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1. Supplementary Table 3 from Next-Generation Sequencing of Pulmonary Large Cell Neuroendocrine Carcinoma Reveals Small Cell Carcinoma–like and Non–Small Cell Carcinoma–like Subsets

Author

Marc Ladanyi, Charles M. Rudin, William D. Travis, Andre L. Moreira, Michael F. Berger, Ronglai Shen, John T. Poirier, Nicholas Socci, Alexander E. Drilon, Paul K. Paik, Anya M. Litvak, Shaozhou K. Tian, Hangjun Wang, Darragh F. Halpenny, Helen Won, Arshi Arora, Jarushka Naidoo, Matthew D. Hellmann, Maria C. Pietanza, and Natasha Rekhtman

Abstract

Supplementary Table 3: Clinicopathologic characteristics

Published
2023
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2. Supplementary Table 5 from Next-Generation Sequencing of Pulmonary Large Cell Neuroendocrine Carcinoma Reveals Small Cell Carcinoma–like and Non–Small Cell Carcinoma–like Subsets

Author

Marc Ladanyi, Charles M. Rudin, William D. Travis, Andre L. Moreira, Michael F. Berger, Ronglai Shen, John T. Poirier, Nicholas Socci, Alexander E. Drilon, Paul K. Paik, Anya M. Litvak, Shaozhou K. Tian, Hangjun Wang, Darragh F. Halpenny, Helen Won, Arshi Arora, Jarushka Naidoo, Matthew D. Hellmann, Maria C. Pietanza, and Natasha Rekhtman

Abstract

Supplementary Table 5: Detailed summary of NOTCH gene family mutations

Published
2023
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3. Supplementary Table 6 from Next-Generation Sequencing of Pulmonary Large Cell Neuroendocrine Carcinoma Reveals Small Cell Carcinoma–like and Non–Small Cell Carcinoma–like Subsets

Author

Marc Ladanyi, Charles M. Rudin, William D. Travis, Andre L. Moreira, Michael F. Berger, Ronglai Shen, John T. Poirier, Nicholas Socci, Alexander E. Drilon, Paul K. Paik, Anya M. Litvak, Shaozhou K. Tian, Hangjun Wang, Darragh F. Halpenny, Helen Won, Arshi Arora, Jarushka Naidoo, Matthew D. Hellmann, Maria C. Pietanza, and Natasha Rekhtman

Abstract

Supplementary Table 6: Complete list of potentially-actionable alterations

Published
2023
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4. Supplementary Table 4 from Next-Generation Sequencing of Pulmonary Large Cell Neuroendocrine Carcinoma Reveals Small Cell Carcinoma–like and Non–Small Cell Carcinoma–like Subsets

Author

Marc Ladanyi, Charles M. Rudin, William D. Travis, Andre L. Moreira, Michael F. Berger, Ronglai Shen, John T. Poirier, Nicholas Socci, Alexander E. Drilon, Paul K. Paik, Anya M. Litvak, Shaozhou K. Tian, Hangjun Wang, Darragh F. Halpenny, Helen Won, Arshi Arora, Jarushka Naidoo, Matthew D. Hellmann, Maria C. Pietanza, and Natasha Rekhtman

Abstract

Supplementary Table 4: Complete list of mutations and copy number alterations detected by MSK-IMPACT in 45 LCNECs

Published
2023
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5. Supplementary Table 7 from Next-Generation Sequencing of Pulmonary Large Cell Neuroendocrine Carcinoma Reveals Small Cell Carcinoma–like and Non–Small Cell Carcinoma–like Subsets

Author

Marc Ladanyi, Charles M. Rudin, William D. Travis, Andre L. Moreira, Michael F. Berger, Ronglai Shen, John T. Poirier, Nicholas Socci, Alexander E. Drilon, Paul K. Paik, Anya M. Litvak, Shaozhou K. Tian, Hangjun Wang, Darragh F. Halpenny, Helen Won, Arshi Arora, Jarushka Naidoo, Matthew D. Hellmann, Maria C. Pietanza, and Natasha Rekhtman

Abstract

Supplementary Table 7: Detailed chemosensitivity data

Published
2023
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6. Data from Next-Generation Sequencing of Pulmonary Large Cell Neuroendocrine Carcinoma Reveals Small Cell Carcinoma–like and Non–Small Cell Carcinoma–like Subsets

Author

Marc Ladanyi, Charles M. Rudin, William D. Travis, Andre L. Moreira, Michael F. Berger, Ronglai Shen, John T. Poirier, Nicholas Socci, Alexander E. Drilon, Paul K. Paik, Anya M. Litvak, Shaozhou K. Tian, Hangjun Wang, Darragh F. Halpenny, Helen Won, Arshi Arora, Jarushka Naidoo, Matthew D. Hellmann, Maria C. Pietanza, and Natasha Rekhtman

Abstract

Purpose: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a highly aggressive neoplasm, whose biologic relationship to small cell lung carcinoma (SCLC) versus non-SCLC (NSCLC) remains unclear, contributing to uncertainty regarding optimal clinical management. To clarify these relationships, we analyzed genomic alterations in LCNEC compared with other major lung carcinoma types.Experimental Design: LCNEC (n = 45) tumor/normal pairs underwent targeted next-generation sequencing of 241 cancer genes by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) platform and comprehensive histologic, immunohistochemical, and clinical analysis. Genomic data were compared with MSK-IMPACT analysis of other lung carcinoma histologies (n = 242).Results: Commonly altered genes in LCNEC included TP53 (78%), RB1 (38%), STK11 (33%), KEAP1 (31%), and KRAS (22%). Genomic profiles segregated LCNEC into 2 major and 1 minor subsets: SCLC-like (n = 18), characterized by TP53+RB1 co-mutation/loss and other SCLC-type alterations, including MYCL amplification; NSCLC-like (n = 25), characterized by the lack of coaltered TP53+RB1 and nearly universal occurrence of NSCLC-type mutations (STK11, KRAS, and KEAP1); and carcinoid-like (n = 2), characterized by MEN1 mutations and low mutation burden. SCLC-like and NSCLC-like subsets revealed several clinicopathologic differences, including higher proliferative activity in SCLC-like tumors (P < 0.0001) and exclusive adenocarcinoma-type differentiation marker expression in NSCLC-like tumors (P = 0.005). While exhibiting predominant similarity with lung adenocarcinoma, NSCLC-like LCNEC harbored several distinctive genomic alterations, including more frequent mutations in NOTCH family genes (28%), implicated as key regulators of neuroendocrine differentiation.Conclusions: LCNEC is a biologically heterogeneous group of tumors, comprising distinct subsets with genomic signatures of SCLC, NSCLC (predominantly adenocarcinoma), and rarely, highly proliferative carcinoids. Recognition of these subsets may inform the classification and management of LCNEC patients. Clin Cancer Res; 22(14); 3618–29. ©2016 AACR.

Published
2023
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7. Supplementary Table 2 from Next-Generation Sequencing of Pulmonary Large Cell Neuroendocrine Carcinoma Reveals Small Cell Carcinoma–like and Non–Small Cell Carcinoma–like Subsets

Author

Marc Ladanyi, Charles M. Rudin, William D. Travis, Andre L. Moreira, Michael F. Berger, Ronglai Shen, John T. Poirier, Nicholas Socci, Alexander E. Drilon, Paul K. Paik, Anya M. Litvak, Shaozhou K. Tian, Hangjun Wang, Darragh F. Halpenny, Helen Won, Arshi Arora, Jarushka Naidoo, Matthew D. Hellmann, Maria C. Pietanza, and Natasha Rekhtman

Abstract

Supplementary Table 2: Immunohistochemical antibodies and protocols

Published
2023
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8. Supplementary Figures 1-6 from Next-Generation Sequencing of Pulmonary Large Cell Neuroendocrine Carcinoma Reveals Small Cell Carcinoma–like and Non–Small Cell Carcinoma–like Subsets

Author

Marc Ladanyi, Charles M. Rudin, William D. Travis, Andre L. Moreira, Michael F. Berger, Ronglai Shen, John T. Poirier, Nicholas Socci, Alexander E. Drilon, Paul K. Paik, Anya M. Litvak, Shaozhou K. Tian, Hangjun Wang, Darragh F. Halpenny, Helen Won, Arshi Arora, Jarushka Naidoo, Matthew D. Hellmann, Maria C. Pietanza, and Natasha Rekhtman

Abstract

Supplementary Figure 1: Example of KRAS-mutated LCNEC: Illustration of NGS and histopathologic features; Supplementary Figure 2: Dot plots for total number of genomic alterations in carcinoid-like vs other LCNECs; Supplementary Figure 3: OncoPrints for chromatin modifier, neurogenesis/neural function, DNA replication/repair and PI3K-AKT-mTOR pathway genes; Supplementary Figure 4: Map of NOTCH mutations; Supplementary Figure 5: Expression of NE genes in transcriptional subgroups of lung adenocarcinoma in TCGA series; Supplementary Figure 6: Kaplan-Meier survival curves

Published
2023
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9. Supplementary Table 1 from Next-Generation Sequencing of Pulmonary Large Cell Neuroendocrine Carcinoma Reveals Small Cell Carcinoma–like and Non–Small Cell Carcinoma–like Subsets

Author

Marc Ladanyi, Charles M. Rudin, William D. Travis, Andre L. Moreira, Michael F. Berger, Ronglai Shen, John T. Poirier, Nicholas Socci, Alexander E. Drilon, Paul K. Paik, Anya M. Litvak, Shaozhou K. Tian, Hangjun Wang, Darragh F. Halpenny, Helen Won, Arshi Arora, Jarushka Naidoo, Matthew D. Hellmann, Maria C. Pietanza, and Natasha Rekhtman

Abstract

Supplementary Table 1: Next-generation sequencing (MSK-IMPACT) gene panel

Published
2023
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11. Abstract 4736: Dose optimization of olaparib plus temozolomide in small cell lung cancer (SCLC) patient-derived xenograft (PDX) models for clinical translation

Author

Benjamin J. Drapkin, Sarah Phat, David T. Myers, Jun Zhong, Beow Y. Yeap, Elisabetta Leo, Anna Stansiszewska, Aaron Smith, Elaine Cadogan, Maria C. Pietanza, Nicholas J. Dyson, and Anna Farago

Subjects
Cancer Research, Oncology
Abstract

Introduction: SCLC is an aggressive high-grade neuroendocrine malignancy in which targeting DNA-damage repair pathways has shown efficacy in pre-clinical and clinical contexts. We previously conducted a phase I/II trial combining the PARP inhibitor olaparib (O) tablets with the alkylating agent temozolomide (T) in patients with relapsed SCLC, in which O and T were both given days (d) 1-7 of each 21 d cycle. The recommended phase 2 dose (RP2D) was O 200 mg PO BID and T 75 mg/m2 PO daily, and the response rate among the first 29 evaluable patients was 41.4%, with the primary toxicities being hematologic (Farago et al., ASCO 2018). Continuous PARP inhibition with O may improve efficacy, though it is unknown how best to incorporate T onto this backbone. Simultaneous clinical testing of multiple dosing schedules for concurrent OT would be impractical. Here we present an optimization of the OT regimen using PDX models generated from patients treated with OT. Methods: SCLC PDX models derived from two patients prior to their durable responses to OT, MGH1518-1B and MGH1528-1, were used for dose optimization. Based on a human-murine comparison of serum Cmax for OT, the estimated murine-equivalents for the RP2D doses were O 25 mg/kg BID and T 6.25 mg/kg/d. The RP2D regimen was then modulated in both dose intensity and duration in a 9-arm PDX trial. The arms included 3 schedule categories, with doses varied within each category: discontinuous regimens (OT d 1-7); continuous O regimens (O d1-21 + T d 1-7); and rapid- or slow-alternating regimens administering O and T on non-overlapping days. Tumor bearing mice were treated when subcutaneous tumors reached a volume of 400-800 cc, enabling measurement of tumor regression (PDX response) and time to volume doubling (PDX TTP). Findings: The RP2D regimen resulted in near-complete response in both models. This degree of regression was recapitulated with nearly all dosing schedules, and was not improved by increasing T to 2x-RP2D. However, the PDX TTP varied. In both models, the longest TTP was seen with continuous O at full- or half-RP2D and d 1-7 T at half-RP2D. This regimen prolonged TTP by 12% in MGH1518-1B and 20% in MGH1528-1, versus discontinuous OT at RP2D. Based on these results, we initiated clinical treatment in a new cohort of patients on OT, with a phase 1 dose escalation starting with O 50 mg BID d 1-21 and T 50 mg/m2 d 1-7 of each 21 d cycle (NCT02446704). At this first dose level, a partial response by RECIST 1.1 criteria was observed in a heavily pre-treated patient, indicating clinical activity of this combination with this new dosing strategy. Conclusions: In PDX models sensitive to OT at our previously determined RP2D, we find that continuous O with intermittent T permits dose reduction of both O and T without loss of efficacy. A clinical trial is ongoing to determine whether this strategy may enable longer-term dosing and improve efficacy in patients. Citation Format: Benjamin J. Drapkin, Sarah Phat, David T. Myers, Jun Zhong, Beow Y. Yeap, Elisabetta Leo, Anna Stansiszewska, Aaron Smith, Elaine Cadogan, Maria C. Pietanza, Nicholas J. Dyson, Anna Farago. Dose optimization of olaparib plus temozolomide in small cell lung cancer (SCLC) patient-derived xenograft (PDX) models for clinical translation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4736.

Published
2019
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12. Long-term quality of life and neuropsychologic functioning for patients with CNS germ-cell tumors: From the First International CNS Germ-Cell Tumor Study

Author

Judith G. Villablanca, Casilda Balmaceda, Howard L. Weiner, Stephen A. Sands, Amy L. Davidow, Stewart J. Kellie, Blanca Diez, Maria C. Pietanza, and Jonathan L. Finlay

Subjects
Adult, Male, Cancer Research, medicine.medical_specialty, Pediatrics, Adolescent, SF-36, Health Status, Intelligence, Neuropsychological Tests, Central Nervous System Neoplasms, Quality of life, Humans, Medicine, Risk factor, Child, Psychiatry, Aged, Radiotherapy, business.industry, Neuropsychology, Middle Aged, Neoplasms, Germ Cell and Embryonal, Tumor Pathology, medicine.disease, Oncology, Quality of Life, Female, Neurology (clinical), Germ cell tumors, Cognition Disorders, business, Neurocognitive, Psychosocial, Follow-Up Studies, Research Article
Abstract

This study evaluated the quality of life and neuropsychologic functioning among patients enrolled between 1989 and 1993 in the First International CNS Germ-Cell Tumor Study. Quality-of-life questionnaires (Short Form-36 or Child Health Questionnaire) were completed on 43 patients at median follow-up of 6.1 years after diagnosis (range, 4.5-8.8 years), and intellectual and academic testing was performed on 22 patients. Psychosocial and physical functioning of patients aged 19 years and older at follow-up was within the average range, whereas the same functioning for patients aged 18 years and younger, as reported by their parents at follow-up, was low average and borderline, respectively. Overall psychosocial and physical health summary scores were positively correlated with age at diagnosis for both groups combined. Those who received CNS radiation therapy (n = 29) reported significantly worse physical health, but similar psychosocial health, compared with those treated without radiation. Neuropsychologic testing indicated full-scale and verbal IQ, reading, spelling, and math skills in the average range, and performance IQ in the low average range. Intelligence and math skills were positively correlated with age at diagnosis. Those with germinomas significantly outperformed those with nongerminomatous/ mixed tumors on all neuropsychological measures administered. Younger patients diagnosed with CNS germ-cell tumors are at increased risk for psychosocial and physical problems as well as neuropsychologic deficits. Exposure to irradiation adversely affects overall physical functioning, whereas tumor pathology appears to be a salient neurocognitive risk factor. Collaborative and randomized studies are required to further elucidate the late effects arising from factors such as age at diagnosis, tumor histology, level of irradiation therapy, and chemotherapy toxicity among these young and potentially curable patients.

Published
2001
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13. NEURO/MEDICAL ONCOLOGY

Author

Irene Helenowski, Naoya Hashimoto, Jan J. Heimans, Toshiki Yoshimine, Johan A F Koekkoek, Evelyne Emery, José L. Asencio, Andrea Chamczuck, Carly Bridge, Gilbert Faure, Barbara-Ann Millar, Arthur Rosiello, Michela Casanova, John Freymann, Giulio Bertani, Jun-ich Adachi, Christian LaFougere, Julianne Bloom, Paul Vincent Opinaldo, Tobey J. McDonald, Alexander Khandji, Maciej M. Mrugala, Agnieszka Kowalska, Clifford G. Robinson, Josef Pichler, Jayesh Mehta, Lisa M. DeAngelis, Katie Slusarz, Rachel Grossman, Juan Armando Mejía, Sadhana Kannan, In Ah Kim, Pierre Soubeyran, Nabil Ahmed, Matthew J. Matasar, David A. Reardon, Marie-Laure Tanguy, Andrea Pace, Vani Santosh, Tackeun Kim, Adrienne C. Lahti, John E. Donahue, Pavlina Poloskova, Marc H. A. Jansen, Nilanjana Banerji, Margaret Schwartz, Matthias Kirsch, Robert Jeraj, Guus A.M.S. van Dongen, Samuel Singer, Tom J. Snijders, Santosh Kesari, Riccardo Soffetti, Takashi Sasayama, Diana Ly, Kaoru Kurisu, Carsten Friedrich, Shinji Kawabata, Cedric Revil, Michael A. Jacobs, Ryuichi Hirayama, Wan-Soo Yoon, Kathleen Lupica, Christopher Reilly, Takuichiro Hideo, Miguel Gil, Josep Garcia, Ming Zheng, Edward K. Avila, Mairéad G McNamara, Hartmut Uschmann, Jeffrey S. Weinberg, Craig H. Moskowitz, Jörg Hense, Manmeet Ahluwalia, Georg Bjarnason, David Corwin, Shakti Ramkissoon, Jad Alshami, Eric C. Leuthardt, Paul Dilfer, Margaret Patton, Lindsey Heathcock, Cees van Montfort, Rakesh Kumar Gupta, Akihiko Yoshida, Carmine Maria Carapella, Guy K. Mckhann, Marian Hajduch, Meinhard Nevinny-Stickel, Patricia Bruns, Ashish Suri, Hernán Carranza, David A. Gutman, Carlos Yepes, Patrick Y. Wen, T. Cloughesy, Anna Kaltenboeck, Carlos Bartels, Paul D. Brown, Lisa Fichtel, Lorenzo Giammattei, Steven Hamilton, Nobuyuki Takayama, Nan Lin, Jan Drappatz, Roland Eils, Akihiro Tsuboi, Patrick Urban, Minesh P. Mehta, Remy Gressin, Zarnie Lwin, Clarence Eng, Ian F. Dunn, Sin-Soo Jeun, Alva B. Weir, Elisa Trevisan, silviya Meletath, Fumiyuki Yamasaki, Scott N. Hwang, Navya Nambudiri, Timothy F. Cloughesy, Paolo Rampini, Kathryn J. Ruddy, Justin Kirby, Marc C. Huisman, Normand Laperriere, Abajo Guijarro, Alberto González-Aguilar, David M. Peereboom, Antoine F. Carpentier, Steven M. Greenberg, Chikashi Ishioka, Sarah C. Gaffey, Sneha Arya, Guy M. McKhann, Richard Curry, Takashi Watanabe, Keishi Makino, Radek Trojanec, Hideo Takeshima, Joseph F. Megyesi, Jasmina I. Ivanova, Victor Rodriguez Berrocal, Marcel Kool, Eric Burton, Sandra K. Johnston, Hideyuki Arita, Konstantina Karabatsou, Robert C. Rostomily, Sean Grimm, Ralph G. Dacey, Karl Olson, Sonia Gómez, Harry C. Schouten, Christof M. Kramm, Fred H. Hochberg, Darren Hargrave, Kazuhiko Sugiyama, Wilhelm Boogerd, Stefano Tiziani, Christine McCluskey, Albert H. Kim, Tejpal Gupta, Ida Martinelli, Friedrich-Wilhelm Kreth, Lennea Coombs, Keith L. Ligon, J. Manuel Sarmiento, David R. Macdonald, Holly Dickinson, Cristian Massacesi, Basile Wittwer, Jung-Il Lee, Volker Hovestadt, Mark Smolkin, Sampath Somanna, Ingo K. Mellinghoff, Nancy Ann Oberheim Bush, Sanjeev Francis, Roland Goldbrunner, Jai Ho Choi, John Sampson, Roy Allan Dominique Torcuator, Kathleen R. Lamborn, Simon V. Liubinas, Daniel J. Sargent, Christina K. Cramer, Francine Armentano, Heather Leeper, Stefan Rutkowski, Prakash Shetty, Arivazhagan Arimappamagan, Alicia Ortega, Enrique Jiménez, Kazuhiro Tanaka, Kolette D. Fly, Seunggu Han, Nicolas U. Gerber, David Schiff, Antonella Castellano, Isabel Arrillaga-Romany, Robert J. Wechsler-Reya, Sophie Taillibert, Macarena de la Fuente, Wolfgang Wick, Monica Bennett, Francesco Cognetti, John de Groot, Michael Gonzales, Leon D. Ortiz, Yoshiaki Shiokawa, George Sachs, Ivo Tremont, Charles A. Conrad, Michael D. Taylor, Igor J. Barani, Shannon Langmead, Lisa Sturla, Doosik Kong, Rebecca D. Folkerth, Garrett Riggs, Yoon-La Choi, Carole Soussain, Calvin Soh, Peter Canoll, Mariza Daras, Melissa Hoag, James Rigas, Dana Cernea, Liu Diane, Kenji Wakiya, Sandra Silberman, Ivan A. Reveles, Jeffrey S. Wefel, Wenting Wu, Marie Blonski, MA Majaid, Vanessa A. Nestor, Maurits W.C.B. Sanders, Cynthia Harrison, Ruxandra Costa, Andrea Hawkins-Daarud, Mark R. Gilbert, Ruth Katz, Masayuki Kanamori, Tomek Janicki, Aaron C. Spalding, Dong-Sup Chung, Lauren Foresman, Fateme Salehi, Allan H. Friedman, Eric P. Winer, Robert Kwiecien, Joachim Kuehl, Motoo Nagane, Stanislaw Burzynski, Tomokazu Aoki, Gregory N. Fuller, Nina Paleologos, Darell D. Bigner, Max Wintermark, Adam E. Flanders, Eiichi Ishikawa, Subramanian Hariharan, Doreen Pachow, Glen Stevens, Ulrich Schüller, Jennifer Lycette, Jennifer Garst, Jeffery T. Williams, Gordana Vlahovic, Tjeerd J. Postma, Tribhwan Vats, Isabel Arrilaga, Krista Follmer, Henry S. Friedman, Kenneth Schwartz, James Perry, Jonas M. Sheehan, Christian Grommes, Annette M. Molinaro, Seung-Ho Yang, Peter Lichter, Naoki Kagawa, Trish Whitcomb, Monica Loghin, Amanda L. Bergner, Miroslav Vaverka, Jayashree Kalpathy-Cramer, Chitra Sarkar, Thomas Davidson, Nithya Ramnath, Leland Rogers, Roberta Rudà, Steven A. Toms, Martin Gore, Khê Hoang-Xuan, Emmanuel Gyan, Hani Malone, Jun-ichi Adachi, Jennifer Rifenburg, Stefan M. Pfister, Luis Carlos Mayor, Vanja Vaccaro, Hannah E. Goldstein, Karen Fink, Eva Dombi, Timothy Cloughsey, Sabina Eigenbrod, Jiri Ehrmann, Li Li, Pamela R. Jackson, Makoto Ohno, Craig Nolan, Gerald P. Linette, Tatjana Seute, Eric Bouffet, Patricia M. M. B. Soetekouw, David J. Pisapia, Marc Remke, Susan Snodgras, David Tran, Keiichi Kobayashi, Warren P. Mason, Setsu Sakamoto, Chiara Bosa, Gabriele Schackert, Alfred Yung, David Cachia, Toshihiko Kuroiwa, María Ángeles Vaz Salgado, F. Lonnqvist, Francesca Piludu, Alvina Acquaye, Keisuke Ueki, Jung Ho Han, Kathy Newell, Mythili Shastry, Yoon Jae Cho, Marco Riva, Laura M. Fayad, Kristin Diefes, André O. von Bueren, Ina Ly, Beatrix Lutiger, Hiroyoshi Suzuki, Jeanette K. Doorduijn, Eiji Kohmura, Olivier Chinot, Ichiyo Shibahara, Nathalie Jansen, Marta Del Álamo de Pedro, Scott L. Pomeroy, Andreas Zwergal, Terri S. Armstrong, Elmar Kirches, Daniel P. Cahill, Howard A. Fine, Cezary Szczylik, Stéphane Oudard, Gregg C. Shepard, Mark G. Kris, Andrea Milbourne, Dominique Jennings, Marco Locatelli, Dereck Amakye, Takumi Kudo, Simon Bailey, Alessandra Fabi, Taketoshi Maehara, Soumen Khatua, Caroline Houllier, Klaus J. Müller, Jaishri O. Blakeley, Karen Kelly, Jonathon Yun, Thomas Gergel, Diane Liu, Eric T. Wong, Alin Borha, Brian J. Williams, Rakesh Jalali, Birgit Geoerger, Naosuke Nonoguchi, Julie Walker, Jasmin Jo, Manmohan Singh, Mary Noel, Denise Lally-Goss, Tracy T. Batchelor, Andrea Falini, Maximilian Niyazi, Jeffrey Raizer, Martin J. van den Bent, Aleksandra Gruslova, Phioanh L. Nghiemphu, Kristin R. Swanson, Maaike J. Vos, Jethro Hu, Rebeca Alcalce Pampliega, Craig S. Sauter, Leena Ketonen, Michael A. Vogelbaum, Donald Picker, Robert Hawkins, Chris Halpin, Otto S. Hoekstra, Elizabeth Vera-Bolanos, Ahmad Awada, Sawan Kumar, Alexandra Benouaich-Amiel, Joseph Pernicone, Noriyuki Kawabata, Andrew H. Kaye, David Brachman, Kurt A. Jaeckle, Cameron J. Nowell, Maria Carlo, Tom Mikkelsen, Jorg Dietrich, Tomonari Suzuki, Kohei Fukuoka, Philippe Aftimos, Christine Schmid-Tannwald, Vera Wenter, Valeria Conte, Scott Turner, Brian J A Gill, John D. Cullen, Jiayi Huang, Saurabh Dahiya, Vincent Delwail, Lien Bekaert, Priya Kumthekar, Roberta Seidman, Scott R. Plotkin, Priya Deshpande, Christopher Zalewski, Vaibhav Patel, Peter Kurniali, Martha Nowosielski, Zvi Ram, Susan M. Chang, Dannis G. van Vuurden, Stuart A. Grossman, Vaishali Suri, Rajan Jain, Christine Carico, Ying Yuan, Yoji Yamashita, Bojana Milojkovic-Kerklaan, Yannick Kerloeguen, Michael B. Sisti, Rameen Beroukhim, Andrea Artoni, Frances McSherry, John J. Evans, Mark E. Shaffrey, Lauren E. Abrey, Akshal S. Patel, Laura Bernal-Vaca, Rolf-Dieter Kortmann, Robert Grubb, Mimi Lee, Jörg-Christian Tonn, Shinobu Yamada, Andrés Quintero, Kazuhiko Mishima, Ania Marszalek, Stephen Gancher, Amal Melhem-Bertrandt, Takamitsu Fujimaki, Monika Warmuth-Metz, George Avgeropoulos, Rifaquat Rahman, Franck Bourdeaut, Frank Feleppa, Jennifer Clarke, Meredith A. Reid, Maria Werner-Wasik, Andrew D. Norden, Kenneth D. Swanson, Jeffrey N. Bruce, Chae-Yong Kim, Steven S. Rosenfeld, Haiyan Jiang, Oliver Schnell, Toshihiro Kumabe, Michael J. Sullivan, W. Gladdines, Glenn J. Lesser, Chang-Ho Yun, Epari Sridhar, Sophie Lebouvier-Sadot, Andrea Baldwin, Chirag G. Patil, Thomas Smith, Shin-Ichi Miyatake, Renato LaRocca, Kent C. Shih, Russell C. Rockne, Katsu Mizukawa, Antonio Omuro, Ryuta Saito, Mohamed H. Hamza, Eunju Hurh, Silke Soucek, Michel Lacroix, Brian J. Scott, Thomas Kaley, Tetsuya Yamamoto, Gregory J. Zipfel, Andrew Lin, Elena Pentsova, Carlos Emilio Restrepo, Utkarsh Bhagat, Masao Matsutani, Andrew B. Lassman, Stephanie L. Pugh, Yasuji Miyakita, Manabu Kinoshita, Christian Hagel, D. Brandsma, Jorge M. Otero, Marco Timmer, Ke Zhang, S. Altintas, Thierry Lamy, Hirofumi Hirano, Mehar Chand Sharma, Wafik S. El-Deiry, Peter A. Sims, Evanthia Galanis, Yong-Kil Hong, Terence J. O'Brien, Haruo Sugiyama, Dieta Brandsma, Loretta Barron, Joshua J. Jacobs, Roger Henriksson, Albert Lai, David White, Xiao-Tang Kong, John D. Hainsworth, Petronella J Lugtenburg, Paul A. Northcott, Maryline Barrie, Kenneth J. Cohen, Tanuj Saaraswat, Xiaobu Ye, Sandra Ruland, Diana M. Haninger, Surasak Phuphanich, Marc C. Chamberlain, Kenneth Aldape, Ewa Matczak, Phyo Kim, Peter Bartenstein, Lumir Hrabalek, Howard Y. Chang, Donatella Tampieri, Fumi Higuchi, Katherine S. Panageas, Allicia C. Girvan, Majid Khan, Stevie Threatt, Tareq Juratli, Mitchel S. Berger, Linda Dirven, Michele Nikolai, Emmanuelle DiTomaso, Sarah Leary, Jan H.M. Schellens, Chuanlu Jiang, Michael Glantz, Harald Sontheimer, Michael D. Prados, Mauricio Lema, Marie-Christine Guiot, Shesh N. Rai, Minhee Won, Carlos Vargas, Eva Galanis, Kazunori Arita, David I. Sandberg, Gianluca Ardolino, Sylvain Choquet, Ondrej Kalita, Michael Rytting, Lorenzo Bello, Luis Ley Urzaiz, Martin J.B. Taphoorn, Kourosh Jafari-Khouzani, Alfred Rademaker, Juan Martinez San Millan, Isabelle Aerts, Sergio Bracarda, John Norton, Mark D. Anderson, Barbara Zarino, Jun Ichi Kuratsu, Nicholas Butowski, Derek R. Johnson, James E. Herndon, Diana Giannarelli, Debra LaFrankie, Filippo Cogiamanian, Yasuyoshi Chiba, Hideo Nakamura, Agnes Jager, Caroline Chung, Paula Warren, Frans S. S. Leijten, Peter Hau, Yusuke Oji, Yuichi Hirose, Kathryn Gilliland, Sadao Kaneko, W. K. Alfred Yung, Roger Stupp, Amy Chung, Yutaka Hata, Mary Frances McAleer, Hee-Won Jung, Miloslava Zlevorová, Brendan Killory, Raymond Sawaya, Anita Chawla, John Trusheim, H. Ian Robins, Judy Lima, Prakash Ambady, Barbara O'Brien, Sonia Bermúdez, Howard Colman, Matthias Gromeier, Jean-Sébastien Guillamo, Maria C. Pietanza, Antonello Vidiri, Laura Guyman, Kristin Swanson, Paul Rosenblatt, Joshua L. Dowling, Lakshmi Nayak, Ashlee Drawz, Yu Jung Kim, Mikael L. Rinne, Shlomit Yust-Katz, Jessi Stevens, Katharine J. Drummond, Patricia Wing, Sarah Taylor, Joshua E. Allen, Ron Schaafsma, John DeGroot, Shigetoshi Yano, Paula Rauschkolb, Anupam Kumar, Soichiro Shibui, M. E. van Linde, Shirish M. Gadgeel, Yoshitaka Narita, Nicholas G. Avgeropoulos, Luca Bertero, Hongjun Wang, Jason K. Rockhill, Suriya Jeyapalan, Yukihiko Sonoda, Hikaru Sasaki, Shirley L. Markant, Masamitsu Nishihara, Daniel J. Brat, Alexandra Flowers, Monica Sierra del Rio, Morgan Prust, Adam M. Sonabend, Pierre A. Robe, James J. Dignam, Julia C. Chisholm, Gregory J. Riely, Mary Gerard, Sajeel Chowdhary, Natalie Jäger, Giovanna M. D'Abaco, James J. Culhane, Tatsunori Okamura, Erik P. Sulman, L. Adriana Esparza, Ivo W. Tremont-Lukats, Emily Porensky, Yoshihiro Oka, Marcelo De Carvalho, Brigitte C. Widemann, Stacey Kalambakas, Rolf D. Kortmann, Stewart Goldman, Jaap C. Reijneveld, Andrew Brenner, Jacob Mandel, Riccardo Draghi, Yunus Arik, Shinji Yamashita, Torsten Pietsch, Tanweer Zaidi, Dawid Schellingerhout, Marta Penas-Prado, Veronica Villani, Adriana Olar, Vanessa L. Merker, Matthias Holdhoff, Joke W. Baars, Katrina H. Smith, Arnab Chakravarti, Giorgio Carrabba, Gertjan J.L. Kaspers, Susan Boulton, Peter A. Forsyth, David T.W. Jones, Anne Baldock, Meier Hsu, Soham Dasgupta, Jeremy Rudnick, Arun Rai, Jessica Sun, Naoki Shinojima, Christian Mawrin, Eita Uchida, Jaswinder Jutla, Koichi Ichimura, Alona Muzikansky, Jean Philippe Maire, Louis B. Nabors, Yuko Matsushita, Emilie Le Rhun, Annick Desjardins, Magali Lecavalier-Barsoum, Laurie Rice, Bradford A. Moffat, Kelly Hempfling, Andrew A. Kanner, Mark W. Kieran, Stephanie M. Robert, Hervé Ghesquières, Alba A. Brandes, E. Sander Connolly, Jingxia Liu, David T. Dicker, Katherine B. Peters, Gregory S. Burzynski, Charles Sweeley, Deborah T. Blumenthal, Nicolás Useche, Tulika Ranjan, Thierry Muanza, Mercedes Garcia Villanueva, Fernando Hakim, Yana Krutoshinskaya, Shintaro Fukushima, Ryo Nishikawa, Damien C. Weber, Michael R. Chicoine, Motomasa Furuse, André Busson, Joseph R. Simpson, Gabriele Röhn, Susanne Koeppen, Arjun Sahgal, Fabio M. Iwamoto, Leland Graves, Sarah Iglseder, Taro Yanagawa, Michael Lahn, Ramaswamy Govindan, Eduardo Roberts Cervantes, Eric S. Wong, Nadine Kliese, Feng Tai, Katja von Hoff, Vincenzo Anelli, Trevor J. Pugh, Andrés F. Cardona, Gebra Cuyun Carter, Yuko Watanabe, Bogdana Suchorska, Manuela Caroli, José Luis Asencio, Eudocia Q. Lee, John Floyd, Lucas Moreno, Samantha J Mills, Jun-ichiro Kuroda, Susan Chi, David N. Louis, Aanchal Kakkar, Elizabeth R. Gerstner, Annika Schlamann, Robert Cavaliere, John L. Villano, Asha Das, Petr Kavan, Takaaki Yanagisawa, Luc Taillandier, Jonathan Fratkin, Günther Stockhammer, Tomasz Janicki, Sherese Fralin, Wafik Zaky, Lisa Scarpace, Kazunari Yoshida, Magalie Hilton, Andrey Korshunov, Aliasgar Moiyadi, Alexandra Gorelick, Alfredo Carrato Mena, Yuya Nishiyama, Riccardo Soffietti, Marina Donativi, Andrew S. Chi, Lauren Schaff, Andrew P. Morokoff, Sophie E. M. Veldhuijzen van Zanten, Hans-Joachim Reimers, John G. Stewart, Clare Ferrigno, Jackson Hamilton, Do-Hyun Nam, Samantha Hammond, Regina Krel, Mika Watanabe, Anna K. Nowak, Elina Tsyvkin, Michael W. McDermott, Jacoline E C Bromberg, Teiji Tominaga, Laila M. Poisson, Lisa Doherty, Alessia Lodi, Vino Apok, Magdalena Kneblova, Michelle Bell, Carl Jaffe, Sunita Dahr, Maria Koh, Pedro Garciarena, J. Gregory Cairncross, Ana Gómez Rueda, Augustus Perez, Ho Jun Seol, Frank Saran, Camillo Porta, Grace Elzinga, Michael Cloney, and Charles P. Hart

Subjects
Cancer Research, medicine.medical_specialty, business.industry, 010403 inorganic & nuclear chemistry, 01 natural sciences, 0104 chemical sciences, 03 medical and health sciences, Abstracts, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, medicine, Medical physics, Neurology (clinical), business
Published
2013

14. Coagulation activation is associated with nicotinamide adenine dinucleotide phosphate oxidase-dependent reactive oxygen species generation in hemodialysis patients

Author

Mario Colucci, Stefania C Pietanza, Giovanni Pertosa, Francesca Incampo, Giuseppe Grandaliano, Loreto Gesualdo, Simona Simone, Margherita Gigante, Marica Cariello, Antonia Loverre, and Francesco Paolo Schena

Subjects
Adult, Male, medicine.medical_specialty, Physiology, Surface Properties, medicine.medical_treatment, Clinical Biochemistry, Biochemistry, Peripheral blood mononuclear cell, chemistry.chemical_compound, In vivo, Renal Dialysis, Internal medicine, medicine, Humans, Sulfones, Molecular Biology, General Environmental Science, chemistry.chemical_classification, Oxidase test, Reactive oxygen species, NADPH Oxidases, Membranes, Artificial, Cell Biology, Nylons, Endocrinology, Coagulation, chemistry, Leukocytes, Mononuclear, General Earth and Planetary Sciences, Female, Polyvinyls, Hemodialysis, Reactive Oxygen Species, Intracellular, Nicotinamide adenine dinucleotide phosphate
Abstract

This study investigated on (i) the role of gp91(phox)/NOX2 in reactive oxygen species (ROS) generation in hemodialysis (HD) patients, and (ii) the link between clotting activation and ROS production in this setting.The study was performed on peripheral blood mononuclear cells (PBMCs) isolated from HD patients randomized to polysulphon/polyamide (S-group, n=30) or ethylene-vinyl-alcohol (EVAL) membrane (E-group, n=30) treatment and from healthy subjects (control group, n=15). ROS generation was increased in PBMCs of HD patients compared with healthy subjects. S-group showed higher levels of intracellular ROS generation than control, whereas E-group did not. In addition, S-group displayed an increase in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity compared with E-group and healthy subjects. A further increase in NADPH activity shortly after HD treatment was observed only in S-group. The plasma levels of the prothrombin fragment F1+2, a marker of in vivo clotting activation, were significantly higher in S-group than in E-group. Moreover, a heightened thrombin generation was recorded in the plasma of S-group. Intracellular ROS production correlated with NADPH oxidase activity and coagulation priming in HD patients. The in vitro validation study demonstrated that incubation of PBMCs with activated FX induced a significant increase in intracellular ROS production, superoxide generation, and gp91(phox)/NOX2 expression.The pivotal role of NADPH oxidase in the upregulation of ROS in HD patients makes this enzyme a potential target for therapeutic intervention in the treatment of HD-related oxidative stress.The EVAL membrane, by reducing clotting activation, inhibits gp91(phox)/NOX2-related ROS production in HD patients.

Published
2011

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