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Thomas Ho Lai Yau School of Medicine, University of Nottingham, Derby, UK

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Kwok-Leung Cheung School of Medicine, University of Nottingham, Derby, UK

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phosphoinositide 3-kinase/v-akt murine thymoma viral oncogene/mammalian target of rapamycin (PI3K/AKT/mTOR) can result in continued proliferation of the cancer cells and hence develop resistance to ET ( Dixon 2014 ). Targeted therapy agents (TAs) are designed to

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Carlos J P Álvarez Laboratorio de Endocrinología Molecular y Celular, CIBER Fisiopatología de la Obesidad y Nutrición (CB06/03), Department of Endocrinology, Departamento de Medicina, Instituto de Investigaciones Sanitarias, Complejo Hospitalario Universitario de Santiago (CHUS), A Choupana, s/n., 15706 Santiago de Compostela, Spain
Laboratorio de Endocrinología Molecular y Celular, CIBER Fisiopatología de la Obesidad y Nutrición (CB06/03), Department of Endocrinology, Departamento de Medicina, Instituto de Investigaciones Sanitarias, Complejo Hospitalario Universitario de Santiago (CHUS), A Choupana, s/n., 15706 Santiago de Compostela, Spain

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María Lodeiro Laboratorio de Endocrinología Molecular y Celular, CIBER Fisiopatología de la Obesidad y Nutrición (CB06/03), Department of Endocrinology, Departamento de Medicina, Instituto de Investigaciones Sanitarias, Complejo Hospitalario Universitario de Santiago (CHUS), A Choupana, s/n., 15706 Santiago de Compostela, Spain
Laboratorio de Endocrinología Molecular y Celular, CIBER Fisiopatología de la Obesidad y Nutrición (CB06/03), Department of Endocrinology, Departamento de Medicina, Instituto de Investigaciones Sanitarias, Complejo Hospitalario Universitario de Santiago (CHUS), A Choupana, s/n., 15706 Santiago de Compostela, Spain

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Marily Theodoropoulou Laboratorio de Endocrinología Molecular y Celular, CIBER Fisiopatología de la Obesidad y Nutrición (CB06/03), Department of Endocrinology, Departamento de Medicina, Instituto de Investigaciones Sanitarias, Complejo Hospitalario Universitario de Santiago (CHUS), A Choupana, s/n., 15706 Santiago de Compostela, Spain
Laboratorio de Endocrinología Molecular y Celular, CIBER Fisiopatología de la Obesidad y Nutrición (CB06/03), Department of Endocrinology, Departamento de Medicina, Instituto de Investigaciones Sanitarias, Complejo Hospitalario Universitario de Santiago (CHUS), A Choupana, s/n., 15706 Santiago de Compostela, Spain

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Jesús P Camiña Laboratorio de Endocrinología Molecular y Celular, CIBER Fisiopatología de la Obesidad y Nutrición (CB06/03), Department of Endocrinology, Departamento de Medicina, Instituto de Investigaciones Sanitarias, Complejo Hospitalario Universitario de Santiago (CHUS), A Choupana, s/n., 15706 Santiago de Compostela, Spain
Laboratorio de Endocrinología Molecular y Celular, CIBER Fisiopatología de la Obesidad y Nutrición (CB06/03), Department of Endocrinology, Departamento de Medicina, Instituto de Investigaciones Sanitarias, Complejo Hospitalario Universitario de Santiago (CHUS), A Choupana, s/n., 15706 Santiago de Compostela, Spain

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Felipe F Casanueva Laboratorio de Endocrinología Molecular y Celular, CIBER Fisiopatología de la Obesidad y Nutrición (CB06/03), Department of Endocrinology, Departamento de Medicina, Instituto de Investigaciones Sanitarias, Complejo Hospitalario Universitario de Santiago (CHUS), A Choupana, s/n., 15706 Santiago de Compostela, Spain
Laboratorio de Endocrinología Molecular y Celular, CIBER Fisiopatología de la Obesidad y Nutrición (CB06/03), Department of Endocrinology, Departamento de Medicina, Instituto de Investigaciones Sanitarias, Complejo Hospitalario Universitario de Santiago (CHUS), A Choupana, s/n., 15706 Santiago de Compostela, Spain
Laboratorio de Endocrinología Molecular y Celular, CIBER Fisiopatología de la Obesidad y Nutrición (CB06/03), Department of Endocrinology, Departamento de Medicina, Instituto de Investigaciones Sanitarias, Complejo Hospitalario Universitario de Santiago (CHUS), A Choupana, s/n., 15706 Santiago de Compostela, Spain

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Yolanda Pazos Laboratorio de Endocrinología Molecular y Celular, CIBER Fisiopatología de la Obesidad y Nutrición (CB06/03), Department of Endocrinology, Departamento de Medicina, Instituto de Investigaciones Sanitarias, Complejo Hospitalario Universitario de Santiago (CHUS), A Choupana, s/n., 15706 Santiago de Compostela, Spain
Laboratorio de Endocrinología Molecular y Celular, CIBER Fisiopatología de la Obesidad y Nutrición (CB06/03), Department of Endocrinology, Departamento de Medicina, Instituto de Investigaciones Sanitarias, Complejo Hospitalario Universitario de Santiago (CHUS), A Choupana, s/n., 15706 Santiago de Compostela, Spain

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antibodies to phospho-p44/42 mitogen-activated protein kinases (MAPK), p44/42 MAPK, phospho-Src(Y416), phospho-Akt HM(S473), phospho-Akt A-loop(T308), Akt, Rictor, phospho-mTOR (S2448), phospho-p70S6K1(T389), phospho-PDK1 (S241), Rictor siRNA and control

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R J Santen
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R X Song
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Z Zhang
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R Kumar
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M-H Jeng
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A Masamura
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J Lawrence Jr
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L Berstein
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W Yue
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specific proteins were scanned and relative optical densities of bands were determined using a Molecular Dynamics scanner and ImageQuant program ( Yue et al. 2002 ). Mammalian target of rapamycin (mTOR) studies The

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T Vandamme Center of Oncological Research (CORE), University of Antwerp, Antwerp, Belgium
Section of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

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M Beyens Center of Oncological Research (CORE), University of Antwerp, Antwerp, Belgium

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G Boons Center of Oncological Research (CORE), University of Antwerp, Antwerp, Belgium

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A Schepers Center of Medical Genetics, University of Antwerp, Antwerp, Belgium

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K Kamp Section of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

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K Biermann Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands

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P Pauwels Department of Pathology, University of Antwerp, Antwerp, Belgium

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W W De Herder Section of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

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L J Hofland Section of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

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M Peeters Center of Oncological Research (CORE), University of Antwerp, Antwerp, Belgium

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G Van Camp Center of Medical Genetics, University of Antwerp, Antwerp, Belgium

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K Op de Beeck Center of Oncological Research (CORE), University of Antwerp, Antwerp, Belgium

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(PI3K/Akt/mTOR) pathway were found in 12–14% of tumors ( Jiao et al . 2011 , Scarpa et al . 2017 ). In the pivotal Radiant-3 trial, treatment with everolimus, an mTOR inhibitor, has demonstrated an improved progression-free survival in advanced

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Elke Tatjana Aristizabal Prada Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Campus Grosshadern, Munich, Germany
Department of Internal Medicine 2, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany
Department of Internal Medicine 4, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany

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Vera Heinzle Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Campus Grosshadern, Munich, Germany
Department of Internal Medicine 2, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany

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Thomas Knösel Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Campus Grosshadern, Munich, Germany
Institute of Pathology, Ludwig-Maximilians-University of Munich, Munich, Germany

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Svenja Nölting Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Campus Grosshadern, Munich, Germany
Department of Internal Medicine 2, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany
Department of Internal Medicine 4, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany

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Gerald Spöttl Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Campus Grosshadern, Munich, Germany
Department of Internal Medicine 2, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany
Department of Internal Medicine 4, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany

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Julian Maurer Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Campus Grosshadern, Munich, Germany
Department of Internal Medicine 2, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany
Department of Internal Medicine 4, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany

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Christine Spitzweg Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Campus Grosshadern, Munich, Germany
Department of Internal Medicine 2, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany
Department of Internal Medicine 4, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany

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Martin Angele Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Campus Grosshadern, Munich, Germany
Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany

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Nina Schmidt Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Campus Grosshadern, Munich, Germany
Department of Internal Medicine 2, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany
Department of Internal Medicine 4, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany

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Felix Beuschlein Department of Internal Medicine 4, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany
Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, Universitätsspital Zürich, Zurich, Switzerland

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Günter K Stalla Clinical Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany

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Rainer Blaser Institute of Medical Statistics and Epidemiology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany

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Klaus A Kuhn Institute of Medical Statistics and Epidemiology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany

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Christoph J Auernhammer Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Campus Grosshadern, Munich, Germany
Department of Internal Medicine 2, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany
Department of Internal Medicine 4, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany

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-Raf-MEK-ERK, the PI3K-Akt-mTOR, the PLCγ-1 and the PKC pathway ( Huang & Reichardt 2003 , Amatu et al . 2016 ). The Trk receptor family has been demonstrated to be implicated in the growth of many different types of cancer, for example, oral squamous cell

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Bruno Heidi Nozima Division of Genetics, Department of Morphology and Genetics, Genetic Bases of Thyroid Tumors Laboratory, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil

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Thais Biude Mendes Division of Genetics, Department of Morphology and Genetics, Genetic Bases of Thyroid Tumors Laboratory, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil

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Gustavo José da Silva Pereira Department of Pharmacology, Calcium Signaling and Cell Death Laboratory, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil

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Rodrigo Pinheiro Araldi Division of Genetics, Department of Morphology and Genetics, Genetic Bases of Thyroid Tumors Laboratory, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil

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Edna Sadayo Miazato Iwamura Laboratório de Patologia Molecular, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil

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Soraya Soubhi Smaili Department of Pharmacology, Calcium Signaling and Cell Death Laboratory, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil

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Gianna Maria Griz Carvalheira Division of Genetics, Department of Morphology and Genetics, Genetic Bases of Thyroid Tumors Laboratory, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil

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Janete Maria Cerutti Division of Genetics, Department of Morphology and Genetics, Genetic Bases of Thyroid Tumors Laboratory, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil

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al. 2004 ). Others have showed that FAM129A is induced under endoplasmic reticulum (ER) stress in few cell types such as liver, kidney and cerebrum and may function to link and coordinate ER stress and mTOR/S6K1 pathway ( Sun et al. 2007

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Dawei Wu Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China

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Dongwei Lv Department of Sports Medicine, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China

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Ting Zhang Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China

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Lianying Guo Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China

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Fangli Ma Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China

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Caihua Zhang Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China

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Guofeng Lv Department of Sports Medicine, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China

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Lin Huang Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China

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purchased for the detection of β-actin (AC-15; Sigma); PRAS40 (Invitrogen); cleaved PARP, p-Akt (S473), p-PDK1, p-PRAS40 (T246), p-PI3K (p85), p-S6 ribosomal protein, p-mTOR (S2448), S6 ribosomal protein, p-IGF1R (Y1135/1136)/p-IR (Y1150/1151), S6, Akt, PI3K

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Eyun Song Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Songpa-gu, Seoul, Republic of Korea

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Dong Eun Song Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Songpa-gu, Seoul, Republic of Korea

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Jonghwa Ahn Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Songpa-gu, Seoul, Republic of Korea

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Tae Yong Kim Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Songpa-gu, Seoul, Republic of Korea

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Won Bae Kim Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Songpa-gu, Seoul, Republic of Korea

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Young Kee Shong Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Songpa-gu, Seoul, Republic of Korea

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Min Ji Jeon Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Songpa-gu, Seoul, Republic of Korea

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Won Gu Kim Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Songpa-gu, Seoul, Republic of Korea

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members of PI3K/AKT/mTOR pathway. The mean depth of target lesions of each sample ranged from 155.6 to 2705.4. Results Tissue samples and clinical data A total of 82 tissues were available for genetic analyses from 64 patients as follows: 63

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Paramita M Ghosh
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Shazli N Malik
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Roble G Bedolla
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Yu Wang
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Margarita Mikhailova
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Thomas J Prihoda
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Dean A Troyer
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Jeffrey I Kreisberg
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phosphorylation at multiple sites ( Grewe et al. 1999 ). p70 S6 kinase is phosphorylated by a phosphoinositide kinase-related kinase, mammalian target of rapamycin (mTOR) at Thr-389. This causes re-folding of the protein resulting in exposure of the Thr-229 site

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Lamis Yehia Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA

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Charis Eng Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA
Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
Germline High Risk Cancer Focus Group, CASE Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA

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mutations in the PTEN tumor suppressor gene. Regardless of clinical phenotype, such individuals with germline PTEN mutations have PTEN hamartoma tumor syndrome. Interestingly, mutations in other genes that encode components of the PI3K/AKT/mTOR

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