFP+ was developed. The GFP expression should allow to distinguish the resistant and parental cells during co-cultivation.</p><p>To study the influence of the co-cultivation on the cell sensitivity to tamoxifen the parent MCF-7 cells (GFP-negative) were co-cultivate with the resistant MCF-7/T/GFP+/cells for 10days, then the cells were treated with tamoxifen and the efficiency of growth inhibitory tamoxifen action was determined. We found, that the co -cultivation of the parent and resistant cells lead to increase in the resistance of the parent cell to tamoxifen, indicating the important role of the contacts, direct or indirect, between hormone sensitive and resistant cells in the development of hormone resistance.</p><p>In general, we evaluate the established results as the first evidence of the possible involvement of the cell–cell underrelations in the realization of the hormonal response, and suppose that the next investigations will give a new insights in the molecular mechanisms of this effects and its role in the formation of the hormone-resistant phenotype of the tumors.</p></div>","PeriodicalId":11675,"journal":{"name":"Ejc Supplements","volume":"13 1","pages":"Pages 48-49"},"PeriodicalIF":0.0,"publicationDate":"2015-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ejcsup.2015.08.087","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54310023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

T117 T117

Ejc Supplements Pub Date : 2015-11-01 Epub Date: 2015-11-23 DOI: 10.1016/j.ejcsup.2015.08.003

A. Alexandrova, A. Chikina

{"title":"T117","authors":"A. Alexandrova, A. Chikina","doi":"10.1016/j.ejcsup.2015.08.003","DOIUrl":"10.1016/j.ejcsup.2015.08.003","url":null,"abstract":"<div><p>During cancer development, tumor cells gain the ability to invade and metastasize. Individual cells use alternative migration modes based on different cellular mechanisms. One of them is mesenchymal motility mode which is driven by leading edge protrusion in the form of filopodia or/and lamellipodia based on Arp2/3 dependent actin polymerization. Mesenchymal motility depends on formation of cell-substrate adhesions, activity of matrix metalloproteases (MMPs) and on activity of small GTPaseRac. Another mode is amoeboid motility, which involves formation of blebs – hollow membrane protrusions extruded from the cell surface by actin-myosin contraction. Amoeboid motility does not need both pronounced cell-substrate adhesions and MMPs activity and required increase of activity of small GTPase Rho. Fibroblasts and scattered epithelial cells migrate by mesenchymal mode, while blood cells – lymphocytes or macrophages mainly use amoeboid mode for migration. It was shown that some treatments cause transition from one motility mode to another. Switches from mesenchymal to amoeboid motility and opposite are called mesenchymal-amoeboid transition (MAT) and amoeboid -mesenchymal transition (AMT) respectively. The ability of cells for such transitions was named as plasticity of migration. We compared the plasticity of migration of normal and tumor cells. To study plasticity of mesenchymally migrated cells (MAT) we choose fibrosarcoma cells HT1080 as tumor and non-transformed subcutaneous fibroblasts 1036 as normal counterpart. To study AMT we choose a few lines of myeloid leukemia THP1, K562, KG1 in contrast to normal leukocytes obtained from healthy donors. We showed that fibrosarcoma cells in opposite to non-transformed fibroblasts could undergo MAT under treatments, which limited mesenchymal migration. Two approaches to limit mesenchymal motility of cells were used. One was decrease of substrate adhesiveness by treatment of coverslips with PolyHema solutions, which simulated the alteration of environmental conditions during cell migration. The other approach was influence on cellular pathways regulated cell motility. We used CK666, the inhibitor of Arp2/3 activity, which stopped actin polymerization and thus lamellipodia formation through Arp2/3 dependent mechanism. We showed that under both treatments the fraction of tumor cells switched from lamellipodia formation to blebbing and thus underwent MAT, while in non-transformed fibroblasts these treatments led to retraction of lamellipodia and significant failure of motility. Both leukemia cells and leucocytes of healthy donors showed blebs formation (amoeboid motility). We induced transition to mesenchymal motility by alteration of culture conditions. The first approach was the increase of substrate adhesiveness by treatment with fibronectin. Another way was to inhibit of small GTPase Rho activity. In result of both treatments, leukemia cells switched from amoeboid to mesenchymal motility (underwent A","PeriodicalId":11675,"journal":{"name":"Ejc Supplements","volume":"13 1","pages":"Pages 1-2"},"PeriodicalIF":0.0,"publicationDate":"2015-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ejcsup.2015.08.003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54308614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

T86 T86

Ejc Supplements Pub Date : 2015-11-01 Epub Date: 2015-11-23 DOI: 10.1016/j.ejcsup.2015.08.006

N. Barlev , O. Fedorova , L. Lezina , S. Piletsky

{"title":"T86","authors":"N. Barlev , O. Fedorova , L. Lezina , S. Piletsky","doi":"10.1016/j.ejcsup.2015.08.006","DOIUrl":"10.1016/j.ejcsup.2015.08.006","url":null,"abstract":"<div><p>Discovery of new pharmacologically active small molecules is an important and rapidly expanding area of modern molecular pharmacology. Given a limited number of proteins that are druggable, it is important to identify as many chemical effectors as possible to define the best regimen of anti-cancer therapy in each particular case. An E3 ubiquitin ligase, Mdm2, which mediates ubiquitin-dependent degradation of the critical tumor suppressor p53, is a promising target for small molecule inhibitors. Using a hybrid approach which combines the rational design of small molecules selected from the virtual library and the high-content screening using cancer cell lines we discovered several new inhibitors of the p53-Mdm2 interaction. These compounds were able to activate and stabilize the p53 protein causing massive apoptosis preferably in p53-positive cells at rates higher than the well-known inhibitor of Mdm2, Nutlin-3. The molecular mechanisms of their action will be discussed.</p><p>As another example of rational design of potential anti-cancer drugs, we will talk about artificial nano-Matrix-Imprinted -Polymers (MIPs) that recognize the structure of peptides and other biological molecules and thus dubbed as “plastic antibodies”. We have generated such nanoparticles against the surface region of the oncogenic receptor, EGFR, which is overexpressed in many forms of solid tumors. Selection of the linear epitope for creating “plastic antibodies” against the receptor was performed by analysis of a three-dimensional structure of the protein. The obtained “plastic antibodies” were specific against the epitope of EGFR. These plastic antibodies when loaded with a genotoxic drug, doxorubicin, were able to specifically induce cell death of breast cancer cell lines that overexpress the EGFR receptor. Experiments in vivo using xenografts of breast cancer cell lines pre-incubated with these plastic antibodies in nude mice showed that they have a pronounced therapeutic effect. Furthermore, since the commercial drug, Cetuximab, recognizes an epitope of EGFR, different from the one recognized by our plastic antibodies, it is likely that the latter may increase the efficacy of the commercial monoclonal antibody. Collectively, we demonstrate that the rationally designed small molecules can be potent and specific drugs for anti-cancer therapy.</p></div>","PeriodicalId":11675,"journal":{"name":"Ejc Supplements","volume":"13 1","pages":"Pages 3-4"},"PeriodicalIF":0.0,"publicationDate":"2015-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ejcsup.2015.08.006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54308670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A111 A111

Ejc Supplements Pub Date : 2015-11-01 Epub Date: 2015-11-23 DOI: 10.1016/j.ejcsup.2015.08.015

L. Buchynska, N. Iurchenko, N. Verko, N. Glushchenko

{"title":"A111","authors":"L. Buchynska, N. Iurchenko, N. Verko, N. Glushchenko","doi":"10.1016/j.ejcsup.2015.08.015","DOIUrl":"10.1016/j.ejcsup.2015.08.015","url":null,"abstract":"<div><h3>Background</h3><p>According to the “immune-editing” theory, immunocompetent cells being important component of the tumor microenvironment can both show antitumor activity and contribute to the tumor progression. Tumor pathophysiological features affect the structural and functional changes of certain components of tumor microenvironment, in particular, increase the number of T-lymphocytes with regulatory activity (Treg). FOXP3, transcription factor, acts as master regulator for suppressive function of Treg. Recent studies have shown FOXP3 is expressed both in immunocompetent cells and tumor cells; however, the function of this gene in malignant tumors of different genesis is ambiguous (GirdhariLal, et al., 2014). The aim of the study was quantitative assessment of subpopulations CD4+, CD8+, FOXP3+-lymphocytes associated with the tumor, FOXP3+-tumor cells and comparison of these parameters with the clinical and morphological characteristics of endometrial cancer (EC).</p></div><div><h3>Materials and methods</h3><p>A total of 40 EC patients who did not receive special treatment before surgery with the mean age 56.9±2.8years were included in the study. Morphological and immunohistochemical methods were used in the study (primary monoclonal antibodies: CD4 – clone 4B12, “Millipore”, USA, CD8 – clone RIV – 11, “Millipore”, USA, FOXP3 – clone 5H5L12, “Invitrogen”, USA, Ki-67 - clone MIB1, “DakoCytomation”, Denmark) and Real-Time PCR was also used to determine the DNA methylation status of FOXP3 gene mathematical statistics.</p></div><div><h3>Results</h3><p>The dependence of the number of intratumoral CD4+-, CD8+- lymphocytes and FOXP3-lymphocytes on such biological characteristics as the degree of differentiation, growth rate and depth of invasion into the myometrium was established. In endometrial adenocarcinomas, low grade content of FOXP3+ lymphocytes increased (27.8±2.6%), number of intratumoral CD4+ (15,3±0,2%), CD8+-lymphocytes (29.6±0.3%) and FOXP3+-tumor cells (15,5±3,3%) decreased in contrast to the same parameters in high grade tumors: FOXP3+-lymphocytes (17.4±3.0%), CD4+ (52.0±2.7%), CD8+ (46.4±5.6%), FOXP3+-tumor cells (27.8±2.6%), <em>p</em>  <0.05) (Spearman rank correlation) was observed between the deep invasion of tumor in myometrium and the number of FOXP3+-tumor cells (<em>R</em>  =<!--> <!-","PeriodicalId":11675,"journal":{"name":"Ejc Supplements","volume":"13 1","pages":"Pages 8-9"},"PeriodicalIF":0.0,"publicationDate":"2015-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ejcsup.2015.08.015","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54308782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

P78 只有

Ejc Supplements Pub Date : 2015-11-01 Epub Date: 2015-11-23 DOI: 10.1016/j.ejcsup.2015.08.023

E. Denisov , T. Gerashchenko , D. Pautova , N. Krakhmal , M. Zavyalova , N. Litviakov , E. Slonimskaya , N. Cherdyntseva , V. Perelmuter

{"title":"P78","authors":"E. Denisov , T. Gerashchenko , D. Pautova , N. Krakhmal , M. Zavyalova , N. Litviakov , E. Slonimskaya , N. Cherdyntseva , V. Perelmuter","doi":"10.1016/j.ejcsup.2015.08.023","DOIUrl":"10.1016/j.ejcsup.2015.08.023","url":null,"abstract":"<div><h3>Background</h3><p>Breast cancer, particularly invasive carcinoma of no special type (IC NST), demonstrates considerable intratumor morphological heterogeneity. Five types of morphological structures representing different architectural arrangements of tumor cells – tubular, alveolar, trabecular, solid structures, and discrete groups have been described in IC NST. Previous studies reported the contribution of intratumor morphological heterogeneity of IC NST to chemotherapy efficiency and lymph node metastasis (Zavyalova et al., 2013; Denisov et al., 2014); however, its role in distant metastasis remains unidentified. Aim: to study the contribution of intratumor morphological heterogeneity of IC NST to distant metastasis and to identify gene expression features of metastatic behavior of different morphological structures.</p></div><div><h3>Materials and methods</h3><p>358 IC NST patients (age range 29–90, mean age 49.89.5, T1-4N0-3M0-1) treated with neoadjuvant chemotherapy (NAC) have been enrolled in this study. Chi-square test and Kaplan–Meier analysis were used to estimate the association between the presence of certain morphological structures in breast tumors and the frequency of distant metastasis and metastasis-free survival. qRT-PCR was applied for measurement of the expression levels of genes involved in cell motility (CDH1, CDH2, CDH3, CTNNA1, CTNNB1, ITGA6, ITGAV, ITGB1, ITGB3, ITGB4, SNAIL, MMP14, ROCK2, L1CAM, MMP2, MMP9, PDPN) and pre-metastatic niche formation (TNFa, TGFb, VEGFa, LOX, M-CSF, GM-CSF, HIF1A, SDF2) in different morphological structures isolated from breast tumors (<em>n</em>  =0.004). The association between alveolar structures and high frequency of hematogenous metastasis was found only in patients with poor response to NAC (<em>p</em>  =0.377). Increased distant metastasis was also shown in patients with trabecular structures as compared to cases without this morphological type (88.3% vs. 70.0%; <em>p</em>  =0.011). No significant association between other morphological structures and distant metastasis was found. Expression analysis showed the presence of cell motility phenotype in all morphological structures. In particular, we found changes in cell adhesion gene expression, which declined in the row: solid–alveolar–trabecular structures–discrete groups of tumor cells (<em>p","PeriodicalId":11675,"journal":{"name":"Ejc Supplements","volume":"13 1","pages":"Page 13"},"PeriodicalIF":0.0,"publicationDate":"2015-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ejcsup.2015.08.023","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54308924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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