Protecting against interepithelial adhesiondm5migu4zj3pb.cloudfront.net/impact/pdf/21/jci_impact_2014_09.pdf · Jeffrey H. Miner Beverly Mitchell Peter J. Mohler Kelle Harbert Moley

jci.org/impactseptember 2014

Also in this issue:

Treating autoimmune inner ear disease 7

Lymphangiogenesis in postpartum breast cancer 8

Sexual dimorphism in glioblastoma 9

Characterizing Schlemm’s canal 10

A summary of this month’s Journal of Clinical investigation

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Protecting against interepithelial adhesion p. 6

Alejandro Aballay

Abul K. Abbas

Domenico Accili

Rexford S. Ahima

Qais Al-Awqati

Kari Alitalo

James Allison

Dario C. Altieri

Masayuki Amagai

Mark E. Anderson

Brian H. Annex

Alan Attie

Jane E. Aubin

Steven P. Balk

Michael F. Beers

John A. Belperio

Nina Bhardwaj

Morris J. Birnbaum

Joyce Bischoff

Mina J. Bissell

Craig Blackstone

Bruce R. Blazar

Nancy Bonini

Brendan Boyce

Jonathan Bromberg

Frank C. Brosius

Hal E. Broxmeyer

Andrew Butler

Michael J. Caplan

Ruben D. Carrasco

Diego H. Castrillon

Harold Chapman

Ajay Chawla

Benjamin K. Chen

Benny J. Chen

Ju Chen

Marie-Françoise Chesselet

Vivian G. Cheung

Yongwon Choi

Thomas Clemens

Ronald G. Collman

Marco Colonna

George Cotsarelis

Shaun R. Coughlin

Christopher M. Counter

Peter D. Crompton

Tyler J. Curiel

David D’alessio

Richard T. D’Aquila

Riccardo Dalla-Favera

Alan Daugherty

Ted Dawson

Sudhansu Dey

Harry C. Dietz III

Michael Dustin

Connie J. Eaves

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Robert V. Farese Jr.

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Journal of Clinical Investigation Consulting Editors

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t h e j o u r n a l o f c l i n i c a l i n v e s t i g a t i o n j c i . o r g / i m p a c t s e p t e m b e r 2 0 1 4 1

editorHoward A. Rockman

Deputy editor Garnett Kelsoe, Bryan L. Roth

Associate editorsSoman N. Abraham, Vann Bennett,Gerard Blobe, Kathleen M. Caron,Marc G. Caron, John P. Chute,Thomas M. Coffman, Anna Mae Diehl,Ronald J. Falk, Michael B. Kastan, Daniel P. Kelly, Mary E. Klotman, Rodger A. Liddle, Nigel Mackman, Larry G. Moss, Deborah M. Muoio, Christopher B. Newgard, Paul W. Noble, Cam Patterson, Geoffrey S. Pitt, Jeffrey C. Rathmell, W. Kimryn Rathmell, Bryan Roth, Jonathan S. Serody, Norman Sharpless, Yiping Yang

Clinical Medicine Associate editorsMichael A. Morse, Andrew J. Muir,Scott M. Palmer, Mark A. Stacy

Asia editorsDavid M. Virshup

Chair, executive CouncilRobert J. Lefkowitz

BiostatisticiansCynthia Coffman, Barry Moser, Maren Olsen

BioethicistArthur L. Caplan

senior science editorSarah C. Jackson

science editorJillian Hurst

Assistant science editorCorinne Williams

editor at largeUshma S. Neill

issn 2324-7703 (print)issn 2325-4556 (online)The American Society for Clinical Investigation holds the rights to and publishes the Journal of Clinical Investigation. The opinions expressed herein are solely those of the authors and are not necessarily endorsed by the ASCI.

Impactseptember 2014

Contact the JCiThe Journal of Clinical Investigation2015 Manchester RoadAnn Arbor, Michigan 48104, USAPhone: 734.222.6050E-mail: [email protected]

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The JCI’s Editorial Board is composed of peer scientists at Duke University Medical Center, the University of North Carolina, Duke-NUS, and the Sanford-Burnham Medical Research Institute. Editorial Board members review and oversee peer review of each manuscript that is submitted to the JCI, and the board meets weekly to discuss the manuscripts undergoing review.

Featured Editor

michael b. Kastan, m.D., ph.D., Associate editor, is the William W. Shingleton Professor of Pharmacology and Cancer Biology at the Duke University School of Medicine and serves as the Executive Director of the Duke Cancer Institute. He is a pediatric oncologist and cancer biologist; his laboratory research concentrates on DNA damage and repair, tumor suppressor genes, and causes of cancer related to genetic predisposition and environmental exposures. Dr. Kastan’s discoveries have had a major impact on our understanding of how cancers develop and respond to chemotherapy and radiation ther-

apy, and of the roles of p53 and ATM in DNA damage signaling. He has received numerous honors for his work, including the AACR G.H.A. Clowes Memorial Award, for outstanding contributions to basic cancer research, and election to the National Academy of Sciences’ Institute of Medicine. He has served as Chair of the Board of Scientific Counselors of the National Cancer Institute, on the boards of directors of the American Association for Cancer Research and the Association of American Cancer Institutes, as editor in chief of Molecular Cancer Research, and as editor of the textbook Clinical Oncology. Dr. Kastan is also a member of the American Society for Clinical Investigation.

publication highlights

Bakkenist CJ, Kastan MB. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature. 2003;421(6922):499–506.

Takagi M, Abasalon M, McLure KG, Kastan MB. Regulation of p53 translation and induction after DNA damage by ribosomal protein L26 and nucleolin. Cell. 2005;123(1):49–63.

Goldstein M, Derheimer FA, Tait-Mulder J, Kastan MB. Nucleolin mediates nucleosome disruption critical for DNA double-strand break repair. Proc Natl Acad Sci U S A. 2013;110(42):16874–16879.

t h e j o u r n a l o f c l i n i c a l i n v e s t i g a t i o n j c i . o r g / i m p a c t s e p t e m b e r 2 0 1 42

Research articles in the current issue of the JCI

AIDS/HIVFCGR2C polymorphisms associate with HIV-1 vaccine protection in rV144 trialShuying S. Li, Peter B. Gilbert, Georgia D. Tomaras, Gustavo Kijak, Guido Ferrari, Rasmi Thomas, Chul-Woo Pyo, Susan Zolla-Pazner, David Montefiori, Hua-Xin Liao, Gary Nabel, Abraham Pinter, David T. Evans, Raphael Gottardo, James Y. Dai, Holly Janes, Daryl Morris, Youyi Fong, Paul T. Edlefsen, Fusheng Li, Nicole Frahm, Michael D. Alpert, Heather Prentice, Supachai Rerks-Ngarm, Punnee Pitisuttithum, Jaranit Kaewkungwal, Sorachai Nitayaphan, Merlin L. Robb, Robert J. O’Connell, Barton F. Haynes, Nelson L. Michael, Jerome H. Kim, M. Juliana McElrath, and Daniel E. Geraghty http://jci.me/75539

more, p. 9

Clinical trialsearly efficacy trial of anakinra in corticosteroid-resistant autoimmune inner ear diseaseAndrea Vambutas, Martin Lesser, Virginia Mullooly, Shresh Pathak, Gerald Zahtz, Lisa Rosen, and Elliot Goldofsky http://jci.me/76503

With related Attending physician by steven D. rauch more, p. 7

Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patientsJennifer E. Adair, Sandra K. Johnston, Maciej M. Mrugala, Brian C. Beard, Laura A. Guyman, Anne L. Baldock, Carly A. Bridge, Andrea Hawkins-Daarud, Jennifer L. Gori, Donald E. Born, Luis F. Gonzalez-Cuyar, Daniel L. Silbergeld, Russell C. Rockne, Barry E. Storer, Jason K. Rockhill, Kristin R. Swanson, and Hans-Peter Kiem http://jci.me/76739

more, p. 7

DermatologyCannabidiol exerts sebostatic and antiinflammatory effects on human sebocytesAttila Oláh, Balázs I. Tóth, István Borbíró, Koji Sugawara, Attila G. Szöllõsi, Gabriella Czifra, Balázs Pál, Lídia Ambrus, Jennifer Kloepper, Emanuela Camera, Matteo Ludovici, Mauro Picardo, Thomas Voets, Christos C. Zouboulis, Ralf Paus, and Tamás Bíró http://jci.me/64628

Developmentperiderm prevents pathological epithelial adhesions during embryogenesisRebecca J. Richardson, Nigel L. Hammond, Pierre A. Coulombe, Carola Saloranta, Heidi O. Nousiainen, Riitta Salonen, Andrew Berry, Neil Hanley, Denis Headon, Riitta Karikoski, and Michael J. Dixon http://jci.me/71946

more, p. 6

EndocrinologyHypomorphism in human NSMCE2 linked to primordial dwarfism and insulin resistanceFelicity Payne, Rita Colnaghi, Nuno Rocha, Asha Seth, Julie Harris, Gillian Carpenter, William E. Bottomley, Eleanor Wheeler, Stephen Wong, Vladimir Saudek, David Savage, Stephen O’Rahilly, Jean-Claude Carel, Inês Barroso, Mark O’Driscoll, and Robert Semple http://jci.me/73264

Glioblastoma therapy

Periderm in development

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Research articles in the current issue of the JCI

menin determines K-rAs proliferative outputs in endocrine cellsChester E. Chamberlain, David W. Scheel, Kathleen McGlynn, Hail Kim, Takeshi Miyatsuka, Juehu Wang, Vinh Nguyen, Shuhong Zhao, Anastasia Mavropoulos, Aswin G. Abraham, Eric O’Neill, Gregory M. Ku, Melanie H. Cobb, Gail R. Martin, and Michael S. German http://jci.me/69004

With related Commentary by Adolfo García-Ocaña and Andrew F. stewart more, p. 12

FGF21 is an endocrine signal of protein restrictionThomas Laeger, Tara M. Henagan, Diana C. Albarado, Leanne M. Redman, George A. Bray, Robert C. Noland, Heike Münzberg, Susan M. Hutson, Thomas W. Gettys, Michael W. Schwartz, and Christopher D. Morrison http://jci.me/74915

With related Commentary by timo D. müller and matthias H. tschöp more, p. 12

GastroenterologyHedgehog signaling regulates FOXA2 in esophageal embryogenesis and barrett’s metaplasiaDavid H. Wang, Anjana Tiwari, Monica E. Kim, Nicholas J. Clemons, Nanda L. Regmi, William A. Hodges, David M. Berman, Elizabeth A. Montgomery, D. Neil Watkins, Xi Zhang, Qiuyang Zhang, Chunfa Jie, Stuart J. Spechler, and Rhonda F. Souza http://jci.me/66603

Hematologyproteasome function is required for platelet productionDallas S. Shi, Matthew C.P. Smith, Robert A. Campbell, Patrick W. Zimmerman, Zechariah B. Franks, Bjorn F. Kraemer, Kellie R. Machlus, Jing Ling, Patrick Kamba, Hansjörg Schwertz, Jesse W. Rowley, Rodney R. Miles, Zhi-Jian Liu, Martha Sola-Visner, Joseph E. Italiano Jr., Hilary Christensen, Walter H.A. Kahr, Dean Y. Li, and Andrew S. Weyrich http://jci.me/75247

ImmunologyIL-10–producing NKt10 cells are a distinct regulatory invariant NKt cell subsetDuygu Sag, Petra Krause, Catherine C. Hedrick, Mitchell Kronenberg, and Gerhard Wingender http://jci.me/72308

p38 signaling inhibits mtOrC1-independent autophagy in senescent human CD8+ t cellsSian M. Henson, Alessio Lanna, Natalie E. Riddell, Ornela Franzese, Richard Macaulay, Stephen J. Griffiths, Daniel J. Puleston, Alexander Scarth Watson, Anna Katharina Simon, Sharon A. Tooze, and Arne N. Akbar http://jci.me/75051

splice-correcting oligonucleotides restore btK function in X-linked agammaglobulinemia modelBurcu Bestas, Pedro M.D. Moreno, K. Emelie M. Blomberg, Dara K. Mohammad, Amer F. Saleh, Tolga Sutlu, Joel Z. Nordin, Peter Guterstam, Manuela O. Gustafsson, Shabnam Kharazi, Barbara Piątosa, Thomas C. Roberts, Mark A. Behlke, Matthew J.A. Wood, Michael J. Gait, Karin E. Lundin, Samir El Andaloussi, Robert Månsson, Anna Berglöf, Jesper Wengel, and C.I. Edvard Smith http://jci.me/76175

A human immunodeficiency caused by mutations in the PIK3R1 geneMarie-Céline Deau, Lucie Heurtier, Pierre Frange, Felipe Suarez, Christine Bole-Feysot, Patrick Nitschke, Marina Cavazzana, Capucine Picard, Anne Durandy, Alain Fischer, and Sven Kracker http://jci.me/75746

With related Commentary by Craig m. Walsh and David A. Fruman more, p. 11

Inflammationshifting FcγrIIA-ItAm from activation to inhibitory configuration ameliorates arthritisSanae Ben Mkaddem, Gilles Hayem, Friederike Jönsson, Elisabetta Rossato, Erwan Boedec, Tarek Boussetta, Jamel El Benna, Pierre Launay, Jean-Michel Goujon, Marc Benhamou, Pierre Bruhns, and Renato C. Monteiro http://jci.me/74572

K-RAS in pancreatic cancer

Proteasome in platelets

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Research articles in the current issue of the JCI

MetabolismVentromedial hypothalamus–specific Ptpn1 deletion exacerbates diet-induced obesity in female miceFranck Chiappini, Karyn J. Catalano, Jennifer Lee, Odile D. Peroni, Jacqueline Lynch, Abha S. Dhaneshwar, Kerry Wellenstein, Alexandra Sontheimer, Benjamin G. Neel, and Barbara B. Kahn http://jci.me/68585

ppArγ ablation sensitizes proopiomelanocortin neurons to leptin during high-fat feedingLihong Long, Chitoku Toda, Jing Kwon Jeong, Tamas L. Horvath, and Sabrina Diano http://jci.me/76220

more, p. 11

OncologyeGFr phosphorylation of DCbLD2 recruits trAF6 and stimulates AKt-promoted tumorigenesisHaizhong Feng, Giselle Y. Lopez, Chung Kwon Kim, Angel Alvarez, Christopher G. Duncan, Ryo Nishikawa, Motoo Nagane, An-Jey A. Su, Philip E. Auron, Matthew L. Hedberg, Lin Wang, Jeffery J. Raizer, John A. Kessler, Andrew T. Parsa, Wei-Qiang Gao, Sung-Hak Kim, Mutsuko Minata, Ichiro Nakano, Jennifer R. Grandis, Roger E. McLendon, Darell D. Bigner, Hui-Kuan Lin, Frank B. Furnari, Webster K. Cavenee, Bo Hu, Hai Yan, and Shi-Yuan Cheng http://jci.me/73093

Cyclooxygenase-2–dependent lymphangiogenesis promotes nodal metastasis of postpartum breast cancerTraci R. Lyons, Virginia F. Borges, Courtney B. Betts, Qiuchen Guo, Puja Kapoor, Holly A. Martinson, Sonali Jindal, and Pepper Schedin http://jci.me/73777

With related Commentary by melody A. swartz more, p. 8

targeted p16Ink4a epimutation causes tumorigenesis and reduces survival in miceDa-Hai Yu, Robert A. Waterland, Pumin Zhang, Deborah Schady, Miao-Hsueh Chen, Yongtao Guan, Manasi Gadkari, and Lanlan Shen http://jci.me/76507

more, p. 8

Arachidonate 15-lipoxygenase is required for chronic myeloid leukemia stem cell survivalYaoyu Chen, Cong Peng, Sheela A. Abraham, Yi Shan, Zhiru Guo, Ngoc Desouza, Giulia Cheloni, Dongguang Li, Tessa L. Holyoake, and Shaoguang Li http://jci.me/66129

sexually dimorphic rb inactivation underlies mesenchymal glioblastoma prevalence in malesTao Sun, Nicole M. Warrington, Jingqin Luo, Michael D. Brooks, Sonika Dahiya, Steven C. Snyder, Rajarshi Sengupta, and Joshua B. Rubin http://jci.me/71048

more, p. 9

Ion channel trpV1-dependent activation of ptp1b suppresses eGFr-associated intestinal tumorigenesisPetrus R. de Jong, Naoki Takahashi, Alexandra R. Harris, Jihyung Lee, Samuel Bertin, James Jeffries, Michael Jung, Jen Duong, Amy I. Triano, Jongdae Lee, Yaron Niv, David S. Herdman, Koji Taniguchi, Chang-Whan Kim, Hui Dong, Lars Eckmann, Stephanie M. Stanford, Nunzio Bottini, Maripat Corr, and Eyal Raz http://jci.me/72340

DeAD-box helicase Dp103 defines metastatic potential of human breast cancersEun Myoung Shin, Hui Sin Hay, Moon Hee Lee, Jen Nee Goh, Tuan Zea Tan, Yin Ping Sen, See Wee Lim, Einas M. Yousef, Hooi Tin Ong, Aye Aye Thike, Xiangjun Kong, Zhengsheng Wu, Earnest Mendoz, Wei Sun, Manuel Salto-Tellez, Chwee Teck Lim, Peter E. Lobie, Yoon Pin Lim, Celestial T. Yap, Qi Zeng, Gautam Sethi, Martin B. Lee, Patrick Tan, Boon Cher Goh, Lance D. Miller, Jean Paul Thiery, Tao Zhu, Louis Gaboury, Puay Hoon Tan, Kam Man Hui, George Wai-Cheong Yip, Shigeki Miyamoto, Alan Prem Kumar, and Vinay Tergaonkar http://jci.me/73451

Development and translational imaging of a TP53 porcine tumorigenesis modelJessica C. Sieren, David K. Meyerholz, Xiao-Jun Wang, Bryan T. Davis, John D. Newell Jr., Emily Hammond, Judy A. Rohret, Frank A. Rohret, Jason T. Struzynski, J. Adam Goeken, Paul W. Naumann, Mariah R. Leidinger, Agshin Taghiyev, Richard Van Rheeden, Jussara Hagen, Benjamin W. Darbro, Dawn E. Quelle, and Christopher S. Rogers http://jci.me/75447

Aldolase C in glioma

TRAF6 in head and neck cancer

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Research articles in the current issue of the JCI

Pulmonologymitophagy-dependent necroptosis contributes to the pathogenesis of COpDKenji Mizumura, Suzanne M. Cloonan, Kiichi Nakahira, Abhiram R. Bhashyam, Morgan Cervo, Tohru Kitada, Kimberly Glass, Caroline A. Owen, Ashfaq Mahmood, George R. Washko, Shu Hashimoto, Stefan W. Ryter, and Augustine M.K. Choi http://jci.me/74985

more, p. 7

Reproductive biologypAX7 expression defines germline stem cells in the adult testisGina M. Aloisio, Yuji Nakada, Hatice D. Saatcioglu, Christopher G. Peña, Michael D. Baker, Edward D. Tarnawa, Jishnu Mukherjee, Hema Manjunath, Abhijit Bugde, Anita L. Sengupta, James F. Amatruda, Ileana Cuevas, F. Kent Hamra, and Diego H. Castrillon http://jci.me/75943

more, p. 11

Vascular biologyA selective microrNA-based strategy inhibits restenosis while preserving endothelial functionGaetano Santulli, Anetta Wronska, Kunihiro Uryu, Thomas G. Diacovo, Melanie Gao, Steven O. Marx, Jan Kitajewski, Jamie M. Chilton, Kemal Marc Akat, Thomas Tuschl, Andrew R. Marks, and Hana Totary-Jain http://jci.me/76069

With related Commentary by mark W. Feinberg more, p. 10

endothelial C-type natriuretic peptide maintains vascular homeostasisAmie J. Moyes, Rayomand S. Khambata, Inmaculada Villar, Kristen J. Bubb, Reshma S. Baliga, Natalie G. Lumsden, Fang Xiao, Paul J. Gane, Anne-Sophie Rebstock, Roberta J. Worthington, Michela I. Simone, Filipa Mota, Fernando Rivilla, Susana Vallejo, Concepción Peiró, Carlos F. Sánchez Ferrer, Snezana Djordjevic, Mark J. Caulfield, Raymond J. MacAllister, David L. Selwood, Amrita Ahluwalia, and Adrian J. Hobbs http://jci.me/74281

VeGF-C–dependent stimulation of lymphatic function ameliorates experimental inflammatory bowel diseaseSilvia D’Alessio, Carmen Correale, Carlotta Tacconi, Alessandro Gandelli, Giovanni Pietrogrande, Stefania Vetrano, Marco Genua, Vincenzo Arena, Antonino Spinelli, Laurent Peyrin-Biroulet, Claudio Fiocchi, and Silvio Danese http://jci.me/72189

Canonical WNt signaling components in vascular development and barrier formationYulian Zhou, Yanshu Wang, Max Tischfielf, John Williams, Philip M. Smallwood, Amir Rattner, Makoto M. Taketo, and Jeremy Nathans http://jci.me/76431

Lymphatic regulator prOX1 determines schlemm’s canal integrity and identityDae-Young Park, Junyeop Lee, Intae Park, Dongwon Choi, Sunju Lee, Sukhyun Song, Yoonha Hwang, Ki Yong Hong, Yoshikazu Nakaoka, Taija Makinen, Pilhan Kim, Kari Alitalo, Young-Kwon Hong, and Gou Young Koh http://jci.me/75392

With related Commentary by Natalie O. Karpinich and Kathleen m. Caron more, p. 10

the schlemm’s canal is a VeGF-C/VeGFr-3–responsive lymphatic-like vesselAleksanteri Aspelund, Tuomas Tammela, Salli Antila, Harri Nurmi, Veli-Matti Leppänen, Georgia Zarkada, Lukas Stanczuk, Mathias Francois, Taija Mäkinen, Pipsa Saharinen, Ilkka Immonen, and Kari Alitalo http://jci.me/75395

With related Commentary by Natalie O. Karpinich and Kathleen m. Caron more, p. 10

PAX7 in testis

PROX1 in Schlemm’s canal

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pterygium syndromes encompass a set of rare birth defects, including popliteal pterygium syndrome, Bartsocas-Papas syndrome, and cocoon syndrome, which are characterized by skin webbing and cranio facial anomalies. While several causative genetic mut ations underlying these congenital disorders have been identified, the underlying molecular pathogenesis remains poorly under-stood. In this issue, a study led by Michael Dixon demonstrates that pathological tissue adhesion in these disorders is due to a defect in formation of the periderm, an epidermal layer that exists transiently during embryogenesis. Using a murine model of popliteal ptery gium syndrome containing a missense mutation in the transcription factor IFN regulatory factor 6 (IRF6), the research team found that periderm formation was absent, resulting in abnormal epithelial adhesions covering the hind limbs, tail, body wall, and facial regions. Similarly, in mice with loss of the gene encoding the NF-κB pathway component IκB kinase-α (IKKα) or muta-tion in the cell-cycle regulator protein stratifin, defec tive periderm formation was also observed. The team showed that periderm expresses adhesion complex proteins in a highly polarized manner and that this cell layer acts as a protective barrier to pre-vent aberrant adhesion between apposed epithelia. Further, they demonstrate that a human fetus with a mutation in IKKα that caused cocoon syndrome also exhibited similar severe inter epithelial adhesions. These findings provide new insights into early epi-dermal development, the function of the periderm, and the pathogenesis of pterygium syndromes. The accompanying image shows a false-colored murine embryo on day 11.5 of development with GFP labeling of the periderm.

Embryonic epidermal layer defect underlies congenital disorders

Editor’s picksresearch

periderm prevents pathological epithelial adhesions during embryogenesisRebecca J. Richardson, Nigel L. Hammond, Pierre A. Coulombe, Carola Saloranta, Heidi O. Nousiainen, Riitta Salonen, Andrew Berry, Neil Hanley, Denis Headon, Riitta Karikoski, and Michael J. Dixon http://jci.me/71946

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Research | Editor’s picks

clinical trials

A clinical trial of an IL-1 receptor antagonist in autoimmune inner ear disease

Genetically modified hematopoietic stem cells increase chemotherapy tolerance in glioblastoma patientsGlioblastoma multiforme frequently becomes resistant to the frontline chemotherapy temozolomide. Resistance is conferred by elevated expression of methylguanine methyltransferase (MGMThi). The antineoplastic agent O6-benzylguanine (O6BG) restores temozolomide sensitivity, but also causes myelosuppression, decreasing chemotherapy tolerance. In this issue, Hans-Peter Kiem and colleagues report on the results of a clinical trial in which seven newly diagnosed glioblastoma patients with MGMThi tumors underwent bone marrow transplants with genetically modified hematopoietic stem cells (HSCs) that were insensitive to O6BG, followed by treatment with a combination of O6BG and temozolomide. Transplantation with the genetically modified HSCs increased the number of tolerated chemotherapy cycles in all seven patients compared with historical controls. Moreover, one patient who underwent an unprecedented nine treatment cycles demonstrated long-term progression-free survival in the absence of additional treatment, and three of seven patients demonstrated significantly improved overall survival compared with historical controls. These results support additional trials of genetically modified HSC transplant in combination with O6BG/temozolomide therapy in patients with MGMThi tumors.

Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patientsJennifer E. Adair, Sandra K. Johnston, Maciej M. Mrugala, Brian C. Beard, Laura A. Guyman, Anne L. Baldock, Carly A. Bridge, Andrea Hawkins-Daarud, Jennifer L. Gori, Donald E. Born, Luis F. Gonzalez-Cuyar, Daniel L. Silbergeld, Russell C. Rockne, Barry E. Storer, Jason K. Rockhill, Kristin R. Swanson, and Hans-Peter Kiem http://jci.me/76739

Autoimmune inner ear disease (AieD) is characterized by progressive sensorineural hearing loss. Most patients initially respond to steroids; however, patients eventually fail to respond to this treatment and lose their hearing. Andrea Vambutas and colleagues previously found that PBMCs of steroid-resistant AIED patients had increased IL-1β release, and this release could be prevented with anakinra, but not dexamethasone. Based on these observations, they conducted a phase I/II clinical trial of the IL-1 receptor antagonist anakinra in 10 patients with AIED. After 84 days of treatment, 7 of 10 patients exhibited a marked improvement in hearing. Moreover, plasma levels of IL-1β were correlated with clinical response. In the accompanying Attending Physician, Steven Rauch discusses how these results support further clinical trials of Anakinra in AIED.

early efficacy trial of anakinra in corticosteroid-resistant autoimmune inner ear diseaseAndrea Vambutas, Martin Lesser, Virginia Mullooly, Shresh Pathak, Gerald Zahtz, Lisa Rosen, and Elliot Goldofsky http://jci.me/76503

related Attending physicianIL-1β inhibition in autoimmune inner ear disease: can you hear me now?Steven D. Rauch http://jci.me/77197

Mitophagy mediates cell death in chronic obstructive pulmonary diseaseChronic obstructive pulmonary disease (CoPD), a consequence of cigarette smoke (CS) exposure, is characterized by emphysema and airway inflammation; however, the molecular mechanisms underlying the disease have not been elucidated. Kenji Mizumura and colleagues used cultured pulmonary epithelial cells and a murine COPD model to demonstrate that CS causes mitochondrial dysfunction (see the accompanying image), elimination of damaged mitochondria

pulmonology

through autophagy (a process known as mitophagy), and subsequent necroptosis (a genetically regulated form of cell death similar to necrosis). Mechanistically, inhibition of mitophagy or necroptosis abrogated CS-induced cell death. Further, the mitophagy mediator PINK1 and the necroptosis scaffold RIP3 were both elevated in human COPD lung. These findings indicate that the mitophagy pathway could potentially serve as a therapeutic target in COPD.

mitophagy-dependent necroptosis contributes to the pathogenesis of COpDKenji Mizumura, Suzanne M. Cloonan, Kiichi Nakahira, Abhiram R. Bhashyam, Morgan Cervo, Tohru Kitada, Kimberly Glass, Caroline A. Owen, Ashfaq Mahmood, George R. Washko, Shu Hashimoto, Stefan W. Ryter, and Augustine M.K. Choi http://jci.me/74985

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Research | Editor’s picks

oncology

Mammary involution promotes postpartum breast cancer metastasis through lymphangiogenesis

Epigenetic silencing of cell cycle regulator p16Ink4a drives tumorigenesisinactivation of the tumor suppressor and cell cycle regulator p16inK4A through promoter CpG island (CGI) methylation is a frequent, early epigenetic event in a variety of human cancers. To determine whether this epigenetic change can initiate tumorigenesis, Da-Hai Yu and colleagues engineered a cis-acting regulatory element to induce methylation of the p16Ink4a promoter in mice. Induced promoter methyl ation resulted in age-dependent suppression of p16INK4A (see the accompanying image) and increased incidence of spontaneous tumors, including lung adenocarcinoma, sarcoma, and lymphoma. In order to more closely model human p16INK4A alterations, Yu and colleagues generated mice with an inactivating mutation in one allele and promoter hyper methylation of the other allele. These mice had accelerated tumorigenesis and shortened tumor-free survival. Taken together, these results demonstrate that epigenetic dysreg ulation of p16Ink4a can drive tumorigenesis.

targeted p16Ink4a epimutation causes tumorigenesis and reduces survival in miceDa-Hai Yu, Robert A. Waterland, Pumin Zhang, Deborah Schady, Miao-Hsueh Chen, Yongtao Guan, Manasi Gadkari, and Lanlan Shen http://jci.me/76507

Mammary involution, or the process by which breast tissue returns to its prepregnancy state, has been implicated in the increased occurrence of metastasis in postpartum breast cancers. In this issue of the JCI, Traci Lyons and colleagues found that human postpartum breast cancers have increased lymphatic vessel density around the tumors, which correlates with greater incidence of lymphatic metastasis. Using a rodent model of postpartum breast cancer, they demonstrated that the microenvironment created by mammary involution allows breast cancer cells to acquire prolymphangiogenic properties that enhance lymphatic expansion, invasion, and metastasis. The accompanying image shows tube formation by lymphatic endothelial cells treated with conditioned media from breast tumors in nulliparous (top) and postpartum (bottom) mice. Mammary tumor-associated lymphangiogenesis in this model

was abrogated by inhibition of COX-2 during involution. In the accompanying Commentary, Melody Swartz discusses the potential of COX-2 as a therapeutic target to prevent metastasis of postpartum breast cancer.

Cyclooxygenase-2–dependent lymphangiogenesis promotes nodal metastasis of postpartum breast cancerTraci R. Lyons, Virginia F. Borges, Courtney B. Betts, Qiuchen Guo, Puja Kapoor, Holly A. Martinson, Sonali Jindal, and Pepper Schedin http://jci.me/73777

related CommentaryInflammatory lymphangiogenesis in postpartum breast tissue remodelingMelody A. Swartz http://jci.me/77765

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Research | Editor’s picks

Differential inactivation of RB underlies brain tumor sexual dimorphism

aids/hiv

Host Fc receptor genotype influences HIV vaccine efficacythe hiV-1 vaccine trial RV144 is the only trial to date to demonstrate some level of vaccine efficacy. Importantly, risk of contracting HIV was shown to be inversely correlated with the generation of IgG antibodies to the V1-V2 region of the HIV envelope. Because several recent studies have demonstrated that humoral immunity is affected by aberrant expression or altered functionality of Fc receptors (FcRs), Shuying Li, Peter Gilbert, and colleagues hypothesized that host FcR genetic variations can influence susceptibility to HIV infection. They identified SNPs in six different human FcR genes (FCGR2A, FCGR2B, FCGR2C, FCGR3A, FCGR3B, and FCAR) and found that a SNP in FCGR2 (rs114943036) was significantly associated with vaccine efficacy to decrease HIV acquisition risk. The vaccine was effective against a particular genotype of HIV in 91% of individuals carrying CT or TT genotypes compared with 15% of individuals carrying the CC genotype. These findings suggest that host factors including FcR and Fc-mediated antibody function influenced vaccine efficacy in the RV144 trial.

FCGR2C polymorphisms associate with HIV-1 vaccine protection in rV144 trialShuying S. Li, Peter B. Gilbert, Georgia D. Tomaras, Gustavo Kijak, Guido Ferrari, Rasmi Thomas, Chul-Woo Pyo, Susan Zolla-Pazner, David Montefiori, Hua-Xin Liao, Gary Nabel, Abraham Pinter, David T. Evans, Raphael Gottardo, James Y. Dai, Holly Janes, Daryl Morris, Youyi Fong, Paul T. Edlefsen, Fusheng Li, Nicole Frahm, Michael D. Alpert, Heather Prentice, Supachai Rerks-Ngarm, Punnee Pitisuttithum, Jaranit Kaewkungwal, Sorachai Nitayaphan, Merlin L. Robb, Robert J. O’Connell, Barton F. Haynes, Nelson L. Michael, Jerome H. Kim, M. Juliana McElrath, and Daniel E. Geraghty http://jci.me/75539

Brain cancer rates exhibit marked sexual disparity, with males being affected significantly more often than females. These differences are consistent regardless of age, indicating that, unlike many sexually dimorphic diseases, the differences in brain cancer rates are not dependent on differences in sex hormone abundance. To identify factors that contribute to the sexual dimorphism of brain tumors, Tao Sun and colleagues modeled mesenchymal glioblastoma (Mes-GBM) using astrocytes from male and female mice by inactivating neurofibromin and p53 in conjunction with EGF treatment. They found that male Mes-GBM astrocytes exhibited greater in vitro growth and colony-forming activity compared with their female counterparts (see the accompanying image) as well as enhanced in vivo tumorigenesis in a xenograft model regardless of the sex of the recipient. Further, male Mes-GBM astrocytes exhibited greater inactivation of

RB, increased proliferation, and greater induction of a clonogenic, stem cell–like population. When loss of RB was equalized, male and female Mes-GBM astrocytes formed tumors of similar size, indicating that intrinsic differences in RB inactivation underlie the sexual dimorphism of Mes-GBM.

sexually dimorphic rb inactivation underlies mesenchymal glioblastoma prevalence in malesTao Sun, Nicole M. Warrington, Jingqin Luo, Michael D. Brooks, Sonika Dahiya, Steven C. Snyder, Rajarshi Sengupta, and Joshua B. Rubin http://jci.me/71048

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Research | Editor’s picks

vascular biology

Schlemm’s canal: ocular lymphatics in plain sightschlemm’s canal (sC) is a specialized vascular structure that drains aqueous humor from the eye and returns it to the systemic circulation. Obstruction of aqueous humor outflow (AHO) directly affects intraocular pressure (IOP), thereby causing ocular disease. In this issue, two research groups, led by Gou Young Koh and Kari Alitalo, demonstrate that lymphangiogenic regulators play a critical role in the development and function of SC. Both groups found that SC expresses lymphatic endothelial markers, including the transcription factor PROX1 and the RTK VEGFR-3. Koh and colleagues showed that developmental and pathological changes in AHO altered the fate of SC endothelial cells, with the lymphatic marker PROX1 becoming undetectable under pathological conditions. Alitalo and colleagues showed that delivery of VEGF-C into the adult eye promoted growth, sprouting, and proliferation of SC endothelial cells and could reduce IOP. In the accompanying Commentary, Natalie Karpinich and Kathleen Caron discuss how these findings reveal the lymphatic characteristics of SC and indicate that therapeutics or diagnostics targeting these lymphatic regulatory pathways could potentially be used to treat IOP-associated pathologies such as glaucoma.

related researchLymphatic regulator prOX1 determines schlemm’s canal integrity and identityDae-Young Park, Junyeop Lee, Intae Park, Dongwon Choi, Sunju Lee, Sukhyun Song, Yoonha Hwang, Ki Yong Hong, Yoshikazu Nakaoka, Taija Makinen, Pilhan Kim, Kari Alitalo, Young-Kwon Hong, and Gou Young Koh http://jci.me/75392

the schlemm’s canal is a VeGF-C/VeGFr-3–responsive lymphatic-like vesselAleksanteri Aspelund, Tuomas Tammela, Salli Antila, Harri Nurmi, Veli-Matti Leppänen, Georgia Zarkada, Lukas Stanczuk, Mathias Francois, Taija Mäkinen, Pipsa Saharinen, Ilkka Immonen, and Kari Alitalo http://jci.me/75395

related Commentaryschlemm’s canal: more than meets the eye, lymphatics in disguiseNatalie O. Karpinich and Kathleen M. Caron http://jci.me/77507

MicroRNA-directed gene delivery selectively targets VSMCs to prevent restenosisPercutaneous coronary intervention (PCi) is a primary treatment for symptomatic coronary artery disease. Unfortunately, such a procedure injures both endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), resulting in restenosis. Numerous drug-eluting stents (DES) have been developed to inhibit VSMC proliferation and restenosis. However, these drugs also attenuate the EC proliferation and migration essential to vascular healing. For instance, sirolimus and its derivatives that are currently used to coat the DES act by preventing downregulation of the cell-cycle regulator p27. Gaetano Santulli and colleagues developed a p27 expression vector (Ad-p27-126TS) bearing four tandem target sequences for an EC-enriched microRNA (miR-126) in order to preserve reendo thelialization of the vessel following PCI. Administration of Ad-p27-126TS in a rat model of PCI selectively protected ECs from overexpression of p27, thereby inhibiting drug-induced cell-cycle arrest but still

allowing for p27 overexpression in VSMCs to inhibit their proliferation and restenosis (see the accompanying image). In the related Commentary, Mark Feinberg discusses how microRNA-targeted gene delivery approaches could potentially be used in the treatment of vascular disease.

A selective microrNA-based strategy inhibits restenosis while preserving endothelial functionGaetano Santulli, Anetta Wronska, Kunihiro Uryu, Thomas G. Diacovo, Melanie Gao, Steven O. Marx, Jan Kitajewski, Jamie M. Chilton, Kemal Marc Akat, Thomas Tuschl, Andrew R. Marks, and Hana Totary-Jain http://jci.me/76069

related CommentaryHealing the injured vessel wall using microrNA-facilitated gene deliveryMark W. Feinberg http://jci.me/77509

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Research | Editor’s picks

immunology

metabolism

reproductive biology

Researchers identify germline stem cells in adult testis

spermatozoa are produced throughout adulthood by a complex, multistep process that requires rare, germline stem cells known as Asingle spermatogonia; however, the precise identity of these stem cells is unknown. Gina Aloisio and colleagues determined that Asingle spermatogonia in mice are actually a population of heterogeneous cells, with a rare subset serving as the stem-like population that is required for sustained spermatogenesis. Additionally, Aloisio and colleagues used lineage-tracing studies to show that PAX7, a satellite stem cell marker in skeletal muscle, is a specific marker for spermatogonial stem cells in the adult testis in mice (see the accompanying image) that is conserved in humans and other mammals. They found that murine PAX7+ cells survived and expanded after chemotherapy and radiotherapy to contribute to the recovery of spermatogenesis.

pAX7 expression defines germline stem cells in the adult testisGina M. Aloisio, Yuji Nakada, Hatice D. Saatcioglu, Christopher G. Peña, Michael D. Baker, Edward D. Tarnawa, Jishnu Mukherjee, Hema Manjunath, Abhijit Bugde, Anita L. Sengupta, James F. Amatruda, Ileana Cuevas, F. Kent Hamra, and Diego H. Castrillon http://jci.me/75943

Mutation-driven alterations in PI3K activity contribute to hypogammaglobulinemiahypogammaglobulinemia is an inherited primary antibody deficiency characterized by reduced levels of all types of gamma globulins, B cell defects, and recurrent infections. In this issue of the JCI, Marie-Céline Deau, Lucie Heurtier, and colleagues used whole-exome sequencing to identify molecular defects in four patients with hypogammaglobulinemia. They identified two different heterozygous mutations in PIK3R1 that resulted in enhanced PI3K activity. Patient T cell blasts carrying the mutation had increased AKT phosphorylation and activation-induced cell death that could be corrected by treatment with a PI3K inhibitor. Moreover, the PIK3R1 mutation reduced proliferation of B and T lymphocytes. In the accompanying Commentary, Craig Walsh and David Fruman discuss how these findings support the notion that alterations in PI3K activity levels contribute to immunodeficiency.

A human immunodeficiency caused by mutations in the PIK3R1 geneMarie-Céline Deau, Lucie Heurtier, Pierre Frange, Felipe Suarez, Christine Bole-Feysot, Patrick Nitschke, Marina Cavazzana, Capucine Picard, Anne Durandy, Alain Fischer, and Sven Kracker http://jci.me/75746

related Commentarytoo much of a good thing: immunodeficiency due to hyperactive pI3K signalingCraig M. Walsh and David A. Fruman http://jci.me/77198

PPARγ mediates central adaptions induced by a high-fat dietActivation of the PPARs increases systemic insulin sensitivity but also promotes increased food intake and weight gain, indicating that PPARs have tissue-specific effects on whole-body energy expenditure. In this issue of the JCI, Lihong Long and colleagues selectively ablated PPARγ in appetite-regulating proopiomelanocortin (POMC) neurons in mice to assess the effects of central PPARγ signaling in energy homeostasis. When the mice were fed a high-fat diet (HFD), PPARγ deficiency decreased peroxisome density, elevated ROS, and induced leptin sensitivity. Animals lacking POMC PPARγ also had increased energy expenditure and locomotor activity; reduced body mass, adiposity, and food intake; and improved glucose metabolism compared with control animals on a HFD. These results indicate that PPARγ mediates HFD-induced adaptations in POMC neurons that regulate whole-body energy balance.

ppArγ ablation sensitizes proopiomelanocortin neurons to leptin during high-fat feedingLihong Long, Chitoku Toda, Jing Kwon Jeong, Tamas L. Horvath, and Sabrina Diano http://jci.me/76220

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Research | Editor’s picks

endocrinology

Cellular context determines K-RAS signaling effects in pancreatic cancersK-RAs–activating mutations drive proliferation in pancreatic ductal adenocarcinomas but suppress proliferation in pancreatic endocrine tumors. Chester Chamberlain and colleagues demonstrated that cellular context determines the opposing effects of K-RAS signaling in these two tumor types. Pancreatic endocrine tumors commonly have inactivating mutations in the tumor suppressors menin and RASSF1A. K-RAS activates two different signaling pathways: a proproliferative pathway mediated by MAPK that is inhibited by menin and an antiproliferative pathway mediated by RASSF1A. Thus, loss of menin and RASSF1A promotes K-RAS activation of the MAPK-mediated proproliferation pathway in the absence of K-RAS–activating mutations (see the accompanying image). In the companion Commentary, Adolfo García-Ocaña and Andrew Stewart discuss how these findings suggest approaches to block proliferation of pancreatic endocrine cells in the context of cancer or drive therapeutic expansion of these cells in the context of diabetes.

menin determines K-rAs proliferative outputs in endocrine cellsChester E. Chamberlain, David W. Scheel, Kathleen McGlynn, Hail Kim, Takeshi Miyatsuka, Juehu Wang, Vinh Nguyen, Shuhong Zhao, Anastasia Mavropoulos, Aswin G. Abraham, Eric O’Neill, Gregory M. Ku, Melanie H. Cobb, Gail R. Martin, and Michael S. German http://jci.me/69004

related Commentary“rAs”ling β cells to proliferate for diabetes: why do we need meN?Adolfo García-Ocaña and Andrew F. Stewart http://jci.me/77764

FGF21 coordinates adaptation to reduced protein intakeFGF21 is a hormone secreted by the liver that coordinates adaptation to starvation in multiple tissues; however, FGF21 levels also increase in response to obesity and do not consistently increase in response to fasting or a ketogenic diet. These observations suggest that FGF21 secretion is dependent on levels of a specific nutrient rather than energy status. In this issue, Thomas Laeger and colleagues demonstrate that serum FGF21 levels are increased by protein restriction, but not by energy restriction, in rodents and humans. Unlike wild-type mice,

Fgf21-deficient mice did not exhibit any changes in weight gain or energy expenditure when protein intake was restricted. Protein restriction induced hepatic FGF21 expression through a mechanism involving nuclear receptor PPARα, the amino acid sensor GCN2, and the translation initiator eIF2α. In the accompanying Commentary, Timo Müller and Matthias Tschöp discuss how these findings establish FGF21 as an endocrine signal that coordinates metabolism and growth under conditions of reduced protein intake.

FGF21 is an endocrine signal of protein restrictionThomas Laeger, Tara M. Henagan, Diana C. Albarado, Leanne M. Redman, George A. Bray, Robert C. Noland, Heike Münzberg, Susan M. Hutson, Thomas W. Gettys, Michael W. Schwartz, and Christopher D. Morrison http://jci.me/74915

related Commentaryplay down protein to play up metabolism?Timo D. Müller and Matthias H. Tschöp http://jci.me/77508

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the identification of chemokines and their receptors provided important insight into leukocyte trafficking. Moreover, the development of antibodies to these molecules allowed for better characterization of T cell subsets associated with different disease states. In 1998, Charles Mackay and colleagues applied these new tools and determined that the majority of T cells in synovial fluid from patients with rheumatoid arthritis (RA) express the chemokine receptors CXCR3 and CXCR5, suggesting that this T cell subset contributes to disease. In this issue, Mackay reflects on his original findings and discusses how subsequent studies have identified CXCR3+ and/or CXCR5+ T cells within inflamed lesions associated with other human autoimmune diseases, including ulcerative colitis and multiple sclerosis. Despite these advances, it is still unclear whether CXCR3+CXCR5+ T cells drive disease pathogenesis. The accompanying image shows some of the mediators and cell types that accumulate

within joints during the articular phase of RA. The inset shows CXCR3+ T cells within synovial fluid from an RA patient.

CXCr3+CCr5+ t cells and autoimmune diseases: guilty as charged?Charles R. Mackay http://jci.me/77837

Features

hindsight

A D V e r t I s e m e N t

Characterization of rheumatoid arthritis–associated T cells

Lasker Giants

conversations with giants in medicine

the Albert and Mary lasker Foundation was established to champion medical research, and since 1945, the Lasker Awards have recognized the contributions of scientists, physicians, philanthropists, and public servants who have made major advances in the understanding, diagnosis, treatment, cure, and prevention of human disease. The JCI has had the privilege of working with the Foundation to write profiles of the award winners, and JCI Editor-at-Large Ushma Neill has had the opportunity to conduct interviews with several of the Lasker laureates as part of the Conversations with Giants in Medicine series. In honor of the Lasker Prizes, which will be awarded this month, Neill and Lasker Foundation president Claire Pomeroy have put together a highlight reel of some of the best moments from interviews with previous Lasker Prize winners. http://jci.me/78053

The JCI welcomes submissions in the following categories:

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Sample article: brown adipose tissue regulates glucose homeostasis and insulin sensitivityKristin I. Stanford, Roeland J.W. Middelbeek, Kristy L. Townsend, Ding An, Eva B. Nygaard, Kristen M. Hitchcox, Kathleen R. Markan, Kazuhiro Nakano, Michael F. Hirshman, Yu-Hua Tseng, and Laurie J. Goodyear

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Sample article: parthenogenetic stem cells for tissue-engineered heart repairMichael Didié, Peter Christalla, Michael Rubart, Vijayakumar Muppala, Stephan Döker, Bernhard Unsöld, Ali El-Armouche, Thomas Rau, Thomas Eschenhagen, Alexander P. Schwoerer, Heimo Ehmke, Udo Schumacher, Sigrid Fuchs, Claudia Lange, Alexander Becker, Wen Tao, John A. Scherschel, Mark H. Soonpaa, Tao Yang, Qiong Lin, Martin Zenke, Dong-Wook Han, Hans R. Schöler, Cornelia Rudolph, Doris Steinemann, Brigitte Schlegelberger, Steve Kattman, Alec Witty, Gordon Keller, Loren J. Field, and Wolfram-Hubertus Zimmermann

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Sample article: recruited brown adipose tissue as an antiobesity agent in humansTakeshi Yoneshiro, Sayuri Aita, Mami Matsushita, Takashi Kayahara, Toshimitsu Kameya, Yuko Kawai, Toshihiko Iwanaga, and Masayuki Saito

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Clinical medicine:research that reports early-stage, effective new therapies that impact disease outcomes in patients.

Sample article: exenatide and the treatment of patients with parkinson’s diseaseIciar Aviles-Olmos, John Dickson, Zinovia Kefalopoulou, Atbin Djamshidian, Peter Ell, Therese Soderlund, Peter Whitton, Richard Wyse, Tom Isaacs, Andrew Lees, Patricia Limousin, and Thomas Foltynie

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