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<article article-type="research-article" dtd-version="1.3" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xml:lang="ru"><front><journal-meta><journal-id journal-id-type="publisher-id">tumors</journal-id><journal-title-group><journal-title xml:lang="ru">Malignant tumours</journal-title><trans-title-group xml:lang="en"><trans-title>Malignant tumours</trans-title></trans-title-group></journal-title-group><issn pub-type="ppub">2224-5057</issn><issn pub-type="epub">2587-6813</issn><publisher><publisher-name>Rosoncoweb</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.18027/2224-5057-2013-3-3-9</article-id><article-id custom-type="elpub" pub-id-type="custom">tumors-47</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="section-heading" xml:lang="ru"><subject>ФУНДАМЕНТАЛЬНАЯ ОНКОЛОГИЯ И ЭКСПЕРИМЕНТАЛЬНАЯ МЕДИЦИНА</subject></subj-group><subj-group subj-group-type="section-heading" xml:lang="en"><subject>FUNDAMENTAL ONCOLOGY AND EXPERIMENTAL MEDICINE</subject></subj-group></article-categories><title-group><article-title>ОПРЕДЕЛЕНИЕ ПЕРЕСТРОЕК ГЕНА ALK В СЕЛЕКТИРОВАННОЙ ПОПУЛЯЦИИ РОССИЙСКИХ БОЛЬНЫХ НЕМЕЛКОКЛЕТОЧНЫМ РАКОМ ЛЕГКОГО</article-title><trans-title-group xml:lang="en"><trans-title>Determination of rearrangements in ALK gene in selected russian population of patients with non-small cell lung cancer</trans-title></trans-title-group></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Демидова</surname><given-names>И. А.</given-names></name><name name-style="western" xml:lang="en"><surname>Demidova</surname><given-names>I. A.</given-names></name></name-alternatives><xref ref-type="aff" rid="aff-1"/></contrib><contrib contrib-type="author" corresp="yes"><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Цепенщикова</surname><given-names>Е. О.</given-names></name><name name-style="western" xml:lang="en"><surname>Tsepenshchikova</surname><given-names>E. O.</given-names></name></name-alternatives><xref ref-type="aff" rid="aff-1"/></contrib><contrib contrib-type="author" corresp="yes"><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Баринов</surname><given-names>А. А.</given-names></name><name name-style="western" xml:lang="en"><surname>Barinov</surname><given-names>A. A.</given-names></name></name-alternatives><xref ref-type="aff" rid="aff-1"/></contrib><contrib contrib-type="author" corresp="yes"><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Гагарин</surname><given-names>И. М.</given-names></name><name name-style="western" xml:lang="en"><surname>Gagarin</surname><given-names>I. M.</given-names></name></name-alternatives><xref ref-type="aff" rid="aff-1"/></contrib><contrib contrib-type="author" corresp="yes"><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Савелов</surname><given-names>Н. А.</given-names></name><name name-style="western" xml:lang="en"><surname>Savelov</surname><given-names>N. A.</given-names></name></name-alternatives><xref ref-type="aff" rid="aff-2"/></contrib><contrib contrib-type="author" corresp="yes"><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Гриневич</surname><given-names>В. Н.</given-names></name><name name-style="western" xml:lang="en"><surname>Grinevich</surname><given-names>V. N.</given-names></name></name-alternatives><xref ref-type="aff" rid="aff-2"/></contrib><contrib contrib-type="author" corresp="yes"><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Тюляндин</surname><given-names>С. А.</given-names></name><name name-style="western" xml:lang="en"><surname>Tyulyandin</surname><given-names>S. A.</given-names></name></name-alternatives><xref ref-type="aff" rid="aff-3"/></contrib></contrib-group><aff xml:lang="ru" id="aff-1"><institution>ГБУЗ МГОБ 62 ДЗМ, лаборатория молекулярной диагностики</institution><country>Russian Federation</country></aff><aff xml:lang="ru" id="aff-2"><institution>ГБУЗ МГОБ 62 ДЗМ, отделение патологической анатомии</institution><country>Russian Federation</country></aff><aff xml:lang="ru" id="aff-3"><institution>ГБУ РОНЦ им. Н. Н. Блохина РАМН, отделение клинической фармакологии и химиотерапии</institution><country>Russian Federation</country></aff><pub-date pub-type="collection"><year>2013</year></pub-date><pub-date pub-type="epub"><day>20</day><month>05</month><year>2015</year></pub-date><volume>0</volume><issue>3</issue><fpage>3</fpage><lpage>9</lpage><permissions><copyright-statement>Copyright &amp;#x00A9; Демидова И.А., Цепенщикова Е.О., Баринов А.А., Гагарин И.М., Савелов Н.А., Гриневич В.Н., Тюляндин С.А., 2015</copyright-statement><copyright-year>2015</copyright-year><copyright-holder xml:lang="ru">Демидова И.А., Цепенщикова Е.О., Баринов А.А., Гагарин И.М., Савелов Н.А., Гриневич В.Н., Тюляндин С.А.</copyright-holder><copyright-holder xml:lang="en">Demidova I.A., Tsepenshchikova E.O., Barinov A.A., Gagarin I.M., Savelov N.A., Grinevich V.N., Tyulyandin S.A.</copyright-holder><license xml:lang="ru" license-type="creative-commons-attribution" xlink:href="https://creativecommons.org/licenses/by/4.0/" xlink:type="simple"><license-p>Данная работа распространяется под лицензией Creative Commons Attribution 4.0.</license-p></license><license xml:lang="en" license-type="creative-commons-attribution" xlink:href="https://creativecommons.org/licenses/by/4.0/" xlink:type="simple"><license-p>This work is licensed under a Creative Commons Attribution 4.0 License.</license-p></license></permissions><self-uri xlink:href="https://www.malignanttumors.org/jour/article/view/47">https://www.malignanttumors.org/jour/article/view/47</self-uri><abstract><p>Определение перестроек гена ALK у больных немелкоклеточным раком легкого (НМРЛ) предложено в качестве обязательной процедуры большинством современных международных рекомендаций по диагностике и лечению онкологических заболеваний. Целью исследования было проведение тестирования методом флюоресцентной гибридизации in situ (FISH) транслокаций с участием гена ALK у пациентов, направленных на тестирование мутаций гена EGFR в рамках Программы Общества онкологов-химиотерапевтов «Совершенствование молекулярно-генетической диагностики с целью повышения эффективности противоопухолевого лечения» www.cancergenome.ru. Успешное тестирование проведено 189 из 200 больных НМРЛ без мутаций гена EGFR. Выявлено 12 позитивных случаев (6,3 %). Показана зависимость частоты выявления реаранжировок гена ALK от гистологической формы опухоли, статуса курения и возраста пациента. Подтверждена эффективность использования метода FISH для широкого тестирования перестроек гена ALK в группе больных с железистыми гистологическими типами НМРЛ.</p></abstract><trans-abstract xml:lang="en"><p>Determination of rearrangements in ALK gene in patients with non-small cell lung cancer (NSCLC), proposed as a mandatory procedure in most current international guidelines for the diagnosis and treatment of cancer. The aim of the study was to conduct a test by fluorescent hybridization in situ (FISH) of translocations involving ALK gene in patients referred for testing for EGFR gene mutations in the framework of the Society of oncologists-chemotherapeutists "Improvement of molecular genetic diagnosis in order to improve the efficiency of anticancer treatment» www.cancergenome.ru. Successful tests conducted in 189 out of 200 patients with NSCLC without mutations EGFR. There 12 positive tests (6.3%). The dependence of the frequency of detection of gene rearrangements of the ALK histological forms of cancer, smoking status and age of the patient was shown. The efficiency of wide FISH testing for ALK gene rearrangements in patients with glandular histological types of NSCLC was confirmed.</p></trans-abstract><kwd-group xml:lang="ru"><kwd>немелкоклеточный рак легкого</kwd><kwd>ген ALK</kwd><kwd>флюоресцентная гибридизация</kwd></kwd-group><kwd-group xml:lang="en"><kwd>non-small cell lung cancer</kwd><kwd>ALK gene</kwd><kwd>fluorescent hybridization</kwd></kwd-group></article-meta></front><back><ref-list><title>References</title><ref id="cit1"><label>1</label><citation-alternatives><mixed-citation xml:lang="ru">American Cancer Society, Cancer Facts &amp; Figures 2012, http://www.cancer.</mixed-citation><mixed-citation xml:lang="en">American Cancer Society, Cancer Facts &amp; Figures 2012, http://www.cancer.</mixed-citation></citation-alternatives></ref><ref id="cit2"><label>2</label><citation-alternatives><mixed-citation xml:lang="ru">org / Research / CancerFactsFigures / 2013</mixed-citation><mixed-citation xml:lang="en">org / Research / CancerFactsFigures / 2013</mixed-citation></citation-alternatives></ref><ref id="cit3"><label>3</label><citation-alternatives><mixed-citation xml:lang="ru">Couraud S, Zalcman G, Milleron B, Morin F, Souquet PJ. Lung cancer in never smokers — A review. Eur. J. Cancer. 2012;48 (9):1299-1311.</mixed-citation><mixed-citation xml:lang="en">Couraud S, Zalcman G, Milleron B, Morin F, Souquet PJ. Lung cancer in never smokers — A review. Eur. J. Cancer. 2012;48 (9):1299-1311.</mixed-citation></citation-alternatives></ref><ref id="cit4"><label>4</label><citation-alternatives><mixed-citation xml:lang="ru">Food and Drug Administration (2011) Summary review (application number: 202570Orig1s000). Food and Drug Administration, Silver Spring.</mixed-citation><mixed-citation xml:lang="en">Food and Drug Administration (2011) Summary review (application number: 202570Orig1s000). Food and Drug Administration, Silver Spring.</mixed-citation></citation-alternatives></ref><ref id="cit5"><label>5</label><citation-alternatives><mixed-citation xml:lang="ru">Lindeman LI, Gagle PT, Beasley MB et al. Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors. Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Arch Pathol Lab Med. 2013; 137 (6):828-60.</mixed-citation><mixed-citation xml:lang="en">Lindeman LI, Gagle PT, Beasley MB et al. Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors. Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Arch Pathol Lab Med. 2013; 137 (6):828-60.</mixed-citation></citation-alternatives></ref><ref id="cit6"><label>6</label><citation-alternatives><mixed-citation xml:lang="ru">Thunnissen E, Bubbendorf L, Dietel M et al. EML4-ALK testing in non-small cell carcinomas of the lung: a review with recommendations. Virchows Arch. 2012;461 (3):245-57.</mixed-citation><mixed-citation xml:lang="en">Thunnissen E, Bubbendorf L, Dietel M et al. EML4-ALK testing in non-small cell carcinomas of the lung: a review with recommendations. Virchows Arch. 2012;461 (3):245-57.</mixed-citation></citation-alternatives></ref><ref id="cit7"><label>7</label><citation-alternatives><mixed-citation xml:lang="ru">John A. Kiernan, Formaldehyde, formalin, paraformaldehyde and glutaraldehyde: What they are and what they do. Microscopy Today 2000; 00-1 pp. 8-12.</mixed-citation><mixed-citation xml:lang="en">John A. Kiernan, Formaldehyde, formalin, paraformaldehyde and glutaraldehyde: What they are and what they do. Microscopy Today 2000; 00-1 pp. 8-12.</mixed-citation></citation-alternatives></ref><ref id="cit8"><label>8</label><citation-alternatives><mixed-citation xml:lang="ru">Yan F, Wu X, Crawford M et al. The search for an optimal DNA, RNA, and protein detection by in situ hybridization, immunohistochemistry, and solution-based methods. Methods. 2010; 52 (4):281-6.</mixed-citation><mixed-citation xml:lang="en">Yan F, Wu X, Crawford M et al. The search for an optimal DNA, RNA, and protein detection by in situ hybridization, immunohistochemistry, and solution-based methods. Methods. 2010; 52 (4):281-6.</mixed-citation></citation-alternatives></ref><ref id="cit9"><label>9</label><citation-alternatives><mixed-citation xml:lang="ru">Camidge DR, Bang Y, Kwak EL, et al. Progression-free survival (PFS) from a phase I study of crizotinib (PF-02341066) in patients with ALK-positive non-small cell lung cancer (NSCLC) [abstract 2501]. J. Clin Oncol. 2011; 29 (suppl): 165s.</mixed-citation><mixed-citation xml:lang="en">Camidge DR, Bang Y, Kwak EL, et al. Progression-free survival (PFS) from a phase I study of crizotinib (PF-02341066) in patients with ALK-positive non-small cell lung cancer (NSCLC) [abstract 2501]. J. Clin Oncol. 2011; 29 (suppl): 165s.</mixed-citation></citation-alternatives></ref><ref id="cit10"><label>10</label><citation-alternatives><mixed-citation xml:lang="ru">Crino L, Kim D-W, Riely G, et al. Initial phase 2 results with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC): PROFILE 1005 [abstract 7514]. J Clin Oncol. 2011;29 (suppl): 479s.</mixed-citation><mixed-citation xml:lang="en">Crino L, Kim D-W, Riely G, et al. Initial phase 2 results with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC): PROFILE 1005 [abstract 7514]. J Clin Oncol. 2011;29 (suppl): 479s.</mixed-citation></citation-alternatives></ref><ref id="cit11"><label>11</label><citation-alternatives><mixed-citation xml:lang="ru">An SJ, Chen ZH, Su J, Zhang XC, Zhong WZ, Yang JJ, et al. Identification of enriched driver gene alterations in subgroups of non-small cell lung cancer patients based on histology and smoking status. PLoS ONE 2012;7: e40109.</mixed-citation><mixed-citation xml:lang="en">An SJ, Chen ZH, Su J, Zhang XC, Zhong WZ, Yang JJ, et al. Identification of enriched driver gene alterations in subgroups of non-small cell lung cancer patients based on histology and smoking status. PLoS ONE 2012;7: e40109.</mixed-citation></citation-alternatives></ref><ref id="cit12"><label>12</label><citation-alternatives><mixed-citation xml:lang="ru">Sasaki T, Rodig SJ, Chirieac LR, Janne PA. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer 2010; 46:1773-80.</mixed-citation><mixed-citation xml:lang="en">Sasaki T, Rodig SJ, Chirieac LR, Janne PA. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer 2010; 46:1773-80.</mixed-citation></citation-alternatives></ref><ref id="cit13"><label>13</label><citation-alternatives><mixed-citation xml:lang="ru">Demidova I., Savelov N., Barinov A, et al. Immunohistochemistry, Fluorescence in Situ Hybridization and Reverse Transcription-Polymerase Chain Reaction for the Detection of Anaplastic Lymphoma Kinase Gene Rearrangements in Non-Small Cell Lung Cancer Patients: Potential Advantages and Methodological Pitfalls. Arch Pathol Lab Med 2013, in press.</mixed-citation><mixed-citation xml:lang="en">Demidova I., Savelov N., Barinov A, et al. Immunohistochemistry, Fluorescence in Situ Hybridization and Reverse Transcription-Polymerase Chain Reaction for the Detection of Anaplastic Lymphoma Kinase Gene Rearrangements in Non-Small Cell Lung Cancer Patients: Potential Advantages and Methodological Pitfalls. Arch Pathol Lab Med 2013, in press.</mixed-citation></citation-alternatives></ref><ref id="cit14"><label>14</label><citation-alternatives><mixed-citation xml:lang="ru">Nishino M, Klepeis V, Yeap B, et al. Histologic and cytomorphologic features of ALK-rearranged lung adenocarcinomas. Mod Pathol.2012; 25 (11):1462-72.</mixed-citation><mixed-citation xml:lang="en">Nishino M, Klepeis V, Yeap B, et al. Histologic and cytomorphologic features of ALK-rearranged lung adenocarcinomas. Mod Pathol.2012; 25 (11):1462-72.</mixed-citation></citation-alternatives></ref><ref id="cit15"><label>15</label><citation-alternatives><mixed-citation xml:lang="ru">Horn L, Pao W. EML4-ALK: Honing In on a New Target in Non — Small-Cell Lung Cancer J Clin Oncol 2009, 27 (26):4232-4235.</mixed-citation><mixed-citation xml:lang="en">Horn L, Pao W. EML4-ALK: Honing In on a New Target in Non — Small-Cell Lung Cancer J Clin Oncol 2009, 27 (26):4232-4235.</mixed-citation></citation-alternatives></ref><ref id="cit16"><label>16</label><citation-alternatives><mixed-citation xml:lang="ru">Rodig S, Mino-Kenudson M, Dacic S, et al. Unique Clinicopathologic Features Characterize ALK-Rearranged Lung Adenocarcinoma in the Western Population. Clin Cancer Res 2009;15 (16): 5216-5223.</mixed-citation><mixed-citation xml:lang="en">Rodig S, Mino-Kenudson M, Dacic S, et al. Unique Clinicopathologic Features Characterize ALK-Rearranged Lung Adenocarcinoma in the Western Population. Clin Cancer Res 2009;15 (16): 5216-5223.</mixed-citation></citation-alternatives></ref><ref id="cit17"><label>17</label><citation-alternatives><mixed-citation xml:lang="ru">Atherly A, Camidge R. The cost-effectiveness of screening lung cancer patients for targeted drug sensitivity markers. British Journal of Cancer (2012) 106, 1100-1106.</mixed-citation><mixed-citation xml:lang="en">Atherly A, Camidge R. The cost-effectiveness of screening lung cancer patients for targeted drug sensitivity markers. British Journal of Cancer (2012) 106, 1100-1106.</mixed-citation></citation-alternatives></ref><ref id="cit18"><label>18</label><citation-alternatives><mixed-citation xml:lang="ru">Weickhardt AJ, Camidge DR. The therapeutic potential of anaplastic lymphoma kinase inhibitors in lung cancer: rationale and clinical evidence. Clin Invest 2011; 1 (8): 1119-1126.</mixed-citation><mixed-citation xml:lang="en">Weickhardt AJ, Camidge DR. The therapeutic potential of anaplastic lymphoma kinase inhibitors in lung cancer: rationale and clinical evidence. Clin Invest 2011; 1 (8): 1119-1126.</mixed-citation></citation-alternatives></ref><ref id="cit19"><label>19</label><citation-alternatives><mixed-citation xml:lang="ru">Show AT, Yeap BY, Mino-Kenudson M et al. Clinical Features</mixed-citation><mixed-citation xml:lang="en">Show AT, Yeap BY, Mino-Kenudson M et al. Clinical Features</mixed-citation></citation-alternatives></ref><ref id="cit20"><label>20</label><citation-alternatives><mixed-citation xml:lang="ru">and Outcome of Patients With Non — Small-Cell Lung Cancer Who Harbor EML4-ALK. J Clin Oncol 2009; 27 (26): 4248-4253.</mixed-citation><mixed-citation xml:lang="en">and Outcome of Patients With Non — Small-Cell Lung Cancer Who Harbor EML4-ALK. J Clin Oncol 2009; 27 (26): 4248-4253.</mixed-citation></citation-alternatives></ref><ref id="cit21"><label>21</label><citation-alternatives><mixed-citation xml:lang="ru">Inamura K, Takeuchi K, Togashi Y, et al: EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset. Mod Pathol 22:508-515, 2009.</mixed-citation><mixed-citation xml:lang="en">Inamura K, Takeuchi K, Togashi Y, et al: EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset. Mod Pathol 22:508-515, 2009.</mixed-citation></citation-alternatives></ref><ref id="cit22"><label>22</label><citation-alternatives><mixed-citation xml:lang="ru">Wong DW, Leung EL, So KK, et al: The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer 115:1723-1733, 2009.</mixed-citation><mixed-citation xml:lang="en">Wong DW, Leung EL, So KK, et al: The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer 115:1723-1733, 2009.</mixed-citation></citation-alternatives></ref><ref id="cit23"><label>23</label><citation-alternatives><mixed-citation xml:lang="ru">Paik HJ, Choi CM, Kim H et al. Clinicopathologic implication of ALK rearrangement in surgically resected lung cancer. A proposal of diagnostic algorithm for ALK-rearranged adenocarcinoma. Lung Cancer 2012; 76:403-409.</mixed-citation><mixed-citation xml:lang="en">Paik HJ, Choi CM, Kim H et al. Clinicopathologic implication of ALK rearrangement in surgically resected lung cancer. A proposal of diagnostic algorithm for ALK-rearranged adenocarcinoma. Lung Cancer 2012; 76:403-409.</mixed-citation></citation-alternatives></ref><ref id="cit24"><label>24</label><citation-alternatives><mixed-citation xml:lang="ru">Paik HJ, Choi CM, Kim H et al. Screening of Anaplastic Lymphoma Kinase Rearrangement by Immunohistochemistry in Non-small Cell Lung Cancer. J Thor Oncol 2011; 6 (3) 266-472.</mixed-citation><mixed-citation xml:lang="en">Paik HJ, Choi CM, Kim H et al. Screening of Anaplastic Lymphoma Kinase Rearrangement by Immunohistochemistry in Non-small Cell Lung Cancer. J Thor Oncol 2011; 6 (3) 266-472.</mixed-citation></citation-alternatives></ref><ref id="cit25"><label>25</label><citation-alternatives><mixed-citation xml:lang="ru">Just P-A, Cazes A, Audebourg A, et al. Histologic subtypes, immunohistochemistry, FISH or molecular screening for the accurate diagnosis of ALK-rearrangement in lung cancer: A comprehensive study of Caucasian non-smokers. Lung Cancer 2011, 76 (3):309-315.</mixed-citation><mixed-citation xml:lang="en">Just P-A, Cazes A, Audebourg A, et al. Histologic subtypes, immunohistochemistry, FISH or molecular screening for the accurate diagnosis of ALK-rearrangement in lung cancer: A comprehensive study of Caucasian non-smokers. Lung Cancer 2011, 76 (3):309-315.</mixed-citation></citation-alternatives></ref><ref id="cit26"><label>26</label><citation-alternatives><mixed-citation xml:lang="ru">Garrido P, de Castro J, Coucha A, et al. Guidelines for biomarker testing in advanced non-small-cell lung cancer. A national consensus of the Spanish Society of Medical Oncology (SEOM) and the Spanish Society of Pathology (SEAP). Clin Transl Oncol 2012; 14:338-349.</mixed-citation><mixed-citation xml:lang="en">Garrido P, de Castro J, Coucha A, et al. Guidelines for biomarker testing in advanced non-small-cell lung cancer. A national consensus of the Spanish Society of Medical Oncology (SEOM) and the Spanish Society of Pathology (SEAP). Clin Transl Oncol 2012; 14:338-349.</mixed-citation></citation-alternatives></ref></ref-list><fn-group><fn fn-type="conflict"><p>The authors declare that there are no conflicts of interest present.</p></fn></fn-group></back></article>
