jci.org/impactfebruary 2014

Also in this issue:

Normalizing glycosphingolipids in SLE 9

“Tie”-ing down tumor vasculature 10

Macrophages eliminate circulating tumor cells 10

Treating osteogenesis imperfecta 12

A summary of this month’s Journal of Clinical investigation

Regulation of neuromuscular synapse maturation p. 6

Alejandro Aballay

Abul K. Abbas

Domenico Accili

Rexford S. Ahima

Qais Al-Awqati

Kari Alitalo

James Allison

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

Jack A. Elias

Joel K. Elmquist

Stephen G. Emerson

Jeffrey A. Engelman

Jonathan A. Epstein

Adrian Erlebacher

Joel D. Ernst

James M. Ervasti

Robert V. Farese Jr.

Eric R. Fearon

Edward A. Fisher

Susan Fisher

Richard A. Flavell

Tatiana Foroud

Velia M. Fowler

Martin Friedlander

Stephen J. Galli

J. Victor Garcia-Martinez

Alfred L. George Jr.

Stanton L. Gerson

Robert E. Gerszten

Todd Golde

Stanley Goldfarb

Larry B. Goldstein

Fred Sanford Gorelick

Kathleen J. Green

J. Timothy Greenamyre

Theresa A. Guise

David Hafler

Jonathan J. Hansen

Raymond C. Harris

Stanley L. Hazen

Peter Heeringa

Brian A. Hemmings

Meenhard Herlyn

Joachim Herz

Katherine A. High

Helen H. Hobbs

Ronald Hoffman

V. Michael Holers

Steven M. Holland

Michael J. Holtzman

Lawrence B. Holzman

Tamas L. Horvath

Gokhan S. Hotamisligil

Steven R. Houser

Scott J. Hultgren

Christopher A. Hunter

Ciro Indolfi

David E. James

William G. Kaelin Jr.

Klaus Kaestner

Mark L. Kahn

Raghu Kalluri

S. Ananth Karumanchi

Robert S. Kass

Masato Kasuga

Dontscho Kerjaschki

Sundeep Khosla

Richard N. Kitsis

Peter S. Klein

Steven Kliewer

Björn C. Knollmann

Walter J. Koch

Jay K. Kolls

Issei Komuro

Christopher D. Kontos

Murray Korc

Gary Koretzky

Calvin Kuo

Antonio La Cava

Fadi G. Lakkis

Terri Laufer

Mitchell A. Lazar

Brendan Lee

William M.F. Lee

Rudolph L. Leibel

Stanley M. Lemon

Jon D. Levine

Ross L. Levine

Klaus Ley

Richard M. Locksley

Gary Lopaschuk

Richard B. Mailman

Andrew R. Marks

Jack Martin

Steven O. Marx

Rodger P. McEver

Elizabeth McNally

Cornelius J. Melief

Shlomo Melmed

George Michalopoulos

Jeffrey H. Miner

Beverly Mitchell

Peter J. Mohler

Kelle Harbert Moley

Jeffrey Molkentin

David D. Moore

Edward E. Morrisey

James H. Morrissey

Deborah M. Muoio

Anthony J. Muslin

Martin G. Myers Jr.

Benjamin G. Neel

Eric N. Olson

Harry T. Orr

William C. Parks

Warren S. Pear

Richard M. Peek Jr.

Sallie R. Permar

David J. Pinsky

Edward Plow

Jeffrey Pollard

Kornelia Polyak

Catherine Postic

Josef Prchal

Alice S. Prince

Louis J. Ptáček

Luigi Puglielli

Pere Puigserver

Bali Pulendran

Ellen Puré

Susan E. Quaggin

Marlene Rabinovitch

Daniel J. Rader

Shahin Rafii

Gwendalyn J. Randolph

Barbara Rehermann

Steven L. Reiner

Sarah A. Robertson

Paul B. Rosenberg

Marc E. Rothenberg

Anil Rustgi

J. Evan Sadler

Junichi Sadoshima

Jose-Alain Sahel

Jean E. Schaffer

Philipp E. Scherer

Michael D. Schneider

Detlef Schuppan

Michael W. Schwartz

William K. Scott

Randy Seeley

Amita Sehgal

Clay Semenkovich

Gregg L. Semenza

John Seykora

Steven D Shapiro

Mari Shinohara

Steven E. Shoelson

Gerald I. Shulman

Roy L. Silverstein

M. Celeste Simon

Mihaela Skobe

Lois Smith

Journal of Clinical Investigation Consulting Editors

Steven R. Smith

Susan S. Smyth

Weihong Song

Ashley L. St. John

Herman F. Staats

Jonathan S. Stamler

John R. Stanley

Colin L. Stewart

Doris Stoffers

Warren Strober

Maureen A. Su

Katalin Susztak

Catharina Svanborg

Ira Tabas

Alan R. Tall

Sakae Tanaka

Victor J. Thannickal

Andrei Thomas-Tikhonenko

Georgia D. Tomaras

Peter Tontonoz

Laurence A. Turka

Raphael H. Valdivia

Marcel R.M. van den Brink

Luc Van Kaer

Matthias von Herrath

Yisong Y. Wan

Hong Wang

David Weinstock

Jeffrey Weiser

Stephen J. Weiss

Bart O. Williams

Joseph C. Wu

Thomas A. Wynn

Rudolf Zechner

Kang Zhang

Len Zon

Ming-Hui Zou

Weiping Zou

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Waste not, want not

editorHoward A. Rockman

Deputy editors Garnett Kelsoe, Norman Sharpless

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, Daniel P. Kelly,Mary E. Klotman, Rodger A. Liddle,Nigel Mackman, Douglas A. Marchuk,Larry G. Moss, Christopher B. Newgard,Paul W. Noble, Cam Patterson, Geoffrey S. Pitt, Jeffrey C. Rathmell, W. Kimryn Rathmell, Bryan Roth, Jonathan S. Serody, Yiping Yang

Clinical Medicine Associate editorsBruce Burnett, Vance G. Fowler Jr.,Michael A. Morse, Andrew J. Muir,Scott M. Palmer, Mark A. Stacy

Asia editorsScott A. Summers, David M. Virshup

Chair, executive CouncilRobert J. Lefkowitz

BiostatisticiansCynthia Coffman, Barry Moser, Maren Olsen

BioethicistArthur L. Caplan

senior science editorSarah C. Jackson

Assistant science editorsJillian Hurst, Corinne 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.

Impactfebruary 2014

Contact the JCiThe Journal of Clinical Investigation2015 Manchester RoadAnn Arbor, Michigan 48104, USAPhone: 734.222.6050E-mail: staff@the-jci.org

full articles online,jci.me/124/2

from the editor

The current JCI editorial board has evaluated ap-proximately 7,000 manuscripts over the past 22 months for their suitability for publication in our journal. I suspect few are aware of the changes we have made to our editorial process to limit review-ers’ requests for what is in our view unnecessary and excessive experimentation. Unfortunately, the peer review process has become increasingly de-layed by reviewers’ insistence on, along with jour-nal editors’ acquiescence to, numerous additional experiments as a condition of acceptance. We at the JCI believe that we can make a difference and

reverse this pernicious trend while still maintaining the highest standards of ex-cellence at the journal. I have instructed the Board to intervene and not require additional requested experiments if the line of investigation is not germane to the core message of the manuscript. Additionally, we are asking reviewers to limit critiques to essential issues and to avoid asking for numerous experi-ments that move the study in new directions. Accordingly, we will evaluate each submission for what it is and not what we think it should become. If we feel the work lacks sufficient rigor or conceptual advance, we will let authors know that it is best to submit their work elsewhere. We feel this approach can reverse dam-aging trends in peer review and improve the process for all of our authors.

We look forward to continuing to serve the JCI community and being on the leading edge of publishing new discoveries that advance our knowledge and change the practice of medicine. As always, I welcome your feedback (editors@the-jci.org).

Howard A. Rockman,Editor in Chief

To read Dr. rockman’s complete editorial, see http://jci.me/75011.

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 f e b r u a r y 2 0 1 42

Research articles in the current issue of the JCI

CardiologyTgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasisWei Li, Qingle Li, Yang Jiao, Lingfeng Qin, Rahmat Ali, Jing Zhou, Jacopo Ferruzzi, Richard W. Kim, Arnar Geirsson, Harry C. Dietz, Stefan Offermanns, Jay D. Humphrey, and George Tellides http://jci.me/69942

Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulationYoshihiko Ichikawa, Mohsen Ghanefar, Marina Bayeva, Rongxue Wu, Arineh Khechaduri, Sathyamangla V. Naga Prasad, R. Kannan Mutharasan, Tejaswitha Jairaj Naik, and Hossein Ardehali http://jci.me/72931

More, p. 7

Clinical medicineDapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose productionAurora Merovci, Carolina Solis-Herrera, Giuseppe Daniele, Roy Eldor, Teresa Vanessa Fiorentino, Devjit Tripathy, Juan Xiong, Zandra Perez, Luke Norton, Muhammad A. Abdul-Ghani, and Ralph A. DeFronzo http://jci.me/70704

With related Commentary by William T. Cefalu More, p. 12

Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patientsEle Ferrannini, Elza Muscelli, Silvia Frascerra, Simona Baldi, Andrea Mari, Tim Heise, Uli C. Broedl, and Hans-Juergen Woerle http://jci.me/72227

With related Commentary by William T. Cefalu More, p. 12

evaluation of teriparatide treatment in adults with osteogenesis imperfectaEric S. Orwoll, Jay Shapiro, Sandra Veith, Ying Wang, Jodi Lapidus, Chaim Vanek, Jan L. Reeder, Tony M. Keaveny, David C. Lee, Mary A. Mullins, Sandesh C.S. Nagamani, and Brendan Lee http://jci.me/71101

With related attending Physician by Nick J. bishop and Jennifer S. Walsh More, p. 12

HematologyThrombocytopenia-associated mutations in the ANKRD26 regulatory region induce MaPK hyperactivationDominique Bluteau, Alessandra Balduini, Nathalie Balayn, Manuela Currao, Paquita Nurden, Caroline Deswarte, Guy Leverger, Patrizia Noris, Silverio Perrotta, Eric Solary, William Vainchenker, Najet Debili, Remi Favier, and Hana Raslova http://jci.me/71861

Aortic wall homeostasis

ANKRD26 in megakaryocytes

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Research articles in the current issue of the JCI

Nrf2-mediated Notch pathway activation enhances hematopoietic reconstitution following myelosuppressive radiationJung-Hyun Kim, Rajesh K. Thimmulappa, Vineet Kumar, Wanchang Cui, Sarvesh Kumar, Ponvijay Kombairaju, Hao Zhang, Joseph Margolick, William Matsui, Thomas Macvittie, Sanjay V. Malhotra, and Shyam Biswal http://jci.me/70812

More, p. 8

ImmunologyNormalizing glycosphingolipids restores function in CD4+ T cells from lupus patientsGeorgia McDonald, Shantal Deepak, Laura Miguel, Cleo J. Hall, David A. Isenberg, Anthony I. Magee, Terry Butters, and Elizabeth C. Jury http://jci.me/69571

With related Commentary by yoko Kidani and Steven J. bensinger More, p. 9

Platelet factor 4 limits Th17 differentiation and cardiac allograft rejectionGuanfang Shi, David J. Field, Kyung-ae Ko, Sara Ture, Kalyan Srivastava, Scott Levy, M. Anna Kowalska, Mortimer Poncz, Deborah J. Fowell, and Craig N. Morrell http://jci.me/71858

With related Commentary by ronjon Chakraverty More, p. 9

Human IgG fc domain engineering enhances antitoxin neutralizing antibody activityStylianos Bournazos, Siu-Kei Chow, Nareen Abboud, Arturo Casadevall, and Jeffrey V. Ravetch http://jci.me/72676

MetabolismInterplay between fGf21 and insulin action in the liver regulates metabolismBrice Emanuelli, Sara G. Vienberg, Graham Smyth, Christine Cheng, Kristin I. Stanford, Manimozhiyan Arumugam, Mervyn D. Michael, Andrew C. Adams, Alexei Kharitonenkov, and C. Ronald Kahn http://jci.me/67353

Nutrient sensing by the mitochondrial transcription machinery dictates oxidative phosphorylationLijun Liu, Minwoo Nam, Wei Fan, Thomas E. Akie, David C. Hoaglin, Gaungping Gao, John F. Keaney Jr., and Marcus P. Cooper http://jci.me/69413

Targeting the cell cycle inhibitor p57Kip2 promotes adult human β cell replicationDana Avrahami, Changhong Li, Ming Yu, Yang Jiao, Jia Zhang, Ali Naji, Seyed Ziaie, Benjamin Glaser, and Klaus H. Kaestner http://jci.me/69519

NeurobiologyNeuronal ferritin heavy chain and drug abuse affect HIV-associated cognitive dysfunctionJonathan Pitcher, Anna Abt, Jaclyn Myers, Rachel Han, Melissa Snyder, Alessandro Graziano, Lindsay Festa, Michele Kutzler, Fernando Garcia, Wen-Jun Gao, Tracy Fischer-Smith, Jay Rappaport, and Olimpia Meucci http://jci.me/70090

More, p. 7

Opioid receptor–triggered spinal mTOrC1 activation contributes to morphine tolerance and hyperalgesiaJi-Tian Xu, Jian-Yuan Zhao, Xiuli Zhao, Davinna Ligons, Vinod Tiwari, Fidelis E. Atianjoh, Chun-Yi Lee, Lingli Liang, Weidong Zang, Dolores Njoku, Srinivasa N. Raja, Myron Yaster, and Yuan-Xiang Tao http://jci.me/70236

More, p. 7

Orexin neurons suppress narcolepsy via 2 distinct efferent pathwaysEmi Hasegawa, Masashi Yanagisawa, Takeshi Sakurai, and Michihiro Mieda http://jci.me/71017

mTORC1 in hyperalgesia

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Research articles in the current issue of the JCI

NeurobiologyChanges in neural network homeostasis trigger neuropsychiatric symptomsAline Winkelmann, Nicola Maggio, Joanna Eller, Gürsel Caliskan, Marcus Semtner, Ute Häussler, René Jüttner, Tamar Dugladze, Birthe Smolinsky, Sarah Kowalczyk, Ewa Chronowska, Günter Schwarz, Fritz G. Rathjen, Gideon Rechavi, Carola A. Haas, Akos Kulik, Tengis Gloveli, Uwe Heinemann, and Jochen C. Meier http://jci.me/71472

requirement of enhanced Survival Motoneuron protein imposed during neuromuscular junction maturationShingo Kariya, Teresa Obis, Caterina Garone, Turgay Akay, Fusako Sera, Shinichi Iwata, Shunichi Homma, and Umrao R. Monani http://jci.me/72017

With related Commentary by Kathryn J. Swoboda More, p. 6

Prion disease tempo determined by host-dependent substrate reductionCharles E. Mays, Chae Kim, Tracy Haldiman, Jacques van der Merwe, Agnes Lau, Jing Yang, Jennifer Grams, Michele A. Di Bari, Romolo Nonno, Glenn C. Telling, Qingzhong Kong, Jan Langeveld, Debbie McKenzie, David Westaway, and Jiri G. Safar http://jci.me/72241

OncologyPhenothiazines induce PP2a-mediated apoptosis in T cell acute lymphoblastic leukemiaAlejandro Gutierrez, Li Pan, Richard W.J. Groen, Frederic Baleydier, Alex Kentsis, Jason Marineau, Ruta Grebliunaite, Elena Kozakewich, Casie Reed, Francoise Pflumio, Sandrine Poglio, Benjamin Uzan, Paul Clemons, Lynn VerPlank, Frank An, Jason Burbank, Stephanie Norton, Nicola Tolliday, Hanno Steen, Andrew P. Weng, Huipin Yuan, James E. Bradner, Constantine Mitsiades, A. Thomas Look, and Jon C. Aster http://jci.me/65093

Macrophages eliminate circulating tumor cells after monoclonal antibody therapyNuray Gül, Liane Babes, Kerstin Siegmund, Rianne Korthouwer, Marijn Bögels, Rens Braster, Gestur Vidarsson, Timo L.M. ten Hagen, Paul Kubes, and Marjolein van Egmond http://jci.me/66776

More, p. 10

Irradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in miceLiufu Deng, Hua Liang, Byron Burnette, Michael Beckett, Thomas Darga, Ralph R. Weichselbaum, and Yang-Xin Fu http://jci.me/67313

Positive feedback between Nf-κb and TNf-α promotes leukemia-initiating cell capacityYuki Kagoya, Akihide Yoshimi, Keisuke Kataoka, Masahiro Nakagawa, Keiki Kumano, Shunya Arai, Hiroshi Kobayashi, Taku Saito, Yoichiro Iwakura, and Mineo Kurokawa http://jci.me/68101

Tie1 deletion inhibits tumor growth and improves angiopoietin antagonist therapyGabriela D’Amico, Emilia A. Korhonen, Andrey Anisimov, Georgia Zarkada, Tanja Holopainen, René Hägerling, Friedemann Kiefer, Lauri Eklund, Raija Sormunen, Harri Elamaa, Rolf A. Brekken, Ralf H. Adams, Gou Young Koh, Pipsa Saharinen, and Kari Alitalo http://jci.me/68897

More, p. 10

erythropoietin promotes breast tumorigenesis through tumor-initiating cell self-renewalBing Zhou, Jeffrey S. Damrauer, Sean T. Bailey, Tanja Hadzic, Youngtae Jeong, Kelly Clark, Cheng Fan, Laura Murphy, Cleo Y. Lee, Melissa A. Troester, C. Ryan Miller, Jian Jin, David Darr, Charles M. Perou, Ross L. Levine, Maximilian Diehn, and William Y. Kim http://jci.me/69804

More, p. 11

Neuronal vesicular trafficking

Macrophages eliminate tumor cells

Tie1 in tumor angiogenesis

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Research articles in the current issue of the JCI

MNK1 pathway activity maintains protein synthesis in rapalog-treated gliomasMichal Grzmil, Roland M. Huber, Daniel Hess, Stephan Frank, Debby Hynx, Gerald Moncayo, Dominique Klein, Adrian Merlo, and Brian A. Hemmings http://jci.me/70198

Inactivation of SaG/rbX2 e3 ubiquitin ligase suppresses KrasG12D-driven lung tumorigenesisHua Li, Mingjia Tan, Lijun Jia, Dongping Wei, Yongchao Zhao, Guoan Chen, Jie Xu, Lili Zhao, Dafydd Thomas, David G. Beer, and Yi Sun http://jci.me/70297

Taxonomy of breast cancer based on normal cell phenotype predicts outcomeSandro Santagata, Ankita Thakkar, Ayse Ergonul, Bin Wang, Terri Woo, Rong Hu, J. Chuck Harrell, George McNamara, Matthew Schwede, Aedin C. Culhane, David Kindelberger, Scott Rodig, Andrea Richardson, Stuart J. Schnitt, Rulla M. Tamimi, and Tan A. Ince http://jci.me/70941

With related Commentary by robert D. Cardiff and alexander D. borowsky More, p. 10

Sustained activation of SMaD3/SMaD4 by fOXM1 promotes TGf-β–dependent cancer metastasisJianfei Xue, Xia Lin, Wen-Tai Chiu, Yao-Hui Chen, Guanzhen Yu, Mingguang Liu, Xin-Hua Feng, Raymond Sawaya, René H. Medema, Mien-Chie Hung, and Suyun Huang http://jci.me/71104

OphthalmologyOTX2 loss causes rod differentiation defect in CrX-associated congenital blindnessJerome E. Roger, Avinash Hiriyanna, Norimoto Gotoh, Hong Hao, Debbie F. Cheng, Rinki Ratnapriya, Marie-Audrey I. Kautzmann, Bo Chang, and Anand Swaroop http://jci.me/72722

PulmonologyPrenatal retinoid deficiency leads to airway hyperresponsiveness in adult miceFelicia Chen, Hector Marquez, Youn-Kyung Kim, Jun Qian, Fengzhi Shao, Alan Fine, William W. Cruikshank, Loredana Quadro, and Wellington V. Cardoso http://jci.me/70291

More, p. 8

Vascular biologyDisruption of vascular Ca2+-activated chloride currents lowers blood pressureChristoph Heinze, Anika Seniuk, Maxim V. Sokolov, Antje K. Huebner, Agnieszka E. Klementowicz, István A. Szijártó, Johanna Schleifenbaum, Helga Vitzthum, Maik Gollasch, Heimo Ehmke, Björn C. Schroeder, and Christian A. Hübner http://jci.me/70025

More, p. 8

Rapalog-treated gliomas

FOXM1 promotes metastasis

Vascular TMEM16A

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Spinal muscular atrophy is a pediatric neuromus-cular disorder that is caused by mutation in the survival of motor neuron 1 gene (SMN1). While there are no currently available therapies for this devastating disease, efforts are underway to de-velop treatments to modulate the paralogous gene SMN2, which can functionally compensate for SMN1 loss and restore motor neuron function in preclinical mouse models. In this month’s issue of the JCI, a research team led by Umrao Monani reports on its search to better understand the tem-poral requirement for survival motoneuron (SMN) proteins using an inducible gene-deletion strategy in mice. While depletion of SMN in neonatal mice produced a phenotype resembling spinal muscular atrophy, SMN deletion had only a modest effect in adult animals. The authors found that the require-ment for SMN was tightly linked to the establish-ment of fully mature neuromuscular synapses in juvenile animals. However, adult animals lacking SMN displayed impaired neuromuscular junction maturation in response to traumatic injury or aging. Cumulatively, these findings suggest that SMN is particularly important during the period of matura-tion and repair of neuromuscular junctions. In an accompanying Commentary, Kathryn Swoboda discusses the importance of these elegant genetic studies and the translational implications for emerging therapeutic strategies to restore SMN. The image here shows a trans-verse section through the mouse spinal cord stained for SMN (green) and choline acetyltransferase (red), with DAPI staining of nuclei. SMN increases in ipsilateral motor neurons following injury to the sciatic nerve.

requirement of enhanced Survival Motoneuron protein imposed during neuromuscular junction maturationShingo Kariya, Teresa Obis, Caterina Garone, Turgay Akay, Fusako Sera, Shinichi Iwata, Shunichi Homma, and Umrao R. Monani http://jci.me/72017

related CommentarySMN-targeted therapeutics for spinal muscular atrophy: are we SMart enough yet? Kathryn J. Swoboda http://jci.me/74142

Timing is everything: neuromuscular junction maturation requires SMN

Editor’s picksresearch

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Research | Editor’s picks

neurobiology

The contribution of drug abuse in HIV-associated cognitive dysfunctionhiV-associated neurocognitive disorders (hAnD) are associated with elevated levels of inflammatory cytokines and excitotoxins as well as neuronal loss and decreased synaptic density, all of which are exacerbated by opiate abuse. Opiates are known to alter the function of CXCR4, a chemokine receptor that plays an essential role in CNS development, function, and protection. Moreover, CXCR4 also plays a role in HIV pathogenesis, serving as a viral coreceptor. Jonathan Pitcher and colleagues investigated the interaction between CXCR4 signaling and opiate abuse in HAND. They demonstrate that both drug abusers and HAND patients had reduced CXCR4 activation and increased levels of the protein ferritin heavy chain (FHC), a negative regulator of CXCR4. These findings were confirmed in a nonhuman primate model of concomitant SIV infection and opiate abuse. Furthermore, overexpression of FHC led to CXCR4 signaling dysfunction in a human cell line and was associated with morphine-induced dendritic spine loss in rats (see accompanying image). Importantly, neuronal FHC levels correlated

with neurocognitive impairment in HIV patients, highlighting the role of the FHC/CXCR4 pathway in HAND.

Neuronal ferritin heavy chain and drug abuse affect HIV-associated cognitive dysfunctionJonathan Pitcher, Anna Abt, Jaclyn Myers, Rachel Han, Melissa Snyder, Alessandro Graziano, Lindsay Festa, Michele Kutzler, Fernando Garcia, Wen-Jun Gao, Tracy Fischer-Smith, Jay Rappaport, and Olimpia Meucci http://jci.me/70090

mTOR activation contributes to opioid-induced analgesic tolerancePatients with chronic pain are at a high risk of developing tolerance and hyperalgesia in response to long-term use of opioid painkillers. Previous studies have indicated that changes in protein translation play a critical role in the development of opioid tolerance. Yuan-Xiang Tao and colleagues report that repeated intrathecal injections of morphine induced mammalian target of rapamycin (mTOR) activation via the μ-opioid receptor in rats (see accompanying image). Activation of mTOR was associated with increased translation and with expression of several tolerance-associated proteins, including neuronal NOS. Loss of mTOR expression in the spinal cord prevented the development of morphine tolerance and hyperalgesia without altering normal pain sensing, whereas elevation of mTOR activity induced tolerance and pain hypersensitivity. These data indicate that mTOR could potentially be used in the management of opioid tolerance.

Opioid receptor–triggered spinal mTOrC1 activation contributes to morphine tolerance and hyperalgesiaJi-Tian Xu, Jian-Yuan Zhao, Xiuli Zhao, Davinna Ligons, Vinod Tiwari, Fidelis E. Atianjoh, Chun-Yi Lee, Lingli Liang, Weidong Zang, Dolores Njoku, Srinivasa N. Raja, Myron Yaster, and Yuan-Xiang Tao http://jci.me/70236

cardiology

Doxorubicin induces mitochondrial iron accumulation in the heartDoxorubicin, an antineoplastic agent that is used to treat a wide range of cancers, can cause severe heart damage. Yoshihiko Ichikawa and colleagues found that doxorubicin specifically induces the accumulation of iron in the mitochondria of cardiomyocytes, with subsequent elevation of ROS production. Overexpression of the mitochondrial iron exporter ABCB8 reduced mitochondrial iron levels and ROS production and protected against doxorubicin-induced cardiomyopathy in mice. These effects could be replicated by treating mice with dexrazoxane, an iron-chelating agent that can reduce mitochondrial iron. Moreover, mitochondrial iron levels were markedly higher in patients with doxorubicin-induced cardiac damage compared with those in patients with other cardiomyopathies.

Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulationYoshihiko Ichikawa, Mohsen Ghanefar, Marina Bayeva, Rongxue Wu, Arineh Khechaduri, Sathyamangla V. Naga Prasad, R. Kannan Mutharasan, Tejaswitha Jairaj Naik, and Hossein Ardehali http://jci.me/72931

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Research | Editor’s picks

vascular biology

Prenatal retinoic acid deficiency alters adult airway structure and functionVitamin A and its active metabolite retinoic acid (RA) are essential for lung formation; however, little is known about how prenatal vitamin A deficiency influences postnatal lung function. Using genetic, pharmacological, and dietary models of RA deficiency in mice, Felicia Chen and colleagues provide evidence that prenatal disruption of RA signaling results in aberrant, overly differentiated smooth muscle in airways. The defect persisted postnatally, regardless of the adult vitamin A status, and was recognized by airway hyperresponsiveness and structural changes in the bronchial smooth muscle. The study uncovers a previously unsuspected role of RA signaling in preventing excessive smooth muscle formation when airways are developing.

Prenatal retinoid deficiency leads to airway hyperresponsiveness in adult miceFelicia Chen, Hector Marquez, Youn-Kyung Kim, Jun Qian, Fengzhi Shao, Alan Fine, William W. Cruikshank, Loredana Quadro, and Wellington V. Cardoso http://jci.me/70291

Enhancement of NRF2 combats radiation-induced myelosuppression

Calcium-activated chloride channel TMEM16A contributes to blood pressure controlhypertension is characterized by an increase in peripheral vascular resistance that is dependent on the vascular tone, or contractile activity, of the vascular smooth muscle cells (VSMCs) in the arterioles. Because ion channels play a central role in regulating contractile activity, Christian Hübner, Björn Schroeder, and colleagues analyzed calcium-activated chloride currents (CACCs) in murine vasculature. They found substantial CACCs in large vessels, including the aorta and carotid arteries, and small vessels in the brain, retina, and skeletal muscle, but these currents were largely absent in medium-sized vessels. Disruption of the calcium-activated chloride channel TMEM16A in vascular cells resulted in decreased systemic blood pressure, as well as a decrease in angiotensin II– induced hypertension in mice. These studies indicate that TMEM16A is a potential therapeutic target for the treatment of hypertension.

Disruption of vascular Ca2+-activated chloride currents lowers blood pressureChristoph Heinze, Anika Seniuk, Maxim V. Sokolov, Antje K. Huebner, Agnieszka E. Klementowicz, István A. Szijártó, Johanna Schleifenbaum, Helga Vitzthum, Maik Gollasch, Heimo Ehmke, Björn C. Schroeder, and Christian A. Hübner http://jci.me/70025

hematology

pulmonology

exposure to ionizing radiation strongly suppresses myeloproliferation, leaving patients vulnerable to infection, bleeding, and death. Jung-Hyun Kim and colleagues found that nuclear factor erythroid-2–related factor 2 (NRF2) enhances the function of hematopoietic stem progenitor cells (HSPCs), while loss of Nrf2 in mice decreased survival after exposure to ionizing radiation. Augmentation of NRF2 signaling by deletion of the negative regulator KEAP1 or treatment with the NRF2 activator 2-trifluoromethyl-2′-methoxychalone (TMC) promoted hematopoietic reconstitution after bone marrow transplantation in mice (bottom row in the accompanying image). Importantly, TMC treatment 24 hours after irradiation mitigated myelosuppression and mortality in mice.

Nrf2-mediated Notch pathway activation enhances hematopoietic reconstitution following myelosuppressive radiationJung-Hyun Kim, Rajesh K. Thimmulappa, Vineet Kumar, Wanchang Cui, Sarvesh Kumar, Ponvijay Kombairaju, Hao Zhang, Joseph Margolick, William Matsui, Thomas Macvittie, Sanjay V. Malhotra, and Shyam Biswal http://jci.me/70812

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Research | Editor’s picks

Altered glycosphingolipid turnover mediates CD4+ T cell dysfunction in SLEsystemic lupus erythematosus (sle) is an autoimmune disorder characterized by multiple defects in the immune system. Georgia McDonald and colleagues investigated the contribution of altered cellular metabolic processes to lymphocyte dysfunction in SLE. Using CD4+ T cells from healthy subjects and SLE patients, they found that cells from SLE patients had altered profiles of lipid raft–associated glycosphingolipids. Further, increased levels of glycosphingolipids were associated with increased expression of liver X receptor β (LXRβ), a regulator of cellular lipid metabolism. Inhibition of glycosphingolipid biosynthesis with N-butyldeoxynojirimycin (NB-DNJ) restored normal glycosphingolipid metabolism (see accompanying image), corrected CD4+ T cell defects, and decreased the B cell production of SLE-associated antibodies. This study demonstrates that alterations in lipid metabolism contribute to SLE pathogenesis. In the accompanying Commentary, Yoko Kidani and Steven Bensinger discuss how therapeutic manipulation of glycosphingolipid pathways could potentially be used to treat SLE.

Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patientsGeorgia McDonald, Shantal Deepak, Laura Miguel, Cleo J. Hall, David A. Isenberg, Anthony I. Magee, Terry Butters, and Elizabeth C. Jury http://jci.me/69571

related CommentaryLipids rule: resetting lipid metabolism restores T cell function in systemic lupus erythematosusYoko Kidani and Steven J. Bensinger http://jci.me/74141

Platelet factor 4 limits Th17 differentiation to promote transplant rejection

Recent studies have demonstrated a proinflammatory role for platelets in acute transplant rejection. In this issue, Craig Morrell and colleagues examined the interaction between platelets and T helper (Th) cells, the major effectors of transplant rejection. They found that chemokine platelet factor 4 (PF4) negatively regulates the differentiation of Th17 cells. Mice lacking PF4 or that were deficient in platelets had amplified immune responses to cardiac transplantation,

including increased numbers of infiltrating Th17 cells (see the accompanying image) and greater levels of plasma IL-17. Additionally, Morrell and colleagues found that activated T cells as well as platelets secrete PF4, allowing these T cells to limit Th17 differentiation. In the accompanying Commentary, Ronjon Chakraverty discusses how these findings impact our understanding of the role of platelets in transplant rejection.

Platelet factor 4 limits Th17 differentiation and cardiac allograft rejectionGuanfang Shi, David J. Field, Kyung-ae Ko, Sara Ture, Kalyan Srivastava, Scott Levy, M. Anna Kowalska, Mortimer Poncz, Deborah J. Fowell, and Craig N. Morrell http://jci.me/71858

related Commentaryan unexpected role for platelets in blocking Th17 differentiationRonjon Chakraverty http://jci.me/74231

immunology

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Research | Editor’s picks

oncology

Search and destroy: liver macrophages eliminate circulating tumor cells

tumor resection can sometimes result in the release of individual tumor cells that can initiate metastases. Pretreatment with monoclonal antibodies can eliminate these circulating tumor cells; however, the underlying mechanisms are unclear. Marjolein van Egmond and colleagues used live-cell intravital fluorescence microscopy to demonstrate that liver macrophages, known as Kupffer cells, remove circulating tumor cells via antibody-dependent phagocytosis. The accompanying image shows a Kupffer cell (blue) phagocytosing a tumor cell (red).

Tumor-targeted antibodies enhanced Kupffer cell sampling of tumor cells and resulted in fast phagocytosis, a process that was dependent on FcγRI and FcγRIV. Importantly, treatment of mice with tumor-specific antibody markedly reduced the occurrence of metastases, and this reduction was dependent on Kupffer cell–mediated phagocytosis. These findings establish an essential role for Kupffer cells in eliminating circulating tumor cells and suggest that monoclonal antibody therapy could be used to eliminate circulating tumor cells.

Macrophages eliminate circulating tumor cells after monoclonal antibody therapyNuray Gül, Liane Babes, Kerstin Siegmund, Rianne Korthouwer, Marijn Bögels, Rens Braster, Gestur Vidarsson, Timo L.M. ten Hagen, Paul Kubes, and Marjolein van Egmond http://jci.me/66776

A new taxonomy for breast cancertraditionally, human breast cancers have been defined by two markers, estrogen receptor and human epidermal growth factor receptor 2, which indicate potential therapeutic targets but do not identify the cell type in which the cancer originated. In this issue, Sandro Santagata, Tan Ince, and colleagues report on a taxonomic system for breast cancers developed using high-throughput multiplex molecular imaging to systematically analyze fifteen markers of normal breast epithelial differentiation, including hormone receptors for androgen, vitamin D, and estrogen. Their work split human breast cancers into four major subtypes that were associated with patient survival differences. This classification offers insight into potential new hormonal therapeutic targets, including triple-negative breast carcinoma, which is currently not treated with hormones. In the accompanying Commentary, Robert Cardiff and Alexander Borowsky discuss how this new taxonomy could help shed light on the cell of origin for breast cancers, thereby advancing our understanding of the disease.

Taxonomy of breast cancer based on normal cell phenotype predicts outcomeSandro Santagata, Ankita Thakkar, Ayse Ergonul, Bin Wang, Terri Woo, Rong Hu, J. Chuck Harrell, George McNamara, Matthew Schwede, Aedin C. Culhane, David Kindelberger, Scott Rodig, Andrea Richardson, Stuart J. Schnitt, Rulla M. Tamimi, and Tan A. Ince http://jci.me/70941

related Commentaryat last: classification of human mammary cells elucidates breast cancer originsRobert D. Cardiff and Alexander D. Borowsky http://jci.me/73910

“Tie”-ing down the tumor blood supplyinhibition of tumor angiogenesis has emerged as a key strategy for reducing tumor growth; however, blocking the primary antiangiogenic targets, VEGF and VEGFR2, is often insufficient to control tumor growth and may cause undesired side effects. Gabriela D’Amico and colleagues examined how loss of Tie1, a ligand-less receptor that interacts with Tie2, affects tumor progression in mice. They found that mice with Tie1-deficient endothelium had decreased tumor angiogenesis and growth. Importantly, this decrease in angiogenesis was specific to tumor-associated vessels, without altering the normal vasculature. Further analysis indicated that Tie1 deletion deregulated key angiogenic signaling pathways of tumor angiogenesis, including VEGF, angiopoietin, and Notch signaling. These findings indicate that Tie1 may be a suitable therapeutic target for the reduction of tumor angiogenesis and growth.

Tie1 deletion inhibits tumor growth and improves angiopoietin antagonist therapyGabriela D’Amico, Emilia A. Korhonen, Andrey Anisimov, Georgia Zarkada, Tanja Holopainen, René Hägerling, Friedemann Kiefer, Lauri Eklund, Raija Sormunen, Harri Elamaa, Rolf A. Brekken, Ralf H. Adams, Gou Young Koh, Pipsa Saharinen, and Kari Alitalo http://jci.me/68897

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a D V e r T I S e M e N T

Erythropoietin promotes tumor-initiating cell self-renewal

Cancer patients frequently suffer from anemia and are treated with recombinant erythropoietin (EPO), a hormone that promotes red blood cell production. Unfortunately, several recent trials have revealed that EPO treatment is correlated with decreased survival, indicating that it may have cancer-promoting activity. Using genetically engineered murine models of breast cancer, Bing Zhou and colleagues investigated the effects of EPO on tumorigenesis and found that EPO treatment promoted the self-renewal of tumor-initiating cells (TICs) through activation of JAK/STAT signaling (see the accompanying image). Importantly,

endogenous EPO expression was negatively correlated with progression-free survival in human breast cancers. Endogenous EPO was induced by hypoxia, which has previously been shown to contribute to TIC self-renewal. Moreover, neutralizing antibodies targeting EPO or the EPO receptor inhibited hypoxia-induced mammosphere formation. Finally, in vivo, the combination of chemotherapy and JAK2 inhibition was more effective than either alone. These findings establish a role for EPO in breast cancer TIC expansion and suggest that JAK2 inhibition in combination with chemotherapy is a potential therapeutic strategy for the treatment of breast cancer.

erythropoietin promotes breast tumorigenesis through tumor-initiating cell self-renewalBing Zhou, Jeffrey S. Damrauer, Sean T. Bailey, Tanja Hadzic, Youngtae Jeong, Kelly Clark, Cheng Fan, Laura Murphy, Cleo Y. Lee, Melissa A. Troester, C. Ryan Miller, Jian Jin, David Darr, Charles M. Perou, Ross L. Levine, Maximilian Diehn, and William Y. Kim http://jci.me/69804

oncology

Research | Editor’s picks

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Research | Editor’s picks

clinical medicine

Clinical trial tests anabolic therapy for osteogenesis imperfecta

Inhibition of kidney glucose transporter improves insulin- mediated tissue glucose disposalDapagliflozin and empagliflozin are pharmacological inhibitors of the low-affinity, high-capacity sodium-glucose cotransporter 2 (SGLT2), which is responsible for the majority of glucose reabsorption in the kidney. In this issue, two research groups led by Ralph DeFronzo and Ele Ferrannini report on clinical studies testing the ability of these drugs to reduce plasma glucose levels in patients with type 2 diabetes. Both groups found that SGLT2 inhibition increased the amount of glucose excreted in the urine (glycosuria), lowered fasting plasma glucose, and improved tissue insulin sensitivity. Paradoxically, SGLT2 inhibition was associated with an increase in endogenous glucose production and decreased insulin secretion; however, overall pancreatic β cell function was improved. William Cefalu discusses the results of these clinical studies in an accompanying Commentary.

related researchDapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose productionAurora Merovci, Carolina Solis-Herrera, Giuseppe Daniele, Roy Eldor, Teresa Vanessa Fiorentino, Devjit Tripathy, Juan Xiong, Zandra Perez, Luke Norton, Muhammad A. Abdul-Ghani, and Ralph A. DeFronzo http://jci.me/70704

Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patientsEle Ferrannini, Elza Muscelli, Silvia Frascerra, Simona Baldi, Andrea Mari, Tim Heise, Uli C. Broedl, and Hans-Juergen Woerle http://jci.me/72227

related CommentaryParadoxical insights into whole body metabolic adaptations following SGLT2 inhibitionWilliam T. Cefalu http://jci.me/74297

evaluation of teriparatide treatment in adults with osteogenesis imperfectaEric S. Orwoll, Jay Shapiro, Sandra Veith, Ying Wang, Jodi Lapidus, Chaim Vanek, Jan L. Reeder, Tony M. Keaveny, David C. Lee, Mary A. Mullins, Sandesh C.S. Nagamani, and Brendan Lee http://jci.me/71101

related attending PhysicianOsteogenesis imperfecta in adultsNick J. Bishop and Jennifer S. Walsh http://jci.me/74230

osteogenesis imperfecta (oi), or brittle bone disease, is a congenital disorder most often caused by mutations in the collagen genes COL1A1 and COL1A2. Drug therapy is intended to reduce fracture risk and is currently focused on bisphosphonates, which have not been shown to be effective in adults. In this issue, Eric Orwoll and colleagues report on a clinical trial testing teriparatide, a recombinant form of parathyroid hormone, in adults with OI. Teriparatide is currently used as a bone anabolic therapy for the treatment of osteoporosis;

however, anabolic therapy has not previously been tested in OI. Orwoll and colleagues found that in patients with mild forms of OI, teriparatide treatment resulted in significantly greater bone density of the hips and lumbar spine, as well as increased vertebral strength, compared with placebo. Patients with more severe forms of the disease did not exhibit significant benefits with teriparatide treatment. In the accompanying Attending Physician article, Nick Bishop and Jennifer Walsh discuss current OI treatment options.

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Features

conversations with giants in medicinehindsight

review

Generation of superoxide in hypercholesterolemia

A delicate balance in bone remodelingthe adult skeleton undergoes continuous remodeling, a process that is necessary to maintain skeletal integrity and to allow the skeleton to serve as a reservoir of calcium and phosphorus. Consequently, a delicate balance between bone resorption and bone formation must be maintained, with imbalances resulting in skeletal diseases such as osteoporosis and arthritis. In this issue, Janet Crane and Xu Cao review the role of bone marrow mesenchymal stem cells (MSCs) in bone remodeling, focusing on the effect of parathyroid hormone and TGF-β signaling in directing MSC fate (see the accompanying image). Additionally, the authors review disorders associated with abnormalities in bone remodeling and mutations in TGF-β signaling pathways that contribute to these diseases.

bone marrow mesenchymal stem cells and TGf-β signaling in bone remodelingJanet L. Crane and Xu Cao http://jci.me/70050

Don GanemDon Ganem, Vice President and head of Global infectious Disease for the Novartis Institutes for Biomedical Research, has spent his career trying to understand and treat microbial pathogens. He began working with microbial genetics as an undergraduate at Harvard in the labs of Walter Gilbert and James Watson, then took a leave of absence from medical school to work on SV40 DNA replication with George Fareed. After finishing medical school and a residency, he worked as a postdoctoral researcher in Harold Varmus’s lab, studying hepatitis B virus. As an independent investigator at UCSF, he identified KSHV as the cause of Kaposi’s sarcoma. In this issue, JCI Editor at Large Ushma Neill interviews Ganem, discussing his early interest in science and his goals for combating microbial infections. http://jci.me/73101

oxidant stress is involved in the pathology of multiple cardiovascular diseases. These disorders are also characterized by alterations in vascular tone and function, which have direct effects on blood pressure and cardiovascular health. In a 1993 JCI article, David Harrison and colleagues showed that there is excess generation of superoxide within hypercholesterolemic vessels. The increased superoxide led to decreased production of the vasodilator NO. Interestingly, removal of the vessel endothelium, which generates NO, abolished superoxide production. In this issue, Harrison discusses these findings in terms of our current understanding of ROS in vascular biology and disease.

from ST segments to endothelial pathophysiology: hypercholesterolemia and endothelial superoxide productionDavid G. Harrison http://jci.me/70336

The JCI accepts submissions in the following categories:

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Sample article: Obesity is associated with hypothalamic injury in rodents and humansJoshua P. Thaler, Chun-Xia Yi, Ellen A. Schur, Stephan J. Guyenet, Bang H. Hwang, Marcelo O. Dietrich, Xiaolin Zhao, David A. Sarruf, Vitaly Izgur, Kenneth R. Maravilla, Hong T. Nguyen, Jonathan D. Fischer, Miles E. Matsen, Brent E. Wisse, Gregory J. Morton, Tamas L. Horvath, Denis G. Baskin, Matthias H. Tschöp, and Michael W. Schwartz

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Sample article: rorγt+ innate lymphocytes and γδ T cells initiate psoriasiform plaque formation in miceStanislav Pantelyushin, Stefan Haak, Barbara Ingold, Paulina Kulig, Frank L. Heppner, Alexander A. Navarini, and Burkhard Becher

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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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