Publications by authors named "James DeGregori"

110 Publications

Targeting tumor-derived NLRP3 reduces melanoma progression by limiting MDSCs expansion.

Proc Natl Acad Sci U S A 2021 Mar;118(10)

Department of Medicine, University of Colorado Denver, Aurora, CO 80045;

Interleukin-1β (IL-1β)-mediated inflammation suppresses antitumor immunity, leading to the generation of a tumor-permissive environment, tumor growth, and progression. Here, we demonstrate that nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing-3 (NLRP3) inflammasome activation in melanoma is linked to IL-1β production, inflammation, and immunosuppression. Analysis of cancer genome datasets (TCGA and GTEx) revealed greater NLRP3 and IL-1β expression in cutaneous melanoma samples ( = 469) compared to normal skin ( = 324), with a highly significant correlation between NLRP3 and IL-1β ( < 0.0001). We show the formation of the NLRP3 inflammasome in biopsies of metastatic melanoma using fluorescent resonance energy transfer analysis for NLRP3 and apoptosis-associated speck-like protein containing a CARD. In vivo, tumor-associated NLRP3/IL-1 signaling induced expansion of myeloid-derived suppressor cells (MDSCs), leading to reduced natural killer and CD8 T cell activity concomitant with an increased presence of regulatory T (Treg) cells in the primary tumors. Either genetic or pharmacological inhibition of tumor-derived NLRP3 by dapansutrile (OLT1177) was sufficient to reduce MDSCs expansion and to enhance antitumor immunity, resulting in reduced tumor growth. Additionally, we observed that the combination of NLRP3 inhibition and anti-PD-1 treatment significantly increased the antitumor efficacy of the monotherapy by limiting MDSC-mediated T cell suppression and tumor progression. These data show that NLRP3 activation in melanoma cells is a protumor mechanism, which induces MDSCs expansion and immune evasion. We conclude that inhibition of NLRP3 can augment the efficacy of anti-PD-1 therapy.
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http://dx.doi.org/10.1073/pnas.2000915118DOI Listing
March 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Authors:
Daniel J Klionsky Amal Kamal Abdel-Aziz Sara Abdelfatah Mahmoud Abdellatif Asghar Abdoli Steffen Abel Hagai Abeliovich Marie H Abildgaard Yakubu Princely Abudu Abraham Acevedo-Arozena Iannis E Adamopoulos Khosrow Adeli Timon E Adolph Annagrazia Adornetto Elma Aflaki Galila Agam Anupam Agarwal Bharat B Aggarwal Maria Agnello Patrizia Agostinis Javed N Agrewala Alexander Agrotis Patricia V Aguilar S Tariq Ahmad Zubair M Ahmed Ulises Ahumada-Castro Sonja Aits Shu Aizawa Yunus Akkoc Tonia Akoumianaki Hafize Aysin Akpinar Ahmed M Al-Abd Lina Al-Akra Abeer Al-Gharaibeh Moulay A Alaoui-Jamali Simon Alberti Elísabet Alcocer-Gómez Cristiano Alessandri Muhammad Ali M Abdul Alim Al-Bari Saeb Aliwaini Javad Alizadeh Eugènia Almacellas Alexandru Almasan Alicia Alonso Guillermo D Alonso Nihal Altan-Bonnet Dario C Altieri Élida M C Álvarez Sara Alves Cristine Alves da Costa Mazen M Alzaharna Marialaura Amadio Consuelo Amantini Cristina Amaral Susanna Ambrosio Amal O Amer Veena Ammanathan Zhenyi An Stig U Andersen Shaida A Andrabi Magaiver Andrade-Silva Allen M Andres Sabrina Angelini David Ann Uche C Anozie Mohammad Y Ansari Pedro Antas Adam Antebi Zuriñe Antón Tahira Anwar Lionel Apetoh Nadezda Apostolova Toshiyuki Araki Yasuhiro Araki Kohei Arasaki Wagner L Araújo Jun Araya Catherine Arden Maria-Angeles Arévalo Sandro Arguelles Esperanza Arias Jyothi Arikkath Hirokazu Arimoto Aileen R Ariosa Darius Armstrong-James Laetitia Arnauné-Pelloquin Angeles Aroca Daniela S Arroyo Ivica Arsov Rubén Artero Dalia Maria Lucia Asaro Michael Aschner Milad Ashrafizadeh Osnat Ashur-Fabian Atanas G Atanasov Alicia K Au Patrick Auberger Holger W Auner Laure Aurelian Riccardo Autelli Laura Avagliano Yenniffer Ávalos Sanja Aveic Célia Alexandra Aveleira Tamar Avin-Wittenberg Yucel Aydin Scott Ayton Srinivas Ayyadevara Maria Azzopardi Misuzu Baba Jonathan M Backer Steven K Backues Dong-Hun Bae Ok-Nam Bae Soo Han Bae Eric H Baehrecke Ahruem Baek Seung-Hoon Baek Sung Hee Baek Giacinto Bagetta Agnieszka Bagniewska-Zadworna Hua Bai Jie Bai Xiyuan Bai Yidong Bai Nandadulal Bairagi Shounak Baksi Teresa Balbi Cosima T Baldari Walter Balduini Andrea Ballabio Maria Ballester Salma Balazadeh Rena Balzan Rina Bandopadhyay Sreeparna Banerjee Sulagna Banerjee Ágnes Bánréti Yan Bao Mauricio S Baptista Alessandra Baracca Cristiana Barbati Ariadna Bargiela Daniela Barilà Peter G Barlow Sami J Barmada Esther Barreiro George E Barreto Jiri Bartek Bonnie Bartel Alberto Bartolome Gaurav R Barve Suresh H Basagoudanavar Diane C Bassham Robert C Bast Alakananda Basu Henri Batoko Isabella Batten Etienne E Baulieu Bradley L Baumgarner Jagadeesh Bayry Rupert Beale Isabelle Beau Florian Beaumatin Luiz R G Bechara George R Beck Michael F Beers Jakob Begun Christian Behrends Georg M N Behrens Roberto Bei Eloy Bejarano Shai Bel Christian Behl Amine Belaid Naïma Belgareh-Touzé Cristina Bellarosa Francesca Belleudi Melissa Belló Pérez Raquel Bello-Morales Jackeline Soares de Oliveira Beltran Sebastián Beltran Doris Mangiaracina Benbrook Mykolas Bendorius Bruno A Benitez Irene Benito-Cuesta Julien Bensalem Martin W Berchtold Sabina Berezowska Daniele Bergamaschi Matteo Bergami Andreas Bergmann Laura Berliocchi Clarisse Berlioz-Torrent Amélie Bernard Lionel Berthoux Cagri G Besirli Sebastien Besteiro Virginie M Betin Rudi Beyaert Jelena S Bezbradica Kiran Bhaskar Ingrid Bhatia-Kissova Resham Bhattacharya Sujoy Bhattacharya Shalmoli Bhattacharyya Md Shenuarin Bhuiyan Sujit Kumar Bhutia Lanrong Bi Xiaolin Bi Trevor J Biden Krikor Bijian Viktor A Billes Nadine Binart Claudia Bincoletto Asa B Birgisdottir Geir Bjorkoy Gonzalo Blanco Ana Blas-Garcia Janusz Blasiak Robert Blomgran Klas Blomgren Janice S Blum Emilio Boada-Romero Mirta Boban Kathleen Boesze-Battaglia Philippe Boeuf Barry Boland Pascale Bomont Paolo Bonaldo Srinivasa Reddy Bonam Laura Bonfili Juan S Bonifacino Brian A Boone Martin D Bootman Matteo Bordi Christoph Borner Beat C Bornhauser Gautam Borthakur Jürgen Bosch Santanu Bose Luis M Botana Juan Botas Chantal M Boulanger Michael E Boulton Mathieu Bourdenx Benjamin Bourgeois Nollaig M Bourke Guilhem Bousquet Patricia Boya Peter V Bozhkov Luiz H M Bozi Tolga O Bozkurt Doug E Brackney Christian H Brandts Ralf J Braun Gerhard H Braus Roberto Bravo-Sagua José M Bravo-San Pedro Patrick Brest Marie-Agnès Bringer Alfredo Briones-Herrera V Courtney Broaddus Peter Brodersen Jeffrey L Brodsky Steven L Brody Paola G Bronson Jeff M Bronstein Carolyn N Brown Rhoderick E Brown Patricia C Brum John H Brumell Nicola Brunetti-Pierri Daniele Bruno Robert J Bryson-Richardson Cecilia Bucci Carmen Buchrieser Marta Bueno Laura Elisa Buitrago-Molina Simone Buraschi Shilpa Buch J Ross Buchan Erin M Buckingham Hikmet Budak Mauricio Budini Geert Bultynck Florin Burada Joseph R Burgoyne M Isabel Burón Victor Bustos Sabrina Büttner Elena Butturini Aaron Byrd Isabel Cabas Sandra Cabrera-Benitez Ken Cadwell Jingjing Cai Lu Cai Qian Cai Montserrat Cairó Jose A Calbet Guy A Caldwell Kim A Caldwell Jarrod A Call Riccardo Calvani Ana C Calvo Miguel Calvo-Rubio Barrera Niels Os Camara Jacques H Camonis Nadine Camougrand Michelangelo Campanella Edward M Campbell François-Xavier Campbell-Valois Silvia Campello Ilaria Campesi Juliane C Campos Olivier Camuzard Jorge Cancino Danilo Candido de Almeida Laura Canesi Isabella Caniggia Barbara Canonico Carles Cantí Bin Cao Michele Caraglia Beatriz Caramés Evie H Carchman Elena Cardenal-Muñoz Cesar Cardenas Luis Cardenas Sandra M Cardoso Jennifer S Carew Georges F Carle Gillian Carleton Silvia Carloni Didac Carmona-Gutierrez Leticia A Carneiro Oliana Carnevali Julian M Carosi Serena Carra Alice Carrier Lucie Carrier Bernadette Carroll A Brent Carter Andreia Neves Carvalho Magali Casanova Caty Casas Josefina Casas Chiara Cassioli Eliseo F Castillo Karen Castillo Sonia Castillo-Lluva Francesca Castoldi Marco Castori Ariel F Castro Margarida Castro-Caldas Javier Castro-Hernandez Susana Castro-Obregon Sergio D Catz Claudia Cavadas Federica Cavaliere Gabriella Cavallini Maria Cavinato Maria L Cayuela Paula Cebollada Rica Valentina Cecarini Francesco Cecconi Marzanna Cechowska-Pasko Simone Cenci Victòria Ceperuelo-Mallafré João J Cerqueira Janete M Cerutti Davide Cervia Vildan Bozok Cetintas Silvia Cetrullo Han-Jung Chae Andrei S Chagin Chee-Yin Chai Gopal Chakrabarti Oishee Chakrabarti Tapas Chakraborty Trinad Chakraborty Mounia Chami Georgios Chamilos David W Chan Edmond Y W Chan Edward D Chan H Y Edwin Chan Helen H Chan Hung Chan Matthew T V Chan Yau Sang Chan Partha K Chandra Chih-Peng Chang Chunmei Chang Hao-Chun Chang Kai Chang Jie Chao Tracey Chapman Nicolas Charlet-Berguerand Samrat Chatterjee Shail K Chaube Anu Chaudhary Santosh Chauhan Edward Chaum Frédéric Checler Michael E Cheetham Chang-Shi Chen Guang-Chao Chen Jian-Fu Chen Liam L Chen Leilei Chen Lin Chen Mingliang Chen Mu-Kuan Chen Ning Chen Quan Chen Ruey-Hwa Chen Shi Chen Wei Chen Weiqiang Chen Xin-Ming Chen Xiong-Wen Chen Xu Chen Yan Chen Ye-Guang Chen Yingyu Chen Yongqiang Chen Yu-Jen Chen Yue-Qin Chen Zhefan Stephen Chen Zhi Chen Zhi-Hua Chen Zhijian J Chen Zhixiang Chen Hanhua Cheng Jun Cheng Shi-Yuan Cheng Wei Cheng Xiaodong Cheng Xiu-Tang Cheng Yiyun Cheng Zhiyong Cheng Zhong Chen Heesun Cheong Jit Kong Cheong Boris V Chernyak Sara Cherry Chi Fai Randy Cheung Chun Hei Antonio Cheung King-Ho Cheung Eric Chevet Richard J Chi Alan Kwok Shing Chiang Ferdinando Chiaradonna Roberto Chiarelli Mario Chiariello Nathalia Chica Susanna Chiocca Mario Chiong Shih-Hwa Chiou Abhilash I Chiramel Valerio Chiurchiù Dong-Hyung Cho Seong-Kyu Choe Augustine M K Choi Mary E Choi Kamalika Roy Choudhury Norman S Chow Charleen T Chu Jason P Chua John Jia En Chua Hyewon Chung Kin Pan Chung Seockhoon Chung So-Hyang Chung Yuen-Li Chung Valentina Cianfanelli Iwona A Ciechomska Mariana Cifuentes Laura Cinque Sebahattin Cirak Mara Cirone Michael J Clague Robert Clarke Emilio Clementi Eliana M Coccia Patrice Codogno Ehud Cohen Mickael M Cohen Tania Colasanti Fiorella Colasuonno Robert A Colbert Anna Colell Miodrag Čolić Nuria S Coll Mark O Collins María I Colombo Daniel A Colón-Ramos Lydie Combaret Sergio Comincini Márcia R Cominetti Antonella Consiglio Andrea Conte Fabrizio Conti Viorica Raluca Contu Mark R Cookson Kevin M Coombs Isabelle Coppens Maria Tiziana Corasaniti Dale P Corkery Nils Cordes Katia Cortese Maria do Carmo Costa Sarah Costantino Paola Costelli Ana Coto-Montes Peter J Crack Jose L Crespo Alfredo Criollo Valeria Crippa Riccardo Cristofani Tamas Csizmadia Antonio Cuadrado Bing Cui Jun Cui Yixian Cui Yong Cui Emmanuel Culetto Andrea C Cumino Andrey V Cybulsky Mark J Czaja Stanislaw J Czuczwar Stefania D'Adamo Marcello D'Amelio Daniela D'Arcangelo Andrew C D'Lugos Gabriella D'Orazi James A da Silva Hormos Salimi Dafsari Ruben K Dagda Yasin Dagdas Maria Daglia Xiaoxia Dai Yun Dai Yuyuan Dai Jessica Dal Col Paul Dalhaimer Luisa Dalla Valle Tobias Dallenga Guillaume Dalmasso Markus Damme Ilaria Dando Nico P Dantuma April L Darling Hiranmoy Das Srinivasan Dasarathy Santosh K Dasari Srikanta Dash Oliver Daumke Adrian N Dauphinee Jeffrey S Davies Valeria A Dávila Roger J Davis Tanja Davis Sharadha Dayalan Naidu Francesca De Amicis Karolien De Bosscher Francesca De Felice Lucia De Franceschi Chiara De Leonibus Mayara G de Mattos Barbosa Guido R Y De Meyer Angelo De Milito Cosimo De Nunzio Clara De Palma Mauro De Santi Claudio De Virgilio Daniela De Zio Jayanta Debnath Brian J DeBosch Jean-Paul Decuypere Mark A Deehan Gianluca Deflorian James DeGregori Benjamin Dehay Gabriel Del Rio Joe R Delaney Lea M D Delbridge Elizabeth Delorme-Axford M Victoria Delpino Francesca Demarchi Vilma Dembitz Nicholas D Demers Hongbin Deng Zhiqiang Deng Joern Dengjel Paul Dent Donna Denton Melvin L DePamphilis Channing J Der Vojo Deretic Albert Descoteaux Laura Devis Sushil Devkota Olivier Devuyst Grant Dewson Mahendiran Dharmasivam Rohan Dhiman Diego di Bernardo Manlio Di Cristina Fabio Di Domenico Pietro Di Fazio Alessio Di Fonzo Giovanni Di Guardo Gianni M Di Guglielmo Luca Di Leo Chiara Di Malta Alessia Di Nardo Martina Di Rienzo Federica Di Sano George Diallinas Jiajie Diao Guillermo Diaz-Araya Inés Díaz-Laviada Jared M Dickinson Marc Diederich Mélanie Dieudé Ivan Dikic Shiping Ding Wen-Xing Ding Luciana Dini Jelena Dinić Miroslav Dinic Albena T Dinkova-Kostova Marc S Dionne Jörg H W Distler Abhinav Diwan Ian M C Dixon Mojgan Djavaheri-Mergny Ina Dobrinski Oxana Dobrovinskaya Radek Dobrowolski Renwick C J Dobson Jelena Đokić Serap Dokmeci Emre Massimo Donadelli Bo Dong Xiaonan Dong Zhiwu Dong Gerald W Dorn Ii Volker Dotsch Huan Dou Juan Dou Moataz Dowaidar Sami Dridi Liat Drucker Ailian Du Caigan Du Guangwei Du Hai-Ning Du Li-Lin Du André du Toit Shao-Bin Duan Xiaoqiong Duan Sónia P Duarte Anna Dubrovska Elaine A Dunlop Nicolas Dupont Raúl V Durán Bilikere S Dwarakanath Sergey A Dyshlovoy Darius Ebrahimi-Fakhari Leopold Eckhart Charles L Edelstein Thomas Efferth Eftekhar Eftekharpour Ludwig Eichinger Nabil Eid Tobias Eisenberg N Tony Eissa Sanaa Eissa Miriam Ejarque Abdeljabar El Andaloussi Nazira El-Hage Shahenda El-Naggar Anna Maria Eleuteri Eman S El-Shafey Mohamed Elgendy Aristides G Eliopoulos María M Elizalde Philip M Elks Hans-Peter Elsasser Eslam S Elsherbiny Brooke M Emerling N C Tolga Emre Christina H Eng Nikolai Engedal Anna-Mart Engelbrecht Agnete S T Engelsen Jorrit M Enserink Ricardo Escalante Audrey Esclatine Mafalda Escobar-Henriques Eeva-Liisa Eskelinen Lucile Espert Makandjou-Ola Eusebio Gemma Fabrias Cinzia Fabrizi Antonio Facchiano Francesco Facchiano Bengt Fadeel Claudio Fader Alex C Faesen W Douglas Fairlie Alberto Falcó Bjorn H Falkenburger Daping Fan Jie Fan Yanbo Fan Evandro F Fang Yanshan Fang Yognqi Fang Manolis Fanto Tamar Farfel-Becker Mathias Faure Gholamreza Fazeli Anthony O Fedele Arthur M Feldman Du Feng Jiachun Feng Lifeng Feng Yibin Feng Yuchen Feng Wei Feng Thais Fenz Araujo Thomas A Ferguson Álvaro F Fernández Jose C Fernandez-Checa Sonia Fernández-Veledo Alisdair R Fernie Anthony W Ferrante Alessandra Ferraresi Merari F Ferrari Julio C B Ferreira Susan Ferro-Novick Antonio Figueras Riccardo Filadi Nicoletta Filigheddu Eduardo Filippi-Chiela Giuseppe Filomeni Gian Maria Fimia Vittorio Fineschi Francesca Finetti Steven Finkbeiner Edward A Fisher Paul B Fisher Flavio Flamigni Steven J Fliesler Trude H Flo Ida Florance Oliver Florey Tullio Florio Erika Fodor Carlo Follo Edward A Fon Antonella Forlino Francesco Fornai Paola Fortini Anna Fracassi Alessandro Fraldi Brunella Franco Rodrigo Franco Flavia Franconi Lisa B Frankel Scott L Friedman Leopold F Fröhlich Gema Frühbeck Jose M Fuentes Yukio Fujiki Naonobu Fujita Yuuki Fujiwara Mitsunori Fukuda Simone Fulda Luc Furic Norihiko Furuya Carmela Fusco Michaela U Gack Lidia Gaffke Sehamuddin Galadari Alessia Galasso Maria F Galindo Sachith Gallolu Kankanamalage Lorenzo Galluzzi Vincent Galy Noor Gammoh Boyi Gan Ian G Ganley Feng Gao Hui Gao Minghui Gao Ping Gao Shou-Jiang Gao Wentao Gao Xiaobo Gao Ana Garcera Maria Noé Garcia Verónica E Garcia Francisco García-Del Portillo Vega Garcia-Escudero Aracely Garcia-Garcia Marina Garcia-Macia Diana García-Moreno Carmen Garcia-Ruiz Patricia García-Sanz Abhishek D Garg Ricardo Gargini Tina Garofalo Robert F Garry Nils C Gassen Damian Gatica Liang Ge Wanzhong Ge Ruth Geiss-Friedlander Cecilia Gelfi Pascal Genschik Ian E Gentle Valeria Gerbino Christoph Gerhardt Kyla Germain Marc Germain David A Gewirtz Elham Ghasemipour Afshar Saeid Ghavami Alessandra Ghigo Manosij Ghosh Georgios Giamas Claudia Giampietri Alexandra Giatromanolaki Gary E Gibson Spencer B Gibson Vanessa Ginet Edward Giniger Carlotta Giorgi Henrique Girao Stephen E Girardin Mridhula Giridharan Sandy Giuliano Cecilia Giulivi Sylvie Giuriato Julien Giustiniani Alexander Gluschko Veit Goder Alexander Goginashvili Jakub Golab David C Goldstone Anna Golebiewska Luciana R Gomes Rodrigo Gomez Rubén Gómez-Sánchez Maria Catalina Gomez-Puerto Raquel Gomez-Sintes Qingqiu Gong Felix M Goni Javier González-Gallego Tomas Gonzalez-Hernandez Rosa A Gonzalez-Polo Jose A Gonzalez-Reyes Patricia González-Rodríguez Ing Swie Goping Marina S Gorbatyuk Nikolai V Gorbunov Kıvanç Görgülü Roxana M Gorojod Sharon M Gorski Sandro Goruppi Cecilia Gotor Roberta A Gottlieb Illana Gozes Devrim Gozuacik Martin Graef Markus H Gräler Veronica Granatiero Daniel Grasso Joshua P Gray Douglas R Green Alexander Greenhough Stephen L Gregory Edward F Griffin Mark W Grinstaff Frederic Gros Charles Grose Angelina S Gross Florian Gruber Paolo Grumati Tilman Grune Xueyan Gu Jun-Lin Guan Carlos M Guardia Kishore Guda Flora Guerra Consuelo Guerri Prasun Guha Carlos Guillén Shashi Gujar Anna Gukovskaya Ilya Gukovsky Jan Gunst Andreas Günther Anyonya R Guntur Chuanyong Guo Chun Guo Hongqing Guo Lian-Wang Guo Ming Guo Pawan Gupta Shashi Kumar Gupta Swapnil Gupta Veer Bala Gupta Vivek Gupta Asa B Gustafsson David D Gutterman Ranjitha H B Annakaisa Haapasalo James E Haber Aleksandra Hać Shinji Hadano Anders J Hafrén Mansour Haidar Belinda S Hall Gunnel Halldén Anne Hamacher-Brady Andrea Hamann Maho Hamasaki Weidong Han Malene Hansen Phyllis I Hanson Zijian Hao Masaru Harada Ljubica Harhaji-Trajkovic Nirmala Hariharan Nigil Haroon James Harris Takafumi Hasegawa Noor Hasima Nagoor Jeffrey A Haspel Volker Haucke Wayne D Hawkins Bruce A Hay Cole M Haynes Soren B Hayrabedyan Thomas S Hays Congcong He Qin He Rong-Rong He You-Wen He Yu-Ying He Yasser Heakal Alexander M Heberle J Fielding Hejtmancik Gudmundur Vignir Helgason Vanessa Henkel Marc Herb Alexander Hergovich Anna Herman-Antosiewicz Agustín Hernández Carlos Hernandez Sergio Hernandez-Diaz Virginia Hernandez-Gea Amaury Herpin Judit Herreros Javier H Hervás Daniel Hesselson Claudio Hetz Volker T Heussler Yujiro Higuchi Sabine Hilfiker Joseph A Hill William S Hlavacek Emmanuel A Ho Idy H T Ho Philip Wing-Lok Ho Shu-Leong Ho Wan Yun Ho G Aaron Hobbs Mark Hochstrasser Peter H M Hoet Daniel Hofius Paul Hofman Annika Höhn Carina I Holmberg Jose R Hombrebueno Chang-Won Hong Yi-Ren Hong Lora V Hooper Thorsten Hoppe Rastislav Horos Yujin Hoshida I-Lun Hsin Hsin-Yun Hsu Bing Hu Dong Hu Li-Fang Hu Ming Chang Hu Ronggui Hu Wei Hu Yu-Chen Hu Zhuo-Wei Hu Fang Hua Jinlian Hua Yingqi Hua Chongmin Huan Canhua Huang Chuanshu Huang Chuanxin Huang Chunling Huang Haishan Huang Kun Huang Michael L H Huang Rui Huang Shan Huang Tianzhi Huang Xing Huang Yuxiang Jack Huang Tobias B Huber Virginie Hubert Christian A Hubner Stephanie M Hughes William E Hughes Magali Humbert Gerhard Hummer James H Hurley Sabah Hussain Salik Hussain Patrick J Hussey Martina Hutabarat Hui-Yun Hwang Seungmin Hwang Antonio Ieni Fumiyo Ikeda Yusuke Imagawa Yuzuru Imai Carol Imbriano Masaya Imoto Denise M Inman Ken Inoki Juan Iovanna Renato V Iozzo Giuseppe Ippolito Javier E Irazoqui Pablo Iribarren Mohd Ishaq Makoto Ishikawa Nestor Ishimwe Ciro Isidoro Nahed Ismail Shohreh Issazadeh-Navikas Eisuke Itakura Daisuke Ito Davor Ivankovic Saška Ivanova Anand Krishnan V Iyer José M Izquierdo Masanori Izumi Marja Jäättelä Majid Sakhi Jabir William T Jackson Nadia Jacobo-Herrera Anne-Claire Jacomin Elise Jacquin Pooja Jadiya Hartmut Jaeschke Chinnaswamy Jagannath Arjen J Jakobi Johan Jakobsson Bassam Janji Pidder Jansen-Dürr Patric J Jansson Jonathan Jantsch Sławomir Januszewski Alagie Jassey Steve Jean Hélène Jeltsch-David Pavla Jendelova Andreas Jenny Thomas E Jensen Niels Jessen Jenna L Jewell Jing Ji Lijun Jia Rui Jia Liwen Jiang Qing Jiang Richeng Jiang Teng Jiang Xuejun Jiang Yu Jiang Maria Jimenez-Sanchez Eun-Jung Jin Fengyan Jin Hongchuan Jin Li Jin Luqi Jin Meiyan Jin Si Jin Eun-Kyeong Jo Carine Joffre Terje Johansen Gail V W Johnson Simon A Johnston Eija Jokitalo Mohit Kumar Jolly Leo A B Joosten Joaquin Jordan Bertrand Joseph Dianwen Ju Jeong-Sun Ju Jingfang Ju Esmeralda Juárez Delphine Judith Gábor Juhász Youngsoo Jun Chang Hwa Jung Sung-Chul Jung Yong Keun Jung Heinz Jungbluth Johannes Jungverdorben Steffen Just Kai Kaarniranta Allen Kaasik Tomohiro Kabuta Daniel Kaganovich Alon Kahana Renate Kain Shinjo Kajimura Maria Kalamvoki Manjula Kalia Danuta S Kalinowski Nina Kaludercic Ioanna Kalvari Joanna Kaminska Vitaliy O Kaminskyy Hiromitsu Kanamori Keizo Kanasaki Chanhee Kang Rui Kang Sang Sun Kang Senthilvelrajan Kaniyappan Tomotake Kanki Thirumala-Devi Kanneganti Anumantha G Kanthasamy Arthi Kanthasamy Marc Kantorow Orsolya Kapuy Michalis V Karamouzis Md Razaul Karim Parimal Karmakar Rajesh G Katare Masaru Kato Stefan H E Kaufmann Anu Kauppinen Gur P Kaushal Susmita Kaushik Kiyoshi Kawasaki Kemal Kazan Po-Yuan Ke Damien J Keating Ursula Keber John H Kehrl Kate E Keller Christian W Keller Jongsook Kim Kemper Candia M Kenific Oliver Kepp Stephanie Kermorgant Andreas Kern Robin Ketteler Tom G Keulers Boris Khalfin Hany Khalil Bilon Khambu Shahid Y Khan Vinoth Kumar Megraj Khandelwal Rekha Khandia Widuri Kho Noopur V Khobrekar Sataree Khuansuwan Mukhran Khundadze Samuel A Killackey Dasol Kim Deok Ryong Kim Do-Hyung Kim Dong-Eun Kim Eun Young Kim Eun-Kyoung Kim Hak-Rim Kim Hee-Sik Kim Hyung-Ryong Kim Jeong Hun Kim Jin Kyung Kim Jin-Hoi Kim Joungmok Kim Ju Hwan Kim Keun Il Kim Peter K Kim Seong-Jun Kim Scot R Kimball Adi Kimchi Alec C Kimmelman Tomonori Kimura Matthew A King Kerri J Kinghorn Conan G Kinsey Vladimir Kirkin Lorrie A Kirshenbaum Sergey L Kiselev Shuji Kishi Katsuhiko Kitamoto Yasushi Kitaoka Kaio Kitazato Richard N Kitsis Josef T Kittler Ole Kjaerulff Peter S Klein Thomas Klopstock Jochen Klucken Helene Knævelsrud Roland L Knorr Ben C B Ko Fred Ko Jiunn-Liang Ko Hotaka Kobayashi Satoru Kobayashi Ina Koch Jan C Koch Ulrich Koenig Donat Kögel Young Ho Koh Masato Koike Sepp D Kohlwein Nur M Kocaturk Masaaki Komatsu Jeannette König Toru Kono Benjamin T Kopp Tamas Korcsmaros Gözde Korkmaz Viktor I Korolchuk Mónica Suárez Korsnes Ali Koskela Janaiah Kota Yaichiro Kotake Monica L Kotler Yanjun Kou Michael I Koukourakis Evangelos Koustas Attila L Kovacs Tibor Kovács Daisuke Koya Tomohiro Kozako Claudine Kraft Dimitri Krainc Helmut Krämer Anna D Krasnodembskaya Carole Kretz-Remy Guido Kroemer Nicholas T Ktistakis Kazuyuki Kuchitsu Sabine Kuenen Lars Kuerschner Thomas Kukar Ajay Kumar Ashok Kumar Deepak Kumar Dhiraj Kumar Sharad Kumar Shinji Kume Caroline Kumsta Chanakya N Kundu Mondira Kundu Ajaikumar B Kunnumakkara Lukasz Kurgan Tatiana G Kutateladze Ozlem Kutlu SeongAe Kwak Ho Jeong Kwon Taeg Kyu Kwon Yong Tae Kwon Irene Kyrmizi Albert La Spada Patrick Labonté Sylvain Ladoire Ilaria Laface Frank Lafont Diane C Lagace Vikramjit Lahiri Zhibing Lai Angela S Laird Aparna Lakkaraju Trond Lamark Sheng-Hui Lan Ane Landajuela Darius J R Lane Jon D Lane Charles H Lang Carsten Lange Ülo Langel Rupert Langer Pierre Lapaquette Jocelyn Laporte Nicholas F LaRusso Isabel Lastres-Becker Wilson Chun Yu Lau Gordon W Laurie Sergio Lavandero Betty Yuen Kwan Law Helen Ka-Wai Law Rob Layfield Weidong Le Herve Le Stunff Alexandre Y Leary Jean-Jacques Lebrun Lionel Y W Leck Jean-Philippe Leduc-Gaudet Changwook Lee Chung-Pei Lee Da-Hye Lee Edward B Lee Erinna F Lee Gyun Min Lee He-Jin Lee Heung Kyu Lee Jae Man Lee Jason S Lee Jin-A Lee Joo-Yong Lee Jun Hee Lee Michael Lee Min Goo Lee Min Jae Lee Myung-Shik Lee Sang Yoon Lee Seung-Jae Lee Stella Y Lee Sung Bae Lee Won Hee Lee Ying-Ray Lee Yong-Ho Lee Youngil Lee Christophe Lefebvre Renaud Legouis Yu L Lei Yuchen Lei Sergey Leikin Gerd Leitinger Leticia Lemus Shuilong Leng Olivia Lenoir Guido Lenz Heinz Josef Lenz Paola Lenzi Yolanda León Andréia M Leopoldino Christoph Leschczyk Stina Leskelä Elisabeth Letellier Chi-Ting Leung Po Sing Leung Jeremy S Leventhal Beth Levine Patrick A Lewis Klaus Ley Bin Li Da-Qiang Li Jianming Li Jing Li Jiong Li Ke Li Liwu Li Mei Li Min Li Min Li Ming Li Mingchuan Li Pin-Lan Li Ming-Qing Li Qing Li Sheng Li Tiangang Li Wei Li Wenming Li Xue Li Yi-Ping Li Yuan Li Zhiqiang Li Zhiyong Li Zhiyuan Li Jiqin Lian Chengyu Liang Qiangrong Liang Weicheng Liang Yongheng Liang YongTian Liang Guanghong Liao Lujian Liao Mingzhi Liao Yung-Feng Liao Mariangela Librizzi Pearl P Y Lie Mary A Lilly Hyunjung J Lim Thania R R Lima Federica Limana Chao Lin Chih-Wen Lin Dar-Shong Lin Fu-Cheng Lin Jiandie D Lin Kurt M Lin Kwang-Huei Lin Liang-Tzung Lin Pei-Hui Lin Qiong Lin Shaofeng Lin Su-Ju Lin Wenyu Lin Xueying Lin Yao-Xin Lin Yee-Shin Lin Rafael Linden Paula Lindner Shuo-Chien Ling Paul Lingor Amelia K Linnemann Yih-Cherng Liou Marta M Lipinski Saška Lipovšek Vitor A Lira Natalia Lisiak Paloma B Liton Chao Liu Ching-Hsuan Liu Chun-Feng Liu Cui Hua Liu Fang Liu Hao Liu Hsiao-Sheng Liu Hua-Feng Liu Huifang Liu Jia Liu Jing Liu Julia Liu Leyuan Liu Longhua Liu Meilian Liu Qin Liu Wei Liu Wende Liu Xiao-Hong Liu Xiaodong Liu Xingguo Liu Xu Liu Xuedong Liu Yanfen Liu Yang Liu Yang Liu Yueyang Liu Yule Liu J Andrew Livingston Gerard Lizard Jose M Lizcano Senka Ljubojevic-Holzer Matilde E LLeonart David Llobet-Navàs Alicia Llorente Chih Hung Lo Damián Lobato-Márquez Qi Long Yun Chau Long Ben Loos Julia A Loos Manuela G López Guillermo López-Doménech José Antonio López-Guerrero Ana T López-Jiménez Óscar López-Pérez Israel López-Valero Magdalena J Lorenowicz Mar Lorente Peter Lorincz Laura Lossi Sophie Lotersztajn Penny E Lovat Jonathan F Lovell Alenka Lovy Péter Lőw Guang Lu Haocheng Lu Jia-Hong Lu Jin-Jian Lu Mengji Lu Shuyan Lu Alessandro Luciani John M Lucocq Paula Ludovico Micah A Luftig Morten Luhr Diego Luis-Ravelo Julian J Lum Liany Luna-Dulcey Anders H Lund Viktor K Lund Jan D Lünemann Patrick Lüningschrör Honglin Luo Rongcan Luo Shouqing Luo Zhi Luo Claudio Luparello Bernhard Lüscher Luan Luu Alex Lyakhovich Konstantin G Lyamzaev Alf Håkon Lystad Lyubomyr Lytvynchuk Alvin C Ma Changle Ma Mengxiao Ma Ning-Fang Ma Quan-Hong Ma Xinliang Ma Yueyun Ma Zhenyi Ma Ormond A MacDougald Fernando Macian Gustavo C MacIntosh Jeffrey P MacKeigan Kay F Macleod Sandra Maday Frank Madeo Muniswamy Madesh Tobias Madl Julio Madrigal-Matute Akiko Maeda Yasuhiro Maejima Marta Magarinos Poornima Mahavadi Emiliano Maiani Kenneth Maiese Panchanan Maiti Maria Chiara Maiuri Barbara Majello Michael B Major Elena Makareeva Fayaz Malik Karthik Mallilankaraman Walter Malorni Alina Maloyan Najiba Mammadova Gene Chi Wai Man Federico Manai Joseph D Mancias Eva-Maria Mandelkow Michael A Mandell Angelo A Manfredi Masoud H Manjili Ravi Manjithaya Patricio Manque Bella B Manshian Raquel Manzano Claudia Manzoni Kai Mao Cinzia Marchese Sandrine Marchetti Anna Maria Marconi Fabrizio Marcucci Stefania Mardente Olga A Mareninova Marta Margeta Muriel Mari Sara Marinelli Oliviero Marinelli Guillermo Mariño Sofia Mariotto Richard S Marshall Mark R Marten Sascha Martens Alexandre P J Martin Katie R Martin Sara Martin Shaun Martin Adrián Martín-Segura Miguel A Martín-Acebes Inmaculada Martin-Burriel Marcos Martin-Rincon Paloma Martin-Sanz José A Martina Wim Martinet Aitor Martinez Ana Martinez Jennifer Martinez Moises Martinez Velazquez Nuria Martinez-Lopez Marta Martinez-Vicente Daniel O Martins Joilson O Martins Waleska K Martins Tania Martins-Marques Emanuele Marzetti Shashank Masaldan Celine Masclaux-Daubresse Douglas G Mashek Valentina Massa Lourdes Massieu Glenn R Masson Laura Masuelli Anatoliy I Masyuk Tetyana V Masyuk Paola Matarrese Ander Matheu Satoaki Matoba Sachiko Matsuzaki Pamela Mattar Alessandro Matte Domenico Mattoscio José L Mauriz Mario Mauthe Caroline Mauvezin Emanual Maverakis Paola Maycotte Johanna Mayer Gianluigi Mazzoccoli Cristina Mazzoni Joseph R Mazzulli Nami McCarty Christine McDonald Mitchell R McGill Sharon L McKenna BethAnn McLaughlin Fionn McLoughlin Mark A McNiven Thomas G McWilliams Fatima Mechta-Grigoriou Tania Catarina Medeiros Diego L Medina Lynn A Megeney Klara Megyeri Maryam Mehrpour Jawahar L Mehta Alfred J Meijer Annemarie H Meijer Jakob Mejlvang Alicia Meléndez Annette Melk Gonen Memisoglu Alexandrina F Mendes Delong Meng Fei Meng Tian Meng Rubem Menna-Barreto Manoj B Menon Carol Mercer Anne E Mercier Jean-Louis Mergny Adalberto Merighi Seth D Merkley Giuseppe Merla Volker Meske Ana Cecilia Mestre Shree Padma Metur Christian Meyer Hemmo Meyer Wenyi Mi Jeanne Mialet-Perez Junying Miao Lucia Micale Yasuo Miki Enrico Milan Małgorzata Milczarek Dana L Miller Samuel I Miller Silke Miller Steven W Millward Ira Milosevic Elena A Minina Hamed Mirzaei Hamid Reza Mirzaei Mehdi Mirzaei Amit Mishra Nandita Mishra Paras Kumar Mishra Maja Misirkic Marjanovic Roberta Misasi Amit Misra Gabriella Misso Claire Mitchell Geraldine Mitou Tetsuji Miura Shigeki Miyamoto Makoto Miyazaki Mitsunori Miyazaki Taiga Miyazaki Keisuke Miyazawa Noboru Mizushima Trine H Mogensen Baharia Mograbi Reza Mohammadinejad Yasir Mohamud Abhishek Mohanty Sipra Mohapatra Torsten Möhlmann Asif Mohmmed Anna Moles Kelle H Moley Maurizio Molinari Vincenzo Mollace Andreas Buch Møller Bertrand Mollereau Faustino Mollinedo Costanza Montagna Mervyn J Monteiro Andrea Montella L Ruth Montes Barbara Montico Vinod K Mony Giacomo Monzio Compagnoni Michael N Moore Mohammad A Moosavi Ana L Mora Marina Mora David Morales-Alamo Rosario Moratalla Paula I Moreira Elena Morelli Sandra Moreno Daniel Moreno-Blas Viviana Moresi Benjamin Morga Alwena H Morgan Fabrice Morin Hideaki Morishita Orson L Moritz Mariko Moriyama Yuji Moriyasu Manuela Morleo Eugenia Morselli Jose F Moruno-Manchon Jorge Moscat Serge Mostowy Elisa Motori Andrea Felinto Moura Naima Moustaid-Moussa Maria Mrakovcic Gabriel Muciño-Hernández Anupam Mukherjee Subhadip Mukhopadhyay Jean M Mulcahy Levy Victoriano Mulero Sylviane Muller Christian Münch Ashok Munjal Pura Munoz-Canoves Teresa Muñoz-Galdeano Christian Münz Tomokazu Murakawa Claudia Muratori Brona M Murphy J Patrick Murphy Aditya Murthy Timo T Myöhänen Indira U Mysorekar Jennifer Mytych Seyed Mohammad Nabavi Massimo Nabissi Péter Nagy Jihoon Nah Aimable Nahimana Ichiro Nakagawa Ken Nakamura Hitoshi Nakatogawa Shyam S Nandi Meera Nanjundan Monica Nanni Gennaro Napolitano Roberta Nardacci Masashi Narita Melissa Nassif Ilana Nathan Manabu Natsumeda Ryno J Naude Christin Naumann Olaia Naveiras Fatemeh Navid Steffan T Nawrocki Taras Y Nazarko Francesca Nazio Florentina Negoita Thomas Neill Amanda L Neisch Luca M Neri Mihai G Netea Patrick Neubert Thomas P Neufeld Dietbert Neumann Albert Neutzner Phillip T Newton Paul A Ney Ioannis P Nezis Charlene C W Ng Tzi Bun Ng Hang T T Nguyen Long T Nguyen Hong-Min Ni Clíona Ní Cheallaigh Zhenhong Ni M Celeste Nicolao Francesco Nicoli Manuel Nieto-Diaz Per Nilsson Shunbin Ning Rituraj Niranjan Hiroshi Nishimune Mireia Niso-Santano Ralph A Nixon Annalisa Nobili Clevio Nobrega Takeshi Noda Uxía Nogueira-Recalde Trevor M Nolan Ivan Nombela Ivana Novak Beatriz Novoa Takashi Nozawa Nobuyuki Nukina Carmen Nussbaum-Krammer Jesper Nylandsted Tracey R O'Donovan Seónadh M O'Leary Eyleen J O'Rourke Mary P O'Sullivan Timothy E O'Sullivan Salvatore Oddo Ina Oehme Michinaga Ogawa Eric Ogier-Denis Margret H Ogmundsdottir Besim Ogretmen Goo Taeg Oh Seon-Hee Oh Young J Oh Takashi Ohama Yohei Ohashi Masaki Ohmuraya Vasileios Oikonomou Rani Ojha Koji Okamoto Hitoshi Okazawa Masahide Oku Sara Oliván Jorge M A Oliveira Michael Ollmann James A Olzmann Shakib Omari M Bishr Omary Gizem Önal Martin Ondrej Sang-Bing Ong Sang-Ging Ong Anna Onnis Juan A Orellana Sara Orellana-Muñoz Maria Del Mar Ortega-Villaizan Xilma R Ortiz-Gonzalez Elena Ortona Heinz D Osiewacz Abdel-Hamid K Osman Rosario Osta Marisa S Otegui Kinya Otsu Christiane Ott Luisa Ottobrini Jing-Hsiung James Ou Tiago F Outeiro Inger Oynebraten Melek Ozturk Gilles Pagès Susanta Pahari Marta Pajares Utpal B Pajvani Rituraj Pal Simona Paladino Nicolas Pallet Michela Palmieri Giuseppe Palmisano Camilla Palumbo Francesco Pampaloni Lifeng Pan Qingjun Pan Wenliang Pan Xin Pan Ganna Panasyuk Rahul Pandey Udai B Pandey Vrajesh Pandya Francesco Paneni Shirley Y Pang Elisa Panzarini Daniela L Papademetrio Elena Papaleo Daniel Papinski Diana Papp Eun Chan Park Hwan Tae Park Ji-Man Park Jong-In Park Joon Tae Park Junsoo Park Sang Chul Park Sang-Youel Park Abraham H Parola Jan B Parys Adrien Pasquier Benoit Pasquier João F Passos Nunzia Pastore Hemal H Patel Daniel Patschan Sophie Pattingre Gustavo Pedraza-Alva Jose Pedraza-Chaverri Zully Pedrozo Gang Pei Jianming Pei Hadas Peled-Zehavi Joaquín M Pellegrini Joffrey Pelletier Miguel A Peñalva Di Peng Ying Peng Fabio Penna Maria Pennuto Francesca Pentimalli Cláudia Mf Pereira Gustavo J S Pereira Lilian C Pereira Luis Pereira de Almeida Nirma D Perera Ángel Pérez-Lara Ana B Perez-Oliva María Esther Pérez-Pérez Palsamy Periyasamy Andras Perl Cristiana Perrotta Ida Perrotta Richard G Pestell Morten Petersen Irina Petrache Goran Petrovski Thorsten Pfirrmann Astrid S Pfister Jennifer A Philips Huifeng Pi Anna Picca Alicia M Pickrell Sandy Picot Giovanna M Pierantoni Marina Pierdominici Philippe Pierre Valérie Pierrefite-Carle Karolina Pierzynowska Federico Pietrocola Miroslawa Pietruczuk Claudio Pignata Felipe X Pimentel-Muiños Mario Pinar Roberta O Pinheiro Ronit Pinkas-Kramarski Paolo Pinton Karolina Pircs Sujan Piya Paola Pizzo Theo S Plantinga Harald W Platta Ainhoa Plaza-Zabala Markus Plomann Egor Y Plotnikov Helene Plun-Favreau Ryszard Pluta Roger Pocock Stefanie Pöggeler Christian Pohl Marc Poirot Angelo Poletti Marisa Ponpuak Hana Popelka Blagovesta Popova Helena Porta Soledad Porte Alcon Eliana Portilla-Fernandez Martin Post Malia B Potts Joanna Poulton Ted Powers Veena Prahlad Tomasz K Prajsnar Domenico Praticò Rosaria Prencipe Muriel Priault Tassula Proikas-Cezanne Vasilis J Promponas Christopher G Proud Rosa Puertollano Luigi Puglielli Thomas Pulinilkunnil Deepika Puri Rajat Puri Julien Puyal Xiaopeng Qi Yongmei Qi Wenbin Qian Lei Qiang Yu Qiu Joe Quadrilatero Jorge Quarleri Nina Raben Hannah Rabinowich Debora Ragona Michael J Ragusa Nader Rahimi Marveh Rahmati Valeria Raia Nuno Raimundo Namakkal-Soorappan Rajasekaran Sriganesh Ramachandra Rao Abdelhaq Rami Ignacio Ramírez-Pardo David B Ramsden Felix Randow Pundi N Rangarajan Danilo Ranieri Hai Rao Lang Rao Rekha Rao Sumit Rathore J Arjuna Ratnayaka Edward A Ratovitski Palaniyandi Ravanan Gloria Ravegnini Swapan K Ray Babak Razani Vito Rebecca Fulvio Reggiori Anne Régnier-Vigouroux Andreas S Reichert David Reigada Jan H Reiling Theo Rein Siegfried Reipert Rokeya Sultana Rekha Hongmei Ren Jun Ren Weichao Ren Tristan Renault Giorgia Renga Karen Reue Kim Rewitz Bruna Ribeiro de Andrade Ramos S Amer Riazuddin Teresa M Ribeiro-Rodrigues Jean-Ehrland Ricci Romeo Ricci Victoria Riccio Des R Richardson Yasuko Rikihisa Makarand V Risbud Ruth M Risueño Konstantinos Ritis Salvatore Rizza Rosario Rizzuto Helen C Roberts Luke D Roberts Katherine J Robinson Maria Carmela Roccheri Stephane Rocchi George G Rodney Tiago Rodrigues Vagner Ramon Rodrigues Silva Amaia Rodriguez Ruth Rodriguez-Barrueco Nieves Rodriguez-Henche Humberto Rodriguez-Rocha Jeroen Roelofs Robert S Rogers Vladimir V Rogov Ana I Rojo Krzysztof Rolka Vanina Romanello Luigina Romani Alessandra Romano Patricia S Romano David Romeo-Guitart Luis C Romero Montserrat Romero Joseph C Roney Christopher Rongo Sante Roperto Mathias T Rosenfeldt Philip Rosenstiel Anne G Rosenwald Kevin A Roth Lynn Roth Steven Roth Kasper M A Rouschop Benoit D Roussel Sophie Roux Patrizia Rovere-Querini Ajit Roy Aurore Rozieres Diego Ruano David C Rubinsztein Maria P Rubtsova Klaus Ruckdeschel Christoph Ruckenstuhl Emil Rudolf Rüdiger Rudolf Alessandra Ruggieri Avnika Ashok Ruparelia Paola Rusmini Ryan R Russell Gian Luigi Russo Maria Russo Rossella Russo Oxana O Ryabaya Kevin M Ryan Kwon-Yul Ryu Maria Sabater-Arcis Ulka Sachdev Michael Sacher Carsten Sachse Abhishek Sadhu Junichi Sadoshima Nathaniel Safren Paul Saftig Antonia P Sagona Gaurav Sahay Amirhossein Sahebkar Mustafa Sahin Ozgur Sahin Sumit Sahni Nayuta Saito Shigeru Saito Tsunenori Saito Ryohei Sakai Yasuyoshi Sakai Jun-Ichi Sakamaki Kalle Saksela Gloria Salazar Anna Salazar-Degracia Ghasem H Salekdeh Ashok K Saluja Belém Sampaio-Marques Maria Cecilia Sanchez Jose A Sanchez-Alcazar Victoria Sanchez-Vera Vanessa Sancho-Shimizu J Thomas Sanderson Marco Sandri Stefano Santaguida Laura Santambrogio Magda M Santana Giorgio Santoni Alberto Sanz Pascual Sanz Shweta Saran Marco Sardiello Timothy J Sargeant Apurva Sarin Chinmoy Sarkar Sovan Sarkar Maria-Rosa Sarrias Surajit Sarkar Dipanka Tanu Sarmah Jaakko Sarparanta Aishwarya Sathyanarayan Ranganayaki Sathyanarayanan K Matthew Scaglione Francesca Scatozza Liliana Schaefer Zachary T Schafer Ulrich E Schaible Anthony H V Schapira Michael Scharl Hermann M Schatzl Catherine H Schein Wiep Scheper David Scheuring Maria Vittoria Schiaffino Monica Schiappacassi Rainer Schindl Uwe Schlattner Oliver Schmidt Roland Schmitt Stephen D Schmidt Ingo Schmitz Eran Schmukler Anja Schneider Bianca E Schneider Romana Schober Alejandra C Schoijet Micah B Schott Michael Schramm Bernd Schröder Kai Schuh Christoph Schüller Ryan J Schulze Lea Schürmanns Jens C Schwamborn Melanie Schwarten Filippo Scialo Sebastiano Sciarretta Melanie J Scott Kathleen W Scotto A Ivana Scovassi Andrea Scrima Aurora Scrivo David Sebastian Salwa Sebti Simon Sedej Laura Segatori Nava Segev Per O Seglen Iban Seiliez Ekihiro Seki Scott B Selleck Frank W Sellke Joshua T Selsby Michael Sendtner Serif Senturk Elena Seranova Consolato Sergi Ruth Serra-Moreno Hiromi Sesaki Carmine Settembre Subba Rao Gangi Setty Gianluca Sgarbi Ou Sha John J Shacka Javeed A Shah Dantong Shang Changshun Shao Feng Shao Soroush Sharbati Lisa M Sharkey Dipali Sharma Gaurav Sharma Kulbhushan Sharma Pawan Sharma Surendra Sharma Han-Ming Shen Hongtao Shen Jiangang Shen Ming Shen Weili Shen Zheni Shen Rui Sheng Zhi Sheng Zu-Hang Sheng Jianjian Shi Xiaobing Shi Ying-Hong Shi Kahori Shiba-Fukushima Jeng-Jer Shieh Yohta Shimada Shigeomi Shimizu Makoto Shimozawa Takahiro Shintani Christopher J Shoemaker Shahla Shojaei Ikuo Shoji Bhupendra V Shravage Viji Shridhar Chih-Wen Shu Hong-Bing Shu Ke Shui Arvind K Shukla Timothy E Shutt Valentina Sica Aleem Siddiqui Amanda Sierra Virginia Sierra-Torre Santiago Signorelli Payel Sil Bruno J de Andrade Silva Johnatas D Silva Eduardo Silva-Pavez Sandrine Silvente-Poirot Rachel E Simmonds Anna Katharina Simon Hans-Uwe Simon Matias Simons Anurag Singh Lalit P Singh Rajat Singh Shivendra V Singh Shrawan K Singh Sudha B Singh Sunaina Singh Surinder Pal Singh Debasish Sinha Rohit Anthony Sinha Sangita Sinha Agnieszka Sirko Kapil Sirohi Efthimios L Sivridis Panagiotis Skendros Aleksandra Skirycz Iva Slaninová Soraya S Smaili Andrei Smertenko Matthew D Smith Stefaan J Soenen Eun Jung Sohn Sophia P M Sok Giancarlo Solaini Thierry Soldati Scott A Soleimanpour Rosa M Soler Alexei Solovchenko Jason A Somarelli Avinash Sonawane Fuyong Song Hyun Kyu Song Ju-Xian Song Kunhua Song Zhiyin Song Leandro R Soria Maurizio Sorice Alexander A Soukas Sandra-Fausia Soukup Diana Sousa Nadia Sousa Paul A Spagnuolo Stephen A Spector M M Srinivas Bharath Daret St Clair Venturina Stagni Leopoldo Staiano Clint A Stalnecker Metodi V Stankov Peter B Stathopulos Katja Stefan Sven Marcel Stefan Leonidas Stefanis Joan S Steffan Alexander Steinkasserer Harald Stenmark Jared Sterneckert Craig Stevens Veronika Stoka Stephan Storch Björn Stork Flavie Strappazzon Anne Marie Strohecker Dwayne G Stupack Huanxing Su Ling-Yan Su Longxiang Su Ana M Suarez-Fontes Carlos S Subauste Selvakumar Subbian Paula V Subirada Ganapasam Sudhandiran Carolyn M Sue Xinbing Sui Corey Summers Guangchao Sun Jun Sun Kang Sun Meng-Xiang Sun Qiming Sun Yi Sun Zhongjie Sun Karen K S Sunahara Eva Sundberg Katalin Susztak Peter Sutovsky Hidekazu Suzuki Gary Sweeney J David Symons Stephen Cho Wing Sze Nathaniel J Szewczyk Anna Tabęcka-Łonczynska Claudio Tabolacci Frank Tacke Heinrich Taegtmeyer Marco Tafani Mitsuo Tagaya Haoran Tai Stephen W G Tait Yoshinori Takahashi Szabolcs Takats Priti Talwar Chit Tam Shing Yau Tam Davide Tampellini Atsushi Tamura Chong Teik Tan Eng-King Tan Ya-Qin Tan Masaki Tanaka Motomasa Tanaka Daolin Tang Jingfeng Tang Tie-Shan Tang Isei Tanida Zhipeng Tao Mohammed Taouis Lars Tatenhorst Nektarios Tavernarakis Allen Taylor Gregory A Taylor Joan M Taylor Elena Tchetina Andrew R Tee Irmgard Tegeder David Teis Natercia Teixeira Fatima Teixeira-Clerc Kumsal A Tekirdag Tewin Tencomnao Sandra Tenreiro Alexei V Tepikin Pilar S Testillano Gianluca Tettamanti Pierre-Louis Tharaux Kathrin Thedieck Arvind A Thekkinghat Stefano Thellung Josephine W Thinwa V P Thirumalaikumar Sufi Mary Thomas Paul G Thomes Andrew Thorburn Lipi Thukral Thomas Thum Michael Thumm Ling Tian Ales Tichy Andreas Till Vincent Timmerman Vladimir I Titorenko Sokol V Todi Krassimira Todorova Janne M Toivonen Luana Tomaipitinca Dhanendra Tomar Cristina Tomas-Zapico Sergej Tomić Benjamin Chun-Kit Tong Chao Tong Xin Tong Sharon A Tooze Maria L Torgersen Satoru Torii Liliana Torres-López Alicia Torriglia Christina G Towers Roberto Towns Shinya Toyokuni Vladimir Trajkovic Donatella Tramontano Quynh-Giao Tran Leonardo H Travassos Charles B Trelford Shirley Tremel Ioannis P Trougakos Betty P Tsao Mario P Tschan Hung-Fat Tse Tak Fu Tse Hitoshi Tsugawa Andrey S Tsvetkov David A Tumbarello Yasin Tumtas María J Tuñón Sandra Turcotte Boris Turk Vito Turk Bradley J Turner Richard I Tuxworth Jessica K Tyler Elena V Tyutereva Yasuo Uchiyama Aslihan Ugun-Klusek Holm H Uhlig Marzena Ułamek-Kozioł Ilya V Ulasov Midori Umekawa Christian Ungermann Rei Unno Sylvie Urbe Elisabet Uribe-Carretero Suayib Üstün Vladimir N Uversky Thomas Vaccari Maria I Vaccaro Björn F Vahsen Helin Vakifahmetoglu-Norberg Rut Valdor Maria J Valente Ayelén Valko Richard B Vallee Angela M Valverde Greet Van den Berghe Stijn van der Veen Luc Van Kaer Jorg van Loosdregt Sjoerd J L van Wijk Wim Vandenberghe Ilse Vanhorebeek Marcos A Vannier-Santos Nicola Vannini M Cristina Vanrell Chiara Vantaggiato Gabriele Varano Isabel Varela-Nieto Máté Varga M Helena Vasconcelos Somya Vats Demetrios G Vavvas Ignacio 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Fengming Wang Guansong Wang Han Wang Hao Wang Hexiang Wang Hong-Gang Wang Jianrong Wang Jigang Wang Jiou Wang Jundong Wang Kui Wang Lianrong Wang Liming Wang Maggie Haitian Wang Meiqing Wang Nanbu Wang Pengwei Wang Peipei Wang Ping Wang Ping Wang Qing Jun Wang Qing Wang Qing Kenneth Wang Qiong A Wang Wen-Tao Wang Wuyang Wang Xinnan Wang Xuejun Wang Yan Wang Yanchang Wang Yanzhuang Wang Yen-Yun Wang Yihua Wang Yipeng Wang Yu Wang Yuqi Wang Zhe Wang Zhenyu Wang Zhouguang Wang Gary Warnes Verena Warnsmann Hirotaka Watada Eizo Watanabe Maxinne Watchon Anna Wawrzyńska Timothy E Weaver Grzegorz Wegrzyn Ann M Wehman Huafeng Wei Lei Wei Taotao Wei Yongjie Wei Oliver H Weiergräber Conrad C Weihl Günther Weindl Ralf Weiskirchen Alan Wells Runxia H Wen Xin Wen Antonia Werner Beatrice Weykopf Sally P Wheatley J Lindsay Whitton Alexander J Whitworth Katarzyna Wiktorska Manon E Wildenberg Tom Wileman Simon Wilkinson Dieter Willbold Brett Williams Robin S B Williams Roger L Williams Peter R Williamson Richard A Wilson Beate Winner Nathaniel J Winsor Steven S Witkin Harald Wodrich Ute Woehlbier Thomas Wollert Esther Wong Jack Ho Wong Richard W Wong Vincent Kam Wai Wong W Wei-Lynn Wong An-Guo Wu Chengbiao Wu Jian Wu Junfang Wu Kenneth K Wu Min Wu Shan-Ying Wu Shengzhou Wu Shu-Yan Wu Shufang Wu William K K Wu Xiaohong Wu Xiaoqing Wu Yao-Wen Wu Yihua Wu Ramnik J Xavier Hongguang Xia Lixin Xia Zhengyuan Xia Ge Xiang Jin Xiang Mingliang Xiang Wei Xiang Bin Xiao Guozhi Xiao Hengyi Xiao Hong-Tao Xiao Jian Xiao Lan Xiao Shi Xiao Yin Xiao Baoming Xie Chuan-Ming Xie Min Xie Yuxiang Xie Zhiping Xie Zhonglin Xie Maria Xilouri Congfeng Xu En Xu Haoxing Xu Jing Xu JinRong Xu Liang Xu Wen Wen Xu Xiulong Xu Yu Xue Sokhna M S Yakhine-Diop Masamitsu Yamaguchi Osamu Yamaguchi Ai Yamamoto Shunhei Yamashina Shengmin Yan Shian-Jang Yan Zhen Yan Yasuo Yanagi Chuanbin Yang Dun-Sheng Yang Huan Yang Huang-Tian Yang Hui Yang Jin-Ming Yang Jing Yang Jingyu Yang Ling Yang Liu Yang Ming Yang Pei-Ming Yang Qian Yang Seungwon Yang Shu Yang Shun-Fa Yang Wannian Yang Wei Yuan Yang Xiaoyong Yang Xuesong Yang Yi Yang Ying Yang Honghong Yao Shenggen Yao Xiaoqiang Yao Yong-Gang Yao Yong-Ming Yao Takahiro Yasui Meysam Yazdankhah Paul M Yen Cong Yi Xiao-Ming Yin Yanhai Yin Zhangyuan Yin Ziyi Yin Meidan Ying Zheng Ying Calvin K Yip Stephanie Pei Tung Yiu Young H Yoo Kiyotsugu Yoshida Saori R Yoshii Tamotsu Yoshimori Bahman Yousefi Boxuan Yu Haiyang Yu Jun Yu Jun Yu Li Yu Ming-Lung Yu Seong-Woon Yu Victor C Yu W Haung Yu Zhengping Yu Zhou Yu Junying Yuan Ling-Qing Yuan Shilin Yuan Shyng-Shiou F Yuan Yanggang Yuan Zengqiang Yuan Jianbo Yue Zhenyu Yue Jeanho Yun Raymond L Yung David N Zacks Gabriele Zaffagnini Vanessa O Zambelli Isabella Zanella Qun S Zang Sara Zanivan Silvia Zappavigna Pilar Zaragoza Konstantinos S Zarbalis Amir Zarebkohan Amira Zarrouk Scott O Zeitlin Jialiu Zeng Ju-Deng Zeng Eva Žerovnik Lixuan Zhan Bin Zhang Donna D Zhang Hanlin Zhang Hong Zhang Hong Zhang Honghe Zhang Huafeng Zhang Huaye Zhang Hui Zhang Hui-Ling Zhang Jianbin Zhang Jianhua Zhang Jing-Pu Zhang Kalin Y B Zhang Leshuai W Zhang Lin Zhang Lisheng Zhang Lu Zhang Luoying Zhang Menghuan Zhang Peng Zhang Sheng Zhang Wei Zhang Xiangnan Zhang Xiao-Wei Zhang Xiaolei Zhang Xiaoyan Zhang Xin Zhang Xinxin Zhang Xu Dong Zhang Yang Zhang Yanjin Zhang Yi Zhang Ying-Dong Zhang Yingmei Zhang Yuan-Yuan Zhang Yuchen Zhang Zhe Zhang Zhengguang Zhang Zhibing Zhang Zhihai Zhang Zhiyong Zhang Zili Zhang Haobin Zhao Lei Zhao Shuang Zhao Tongbiao Zhao Xiao-Fan Zhao Ying Zhao Yongchao Zhao Yongliang Zhao Yuting Zhao Guoping Zheng Kai Zheng Ling Zheng Shizhong Zheng Xi-Long Zheng Yi Zheng Zu-Guo Zheng Boris Zhivotovsky Qing Zhong Ao Zhou Ben Zhou Cefan Zhou Gang Zhou Hao Zhou Hong Zhou Hongbo Zhou Jie Zhou Jing Zhou Jing Zhou Jiyong Zhou Kailiang Zhou Rongjia Zhou Xu-Jie Zhou Yanshuang Zhou Yinghong Zhou Yubin Zhou Zheng-Yu Zhou Zhou Zhou Binglin Zhu Changlian Zhu Guo-Qing Zhu Haining Zhu Hongxin Zhu Hua Zhu Wei-Guo Zhu Yanping Zhu Yushan Zhu Haixia Zhuang Xiaohong Zhuang Katarzyna Zientara-Rytter Christine M Zimmermann Elena Ziviani Teresa Zoladek Wei-Xing Zong Dmitry B Zorov Antonio Zorzano Weiping Zou Zhen Zou Zhengzhi Zou Steven Zuryn Werner Zwerschke Beate Brand-Saberi X Charlie Dong Chandra Shekar Kenchappa Zuguo Li Yong Lin Shigeru Oshima Yueguang Rong Judith C Sluimer Christina L Stallings Chun-Kit Tong

Autophagy 2021 Feb 8:1-382. Epub 2021 Feb 8.

Hong Kong Baptist University, School of Chinese Medicine, Hong Kong, China.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
February 2021

Shedding Light on Mutant Clonal Dynamics and Cancer Risk in the Skin.

Cancer Discov 2021 Feb;11(2):227-229

Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.

In this issue of , Fowler and colleagues conduct a thorough characterization of the dynamics of mutant clones in phenotypically normal human skin. Their results extend previous studies by showing that human skin is composed in large part of clones harboring mutations frequently observed in human cancer, while at the same time they uncover a previously unappreciated biological heterogeneity among nearby clones and across different body sites..
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http://dx.doi.org/10.1158/2159-8290.CD-20-1644DOI Listing
February 2021

Interleukin-37 improves T-cell-mediated immunity and chimeric antigen receptor T-cell therapy in aged backgrounds.

Aging Cell 2021 02 22;20(2):e13309. Epub 2021 Jan 22.

Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.

Aging-associated declines in innate and adaptive immune responses are well documented and pose a risk for the growing aging population, which is predicted to comprise greater than 40 percent of the world's population by 2050. Efforts have been made to improve immunity in aged populations; however, safe and effective protocols to accomplish this goal have not been universally established. Aging-associated chronic inflammation is postulated to compromise immunity in aged mice and humans. Interleukin-37 (IL-37) is a potent anti-inflammatory cytokine, and we present data demonstrating that IL-37 gene expression levels in human monocytes significantly decline with age. Furthermore, we demonstrate that transgenic expression of interleukin-37 (IL-37) in aged mice reduces or prevents aging-associated chronic inflammation, splenomegaly, and accumulation of myeloid cells (macrophages and dendritic cells) in the bone marrow and spleen. Additionally, we show that IL-37 expression decreases the surface expression of programmed cell death protein 1 (PD-1) and augments cytokine production from aged T-cells. Improved T-cell function coincided with a youthful restoration of Pdcd1, Lat, and Stat4 gene expression levels in CD4 T-cells and Lat in CD8 T-cells when aged mice were treated with recombinant IL-37 (rIL-37) but not control immunoglobin (Control Ig). Importantly, IL-37-mediated rejuvenation of aged endogenous T-cells was also observed in aged chimeric antigen receptor (CAR) T-cells, where improved function significantly extended the survival of mice transplanted with leukemia cells. Collectively, these data demonstrate the potency of IL-37 in boosting the function of aged T-cells and highlight its therapeutic potential to overcome aging-associated immunosenescence.
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http://dx.doi.org/10.1111/acel.13309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884049PMC
February 2021

Approaching Cancer Evolution from Different Angles.

iScience 2020 Nov 22;23(11):101661. Epub 2020 Oct 22.

Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, U S A.

Dr Francesca Ciccarelli (The Francis Crick Institute, UK) and Dr James De Gregori (University of Colorado, USA) interview 3 top scientists in clinical (Dr Charles Swanton, The Francis Crick Institute, UK), molecular (Dr Kornelia Polyak, Dana-Farber Cancer Institute, USA), and evolutionary cancer research (Dr Carlo Maley, Arizona State University, USA) to discuss the current status of knowledge, the challenges, and the opportunities to move the field forward.
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http://dx.doi.org/10.1016/j.isci.2020.101661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586103PMC
November 2020

Cancer Screening, Surrogates of Survival, and the Soma.

Cancer Cell 2020 10 17;38(4):433-437. Epub 2020 Sep 17.

Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. Electronic address:

Screening leads to meaningful reductions in deaths from cancers. However, reductions in all-cause mortality (ACM) are harder to demonstrate. Failure to demonstrate ACM benefit should not diminish advances in cancer screening. We consider how co-morbidities related to an aging and damaged soma can hinder achievement of ACM benefit.
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http://dx.doi.org/10.1016/j.ccell.2020.09.003DOI Listing
October 2020

Nicotinamide Metabolism Mediates Resistance to Venetoclax in Relapsed Acute Myeloid Leukemia Stem Cells.

Cell Stem Cell 2020 Nov 20;27(5):748-764.e4. Epub 2020 Aug 20.

Division of Hematology, University of Colorado Denver, Aurora, CO 80045, USA. Electronic address:

We previously demonstrated that leukemia stem cells (LSCs) in de novo acute myeloid leukemia (AML) patients are selectively reliant on amino acid metabolism and that treatment with the combination of venetoclax and azacitidine (ven/aza) inhibits amino acid metabolism, leading to cell death. In contrast, ven/aza fails to eradicate LSCs in relapsed/refractory (R/R) patients, suggesting altered metabolic properties. Detailed metabolomic analysis revealed elevated nicotinamide metabolism in relapsed LSCs, which activates both amino acid metabolism and fatty acid oxidation to drive OXPHOS, thereby providing a means for LSCs to circumvent the cytotoxic effects of ven/aza therapy. Genetic and pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in nicotinamide metabolism, demonstrated selective eradication of R/R LSCs while sparing normal hematopoietic stem/progenitor cells. Altogether, these findings demonstrate that elevated nicotinamide metabolism is both the mechanistic basis for ven/aza resistance and a metabolic vulnerability of R/R LSCs.
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http://dx.doi.org/10.1016/j.stem.2020.07.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655603PMC
November 2020

The special issue on cancer and evolution: Lessons learned.

Authors:
James DeGregori

Evol Appl 2020 Aug 13;13(7):1784-1790. Epub 2020 Jul 13.

Department of Biochemistry and Molecular Genetics Department of Immunology and Microbiology University of Colorado Anschutz Medical Campus Aurora CO USA.

This special issue of evolutionary applications focused on the evolution of cancer has provided a wealth of different viewpoints and results from leaders in the field. Together, these papers emphasize the importance of a broad perspective in order to understand why we and other animals get cancer, how it evolves within an individual, and what we can do about it. We can no longer take reductionist approaches that consider only the cancer cells and their genes. Instead, we need to understand how millions of years of evolution have guided strategies that shape cancer risk, why cancer risk varies across different animals, how cancer risk can vary in a population and be influenced by ecology (and influence this ecology), and of course how cancers evolve within us and the evolutionarily informed strategies to counter their impact. My goal here will be to "bring it all home," providing a refresher of lessons learned with added kibitzing.
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http://dx.doi.org/10.1111/eva.13040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428814PMC
August 2020

The three dimensions of somatic evolution: Integrating the role of genetic damage, life-history traits, and aging in carcinogenesis.

Evol Appl 2020 Aug 20;13(7):1569-1580. Epub 2020 Mar 20.

Department of Biochemistry and Molecular Genetics University of Colorado Anschutz Medical Campus Aurora Colorado.

Tumors result from genetic and epigenetic alterations that change cellular survival and differentiation probabilities, promoting clonal dominance. Subsequent genetic and selection processes in tumors allow cells to lose their tissue fidelity and migrate to other parts of the body, turning tumors into cancer. However, the relationship between genetic damage and cancer is not linear, showing remarkable and sometimes seemingly counterintuitive patterns for different tissues and across animal taxa. In the present paper, we attempt to integrate our understanding of somatic evolution and cancer as a product of three major orthogonal processes: occurrence of somatic mutations, evolution of species-specific life-history traits, and physiological aging. Patterns of cancer risk have been shaped by selective pressures experienced by animal populations over millions of years, influencing and influenced by selection acting on traits ranging from mutation rate to reproductive strategies to longevity. We discuss how evolution of species shapes their cancer profiles alongside and in connection with other evolving life-history traits and how this process explains the patterns of cancer incidence we observe in humans and other animals.
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http://dx.doi.org/10.1111/eva.12947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428813PMC
August 2020

A somatic evolutionary model of the dynamics of aneuploid cells during hematopoietic reconstitution.

Sci Rep 2020 07 22;10(1):12198. Epub 2020 Jul 22.

Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.

Aneuploidy is a feature of many cancers. Recent studies demonstrate that in the hematopoietic stem and progenitor cell (HSPC) compartment aneuploid cells have reduced fitness and are efficiently purged from the bone marrow. However, early phases of hematopoietic reconstitution following bone marrow transplantation provide a window of opportunity whereby aneuploid cells rise in frequency, only to decline to basal levels thereafter. Here we demonstrate by Monte Carlo modeling that two mechanisms could underlie this aneuploidy peak: rapid expansion of the engrafted HSPC population and bone marrow microenvironment degradation caused by pre-transplantation radiation treatment. Both mechanisms reduce the strength of purifying selection acting in early post-transplantation bone marrow. We explore the contribution of other factors such as alterations in cell division rates that affect the strength of purifying selection, the balance of drift and selection imposed by the HSPC population size, and the mutation-selection balance dependent on the rate of aneuploidy generation per cell division. We propose a somatic evolutionary model for the dynamics of cells with aneuploidy or other fitness-reducing mutations during hematopoietic reconstitution following bone marrow transplantation. Similar alterations in the strength of purifying selection during cancer development could help explain the paradox of aneuploidy abundance in tumors despite somatic fitness costs.
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http://dx.doi.org/10.1038/s41598-020-68729-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376010PMC
July 2020

Aging, inflammation, and HSC.

Authors:
James DeGregori

Blood 2020 07;136(2):153-154

University of Colorado Anschutz Medical Campus.

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http://dx.doi.org/10.1182/blood.2020006070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357189PMC
July 2020

Cancer as a disease of old age: changing mutational and microenvironmental landscapes.

Br J Cancer 2020 03 11;122(7):943-952. Epub 2020 Feb 11.

Department of Biochemistry and Molecular Genetics, Integrated Department of Immunology, Department of Pediatrics, Department of Medicine (Section of Hematology), University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.

Why do we get cancer mostly when we are old? According to current paradigms, the answer is simple: mutations accumulate in our tissues throughout life, and some of these mutations contribute to cancers. Although mutations are necessary for cancer development, a number of studies shed light on roles for ageing and exposure-dependent changes in tissue landscapes that determine the impact of oncogenic mutations on cellular fitness, placing carcinogenesis into an evolutionary framework. Natural selection has invested in somatic maintenance to maximise reproductive success. Tissue maintenance not only ensures functional robustness but also prevents the occurrence of cancer through periods of likely reproduction by limiting selection for oncogenic events in our cells. Indeed, studies in organisms ranging from flies to humans are revealing conserved mechanisms to eliminate damaged or oncogenically initiated cells from tissues. Reports of the existence of striking numbers of oncogenically initiated clones in normal tissues and of how this clonal architecture changes with age or external exposure to noxious substances provide critical insight into the early stages of cancer development. A major challenge for cancer biology will be the integration of these studies with epidemiology data into an evolutionary theory of carcinogenesis, which could have a large impact on addressing cancer risk and treatment.
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http://dx.doi.org/10.1038/s41416-019-0721-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109142PMC
March 2020

Of mice, genes and aging.

Authors:
James DeGregori

Haematologica 2020 31;105(2):246-248. Epub 2020 Jan 31.

Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

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http://dx.doi.org/10.3324/haematol.2019.238683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012487PMC
July 2020

Molecular Biology and Evolution of Cancer: From Discovery to Action.

Mol Biol Evol 2020 02;37(2):320-326

Department of Biostatistics, Yale School of Public Health, New Haven, CT.

Cancer progression is an evolutionary process. During this process, evolving cancer cell populations encounter restrictive ecological niches within the body, such as the primary tumor, circulatory system, and diverse metastatic sites. Efforts to prevent or delay cancer evolution-and progression-require a deep understanding of the underlying molecular evolutionary processes. Herein we discuss a suite of concepts and tools from evolutionary and ecological theory that can inform cancer biology in new and meaningful ways. We also highlight current challenges to applying these concepts, and propose ways in which incorporating these concepts could identify new therapeutic modes and vulnerabilities in cancer.
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http://dx.doi.org/10.1093/molbev/msz242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993850PMC
February 2020

Somatic maintenance impacts the evolution of mutation rate.

BMC Evol Biol 2019 08 23;19(1):172. Epub 2019 Aug 23.

Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO, 80045, USA.

Background: The evolution of multi-cellular animals has produced a conspicuous trend toward increased body size. This trend has introduced at least two novel problems: an expected elevated risk of somatic disorders, such as cancer, and declining evolvability due to generally reduced population size, lower reproduction rate and extended generation time. Low population size is widely recognized to explain the high mutation rates in animals by limiting the presumed universally negative selection acting on mutation rates.

Results: Here, we present evidence from stochastic modeling that the direction and strength of selection acting on mutation rates is highly dependent on the evolution of somatic maintenance, and thus longevity, which modulates the cost of somatic mutations.

Conclusions: We argue that the impact of the evolution of longevity on mutation rates may have been critical in facilitating animal evolution.
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http://dx.doi.org/10.1186/s12862-019-1496-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708161PMC
August 2019

Studying Cancer Evolution and Therapeutic Responses in Different Organs: The Pros and Cons of a Broad Focus.

Cancer Res 2019 Sep 22;79(18):4582-4584. Epub 2019 Aug 22.

Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Cellular adaptation brought upon by insults such as old age and therapeutic exposure is a complex phenomenon in which cells undergo adaptive phenotypic changes. Our lab has focused on understanding the mechanisms underlying adaptation during the evolution of cancer, from the early stages of development to the ability of cancer cells to escape therapeutic challenges. Our studies span hematopoietic and lung systems. Herein, we discuss the advantages and disadvantages involved in studying two vastly different organ systems. Through the use of these organ/cancer model systems, we hope to develop interventions to limit oncogenic adaptation leading to cancer development and to prevent adaptation of cancers following treatment leading to cancer relapse.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-1303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744964PMC
September 2019

FERMI: A Novel Method for Sensitive Detection of Rare Mutations in Somatic Tissue.

G3 (Bethesda) 2019 09 4;9(9):2977-2987. Epub 2019 Sep 4.

Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO 80045

With growing interest in monitoring mutational processes in normal tissues, tumor heterogeneity, and cancer evolution under therapy, the ability to accurately and economically detect ultra-rare mutations is becoming increasingly important. However, this capability has often been compromised by significant sequencing, PCR and DNA preparation error rates. Here, we describe FERMI (Fast Extremely Rare Mutation Identification) - a novel method designed to eliminate the majority of these sequencing and library-preparation errors in order to significantly improve rare somatic mutation detection. This method leverages barcoded targeting probes to capture and sequence DNA of interest with single copy resolution. The variant calls from the barcoded sequencing data are then further filtered in a position-dependent fashion against an adaptive, context-aware null model in order to distinguish true variants. As a proof of principle, we employ FERMI to probe bone marrow biopsies from leukemia patients, and show that rare mutations and clonal evolution can be tracked throughout cancer treatment, including during historically intractable periods like minimum residual disease. Importantly, FERMI is able to accurately detect nascent clonal expansions within leukemias in a manner that may facilitate the early detection and characterization of cancer relapse.
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http://dx.doi.org/10.1534/g3.119.400438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723130PMC
September 2019

Measuring Aging and Identifying Aging Phenotypes in Cancer Survivors.

J Natl Cancer Inst 2019 12;111(12):1245-1254

Observational data have shown that some cancer survivors develop chronic conditions like frailty, sarcopenia, cardiac dysfunction, and mild cognitive impairment earlier and/or at a greater burden than similarly aged individuals never diagnosed with cancer or exposed to systemic or targeted cancer therapies. In aggregate, cancer- and treatment-related physical, cognitive, and psychosocial late- and long-term morbidities experienced by cancer survivors are hypothesized to represent accelerated or accentuated aging trajectories. However, conceptual, measurement, and methodological challenges have constrained efforts to identify, predict, and mitigate aging-related consequences of cancer and cancer treatment. In July 2018, the National Cancer Institute convened basic, clinical, and translational science experts for a think tank titled "Measuring Aging and Identifying Aging Phenotypes in Cancer Survivors." Through the resulting deliberations, several research and resource needs were identified, including longitudinal studies to examine aging trajectories that include detailed data from before, during, and after cancer treatment; mechanistic studies to elucidate the pathways that lead to the emergence of aging phenotypes in cancer survivors; long-term clinical surveillance to monitor survivors for late-emerging effects; and tools to integrate multiple data sources to inform understanding of how cancer and its therapies contribute to the aging process. Addressing these needs will help expand the evidence base and inform strategies to optimize healthy aging of cancer survivors.
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http://dx.doi.org/10.1093/jnci/djz136DOI Listing
December 2019

TNF-α-driven inflammation and mitochondrial dysfunction define the platelet hyperreactivity of aging.

Blood 2019 08 16;134(9):727-740. Epub 2019 Jul 16.

Center for Cancer and Blood Disorders, Department of Pediatrics and.

Aging and chronic inflammation are independent risk factors for the development of atherothrombosis and cardiovascular disease. We hypothesized that aging-associated inflammation promotes the development of platelet hyperreactivity and increases thrombotic risk during aging. Functional platelet studies in aged-frail adults and old mice demonstrated that their platelets are hyperreactive and form larger thrombi. We identified tumor necrosis factor α (TNF-α) as the key aging-associated proinflammatory cytokine responsible for platelet hyperreactivity. We further showed that platelet hyperreactivity is neutralized by abrogating signaling through TNF-α receptors in vivo in a mouse model of aging. Analysis of the bone marrow compartments showed significant platelet-biased hematopoiesis in old mice reflected by increased megakaryocyte-committed progenitor cells, megakaryocyte ploidy status, and thrombocytosis. Single-cell RNA-sequencing analysis of native mouse megakaryocytes showed significant reprogramming of inflammatory, metabolic, and mitochondrial gene pathways in old mice that appeared to play a significant role in determining platelet hyperreactivity. Platelets from old mice (where TNF-α was endogenously increased) and from young mice exposed to exogenous TNF-α exhibited significant mitochondrial changes characterized by elevated mitochondrial mass and increased oxygen consumption during activation. These mitochondrial changes were mitigated upon TNF-α blockade. Similar increases in platelet mitochondrial mass were seen in platelets from patients with myeloproliferative neoplasms, where TNF-α levels are also increased. Furthermore, metabolomics studies of platelets from young and old mice demonstrated age-dependent metabolic profiles that may differentially poise platelets for activation. Altogether, we present previously unrecognized evidence that TNF-α critically regulates megakaryocytes resident in the bone marrow niche and aging-associated platelet hyperreactivity and thrombosis.
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http://dx.doi.org/10.1182/blood.2019000200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716075PMC
August 2019

Cysteine depletion targets leukemia stem cells through inhibition of electron transport complex II.

Blood 2019 07 17;134(4):389-394. Epub 2019 May 17.

Division of Hematology and.

We have previously demonstrated that oxidative phosphorylation is required for the survival of human leukemia stem cells (LSCs) from patients with acute myeloid leukemia (AML). More recently, we demonstrated that LSCs in patients with de novo AML rely on amino acid metabolism to drive oxidative phosphorylation. Notably, although overall levels of amino acids contribute to LSC energy metabolism, our current findings suggest that cysteine may be of particular importance for LSC survival. We demonstrate that exogenous cysteine is metabolized exclusively to glutathione. Upon cysteine depletion, glutathione synthesis is impaired, leading to reduced glutathionylation of succinate dehydrogenase A (SDHA), a key component of electron transport chain complex (ETC) II. Loss of SDHA glutathionylation impairs ETC II activity, thereby inhibiting oxidative phosphorylation, reducing production of ATP, and leading to LSC death. Given the role of cysteine in driving LSC energy production, we tested cysteine depletion as a potential therapeutic strategy. Using a novel cysteine-degrading enzyme, we demonstrate selective eradication of LSCs, with no detectable effect on normal hematopoietic stem/progenitor cells. Together, these findings indicate that LSCs are aberrantly reliant on cysteine to sustain energy metabolism, and that targeting this axis may represent a useful therapeutic strategy.
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http://dx.doi.org/10.1182/blood.2019898114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659257PMC
July 2019

A generalized theory of age-dependent carcinogenesis.

Elife 2019 04 29;8. Epub 2019 Apr 29.

Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, United States.

The Multi-Stage Model of Carcinogenesis (MMC), developed in the 1950 s-70s, postulated carcinogenesis as a Darwinian somatic selection process. The cellular organization of tissues was then poorly understood, with almost nothing known about cancer drivers and stem cells. The MMC paradigm was later confirmed, and cancer incidence was explained as a function of mutation occurrence. However, the MMC has never been tested for its ability to account for the discrepancies in the number of driver mutations and the organization of the stem cell compartments underlying different cancers that still demonstrate nearly universal age-dependent incidence patterns. Here we demonstrate by Monte Carlo modeling the impact of key somatic evolutionary parameters on the MMC performance, revealing that two additional major mechanisms, aging-dependent somatic selection and life history-dependent evolution of species-specific tumor suppressor mechanisms, need to be incorporated into the MMC to make it capable of generalizing cancer incidence across tissues and species.

Editorial Note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).
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http://dx.doi.org/10.7554/eLife.39950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488293PMC
April 2019

Targeting Glutamine Metabolism and Redox State for Leukemia Therapy.

Clin Cancer Res 2019 07 2;25(13):4079-4090. Epub 2019 Apr 2.

Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Purpose: Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the accumulation of immature myeloid precursor cells. AML is poorly responsive to conventional chemotherapy and a diagnosis of AML is usually fatal. More effective and less toxic forms of therapy are desperately needed. AML cells are known to be highly dependent on the amino acid glutamine for their survival. These studies were directed at determining the effects of glutaminase inhibition on metabolism in AML and identifying general weaknesses that can be exploited therapeutically.

Experimental Design: AML cancer cell lines, primary AML cells, and mouse models of AML and acute lymphoblastic leukemia (ALL) were utilized.

Results: We show that blocking glutamine metabolism through the use of a glutaminase inhibitor (CB-839) significantly impairs antioxidant glutathione production in multiple types of AML, resulting in accretion of mitochondrial reactive oxygen species (mitoROS) and apoptotic cell death. Moreover, glutaminase inhibition makes AML cells susceptible to adjuvant drugs that further perturb mitochondrial redox state, such as arsenic trioxide (ATO) and homoharringtonine (HHT). Indeed, the combination of ATO or HHT with CB-839 exacerbates mitoROS and apoptosis, and leads to more complete cell death in AML cell lines, primary AML patient samples, and using mouse models of AML. In addition, these redox-targeted combination therapies are effective in eradicating ALL cells and .

Conclusions: Targeting glutamine metabolism in combination with drugs that perturb mitochondrial redox state represents an effective and potentially widely applicable therapeutic strategy for treating multiple types of leukemia.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642698PMC
July 2019

Decoy fitness peaks, tumor suppression, and aging.

Aging Cell 2019 06 8;18(3):e12938. Epub 2019 Mar 8.

Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado.

Recent reports by Martincorena et al and Yokoyama et al reveal unanticipated dynamics of somatic evolution in the esophageal epithelium, with clonal expansions apparently driven by mutations in Notch1 dominating the epithelium even in middle-aged individuals, far outpacing the prevalence of these mutations in esophageal cancers. We propose a model whereby the promotion of clonal expansions by mutations such as in Notch1 can limit more malignant somatic evolutionary trajectories until old ages.
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http://dx.doi.org/10.1111/acel.12938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516171PMC
June 2019

Urea Cycle Sustains Cellular Energetics upon EGFR Inhibition in EGFR-Mutant NSCLC.

Mol Cancer Res 2019 06 26;17(6):1351-1364. Epub 2019 Feb 26.

Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Mutations in oncogenes and tumor suppressor genes engender unique metabolic phenotypes crucial to the survival of tumor cells. EGFR signaling has been linked to the rewiring of tumor metabolism in non-small cell lung cancer (NSCLC). We have integrated the use of a functional genomics screen and metabolomics to identify metabolic vulnerabilities induced by EGFR inhibition. These studies reveal that following EGFR inhibition, EGFR-driven NSCLC cells become dependent on the urea cycle and, in particular, the urea cycle enzyme CPS1. Combining knockdown of CPS1 with EGFR inhibition further reduces cell proliferation and impedes cell-cycle progression. Profiling of the metabolome demonstrates that suppression of CPS1 potentiates the effects of EGFR inhibition on central carbon metabolism, pyrimidine biosynthesis, and arginine metabolism, coinciding with reduced glycolysis and mitochondrial respiration. We show that EGFR inhibition and CPS1 knockdown lead to a decrease in arginine levels and pyrimidine derivatives, and the addition of exogenous pyrimidines partially rescues the impairment in cell growth. Finally, we show that high expression of CPS1 in lung adenocarcinomas correlated with worse patient prognosis in publicly available databases. These data collectively reveal that NSCLC cells have a greater dependency on the urea cycle to sustain central carbon metabolism, pyrimidine biosynthesis, and arginine metabolism to meet cellular energetics upon inhibition of EGFR. IMPLICATIONS: Our results reveal that the urea cycle may be a novel metabolic vulnerability in the context of EGFR inhibition, providing an opportunity to develop rational combination therapies with EGFR inhibitors for the treatment of EGFR-driven NSCLC.
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http://dx.doi.org/10.1158/1541-7786.MCR-18-1068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548670PMC
June 2019

SIX2 Mediates Late-Stage Metastasis via Direct Regulation of and Induction of a Cancer Stem Cell Program.

Cancer Res 2019 02 3;79(4):720-734. Epub 2019 Jan 3.

Integrated Physiology Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado.

The capacity for tumor cells to metastasize efficiently is directly linked to their ability to colonize secondary sites. Here we identify Six2, a developmental transcription factor, as a critical regulator of a breast cancer stem cell program that enables metastatic colonization. In several triple-negative breast cancer (TNBC) models, Six2 enhanced the expression of genes associated with embryonic stem cell programs. Six2 directly bound the Srr2 enhancer, promoting expression and downstream expression of , which are both key pluripotency factors. Regulation of by Six2 enhanced cancer stem cell properties and increased metastatic colonization. and expression correlated highly in breast cancers including TNBC, where a Six2 expression signature was predictive of metastatic burden and poor clinical outcome. Our findings demonstrate that a SIX2/SOX2 axis is required for efficient metastatic colonization, underscoring a key role for stemness factors in outgrowth at secondary sites. SIGNIFICANCE: These findings provide novel mechanistic insight into stemness and the metastatic outgrowth of triple-negative breast cancer cells. http://cancerres.aacrjournals.org/content/canres/79/4/720/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-1791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586234PMC
February 2019

Inhibition of Amino Acid Metabolism Selectively Targets Human Leukemia Stem Cells.

Cancer Cell 2018 11;34(5):724-740.e4

Division of Hematology, University of Colorado Denver, Anschutz Medical Campus, 12700 East 19(th) Avenue, Aurora, CO 80045, USA. Electronic address:

In this study we interrogated the metabolome of human acute myeloid leukemia (AML) stem cells to elucidate properties relevant to therapeutic intervention. We demonstrate that amino acid uptake, steady-state levels, and catabolism are all elevated in the leukemia stem cell (LSC) population. Furthermore, LSCs isolated from de novo AML patients are uniquely reliant on amino acid metabolism for oxidative phosphorylation and survival. Pharmacological inhibition of amino acid metabolism reduces oxidative phosphorylation and induces cell death. In contrast, LSCs obtained from relapsed AML patients are not reliant on amino acid metabolism due to their ability to compensate through increased fatty acid metabolism. These findings indicate that clinically relevant eradication of LSCs can be achieved with drugs that target LSC metabolic vulnerabilities.
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http://dx.doi.org/10.1016/j.ccell.2018.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280965PMC
November 2018

Adenoviral vectors transduce alveolar macrophages in lung cancer models.

Oncoimmunology 2018;7(6):e1438105. Epub 2018 Mar 6.

Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver Anschutz Medical Campus, Aurora, CO.

Adenoviral vectors expressing Cre recombinase are commonly used to initiate tumor formation in murine lung cancer models. While these vectors are designed to target genetic recombination to lung epithelial cells, adenoviruses can infect additional cell types that potentially influence tumor development. Our goal was to explore the consequences of adenoviral-mediated alveolar macrophage (AM) transduction in a Kras-initiated lung tumor model. As expected, treatment of animals harboring the Kras allele and an inducible green fluorescence protein (GFP) tracking allele with an adenoviral vector expressing Cre recombinase under the control of the cytomegalovirus (CMV) promoter (Ad5-CMV-Cre), caused GFP-positive lung adenocarcinomas. Surprisingly, however, up to 70% of the total GFP cells were AM, and GFP AM could be detected 6 months after tumor initiation, and transduced AM demonstrated Kras activation and increased proliferation. In contrast, recombination was not detected in other immune cell populations and AM recombination could be eliminated by tumor initiation with an adenovirus expressing Cre recombinase under the control of the surfactant protein C (SPC) promoter. In addition, AM isolated from Kras animals and transduced by Ad5-CMV-Cre displayed prolonged survival and increased the growth of murine lung adenocarcinoma CMT/167 cells when co-injected in an orthotopic flank model. Given the importance of the immune system in tumor development and progression, inadvertent AM transduction by Ad5-CMV-Cre merits careful consideration during lung cancer model selection particularly if studies evaluating the tumor-immune interactions are planned.
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http://dx.doi.org/10.1080/2162402X.2018.1438105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980415PMC
March 2018

ALK is a critical regulator of the MYC-signaling axis in ALK positive lung cancer.

Oncotarget 2018 Feb 16;9(10):8823-8835. Epub 2018 Jan 16.

University of Colorado Cancer Center, Aurora, CO, USA.

A subset of lung cancers is dependent on the anaplastic lymphoma kinase () oncogene for survival, a mechanism that is exploited by the use of the ALK inhibitor crizotinib. Despite exceptional initial tumor responses to ALK inhibition by crizotinib, durable clinical response is limited and the emergence of drug resistance occurs. Furthermore, intrinsic resistance is frequently observed, where patients fail to respond initially to ALK-inhibitor therapy. These events demonstrate the underlying complexity of a molecularly-defined oncogene-driven cancer and highlights the need to identify compensating survival pathways. Using a loss-of-function whole genome short-hairpin (shRNA) screen, we identified MYCBP as a determinant of response to crizotinib, implicating the MYC signaling axis in resistance to crizotinib-treated NSCLC. Further analysis reveals that ALK regulates transcriptional expression of and activates c-MYC transactivation of c-MYC target genes. Inhibition of by RNAi or small molecules sensitizes cells to crizotinib. Taken together, our findings demonstrate a dual oncogene mechanism, where ALK positively regulates the MYC signaling axis, providing an additional oncogene target whose inhibition may prevent or overcome resistance.
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http://dx.doi.org/10.18632/oncotarget.24260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823650PMC
February 2018