jci.org/this-month

Hypoxia reduction in prostate tumors boosts immunotherapy response 3

β1-Adrenergic receptors regulate human bone turnover 3

Nuclear receptor NR4A1 regulates adipogenic capacity in obesity 3

Siglec blockade enhances antitumor immunity 4

Renin super-enhancers facilitate systemic renin homeostasis 4

JCI This Month is a summary of the most recent articles in The Journal of Clinical Investigation and JCI Insight

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November 2018

Blocking angiopoietin-2 mitigates pathological heart repair p. 2

This Month

Journal of Clinical Investigation Consulting Editors

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j c i . o r g / t h i s - m o n t h n o v e m b e r 2 0 1 8 1

For the JCIEditorRexford S. Ahima

Deputy EditorsArturo Casadevall, Gregg L. Semenza, Gordon F. Tomaselli

Associate EditorsRichard F. Ambinder, Mark E. Anderson, Mary Y. Armanios, William R. Bishai, Robert A. Brodsky, Peter A. Calabresi, Thomas L. Clemens, Franco R. D’Alessio, Ted M. Dawson, Angelo M. DeMarzo, Stephen Desiderio, Mark Donowitz, Andrew P. Feinberg, Paul M. Hassoun, Elizabeth M. Jaffee, Mariana J. Kaplan, Marikki Laiho, Leo Luznik, Marcela V. Maus, Timothy H. Moran, Laszlo Nagy, William Nelson, Brian O’Rourke, Ben Ho Park, Jonathan D. Powell, Thomas C. Quinn, Hamid Rabb, Jean-Pierre Raufman, Stuart C. Ray, Jeffrey D. Rothstein, Jonathan Schneck, Akrit S. Sodhi, Charlotte J. Sumner, Simeon I. Taylor, David L. Thomas, Robert G. Weiss, Sarah J. Wheelan, Marsha Wills-Karp

Editorial Advisory GroupPeter Agre, Carol W. Grieder, Paul B. Rothman, Diane E. Griffin, and David Valle

BiostatisticianEliseo Guallar

Computational BiologistPatrick Cahan

JCI ScholarsJustin Lowenthal, Austin K. Mattox

Staff EditorsExecutive EditorSarah C. Jackson

Science EditorsElyse Dankoski, Monika Deshpande, Corinne Williams

Editor at LargeUshma S. Neill

JCI This Month ISSN 2324-7703 (print);ISSN 2325-4556 (online)

For the full JCI online: jci.me/128/11

This MonthNovember 2018

Contact the JCI and JCI Insight2015 Manchester RoadAnn Arbor, Michigan 48104, USAPhone: 734.222.6050Email: staff@the-jci.org (JCI); staff@insight.jci.org (JCI Insight)

The American Society for Clinical Investigation holds the rights to and publishes the Journal of Clinical Investigation and JCI Insight. The opinions expressed herein are solely those of the authors and are not necessarily endorsed by the ASCI.

The JCI’s Editorial Board is composed of peer scientists at Johns Hopkins University School of Medicine, the University of Maryland School of Medicine, and the National Institutes of Health. Editorial Board members review and oversee peer review of each manuscript that is submitted to the JCI, and the Board meets weekly to discuss manuscripts undergoing review.

Featured Editor

Elizabeth M. Jaffee, MD, Associate Editor, is the Dana and Albert “Cubby” Broccoli Professor of Oncology, Co-Director of Gastrointestinal Cancer Programs, and Deputy Director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University. Dr. Jaffee is recognized as a leader in the field of cancer immunology, specializing in the preclinical and early clinical development of

immunotherapies for breast and pancreatic cancers. She is member of the Association of American Physicians, serves on multiple advisory councils for the National Cancer Institute and Cancer Research Institute, and is currently President of the American Association for Cancer Research.

Publication highlights

Hopkins AC, Yarchoan M, Durham JN, Yusko EC, Rytlewski JA, Robins HS, Laheru DA, Le DT, Lutz ER, Jaffee EM. T cell receptor repertoire features associated with survival in immunotherapy-treated pancreatic ductal adenocarcinoma. JCI Insight. 2018;3(13):e122092.

Yarchoan M, Johnson BA, Lutz ER, Laheru DA, Jaffee EM. Targeting neoantigens to augment antitumour immunity. Nat Rev Cancer. 2017;17(4):209–222.

Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med. 2017;377(25):2500–2501.

Le DT, Wang-Gillam A, Picozzi V, Greten TF, Crocenzi T, Springett G, Morse M, Zeh H, Cohen D, Fine RL, Onners B, Uram JN, Laheru DA, Lutz ER, Solt S, Murphy AL, Skoble J, Lemmens E, Grous J, Dubensky T Jr, Brockstedt DG, Jaffee EM. Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J Clin Oncol. 2015;33(12):1325–1333.

(ASCI) indicates corresponding authors who are ASCI members.

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research

Editor’s picks

on the jci cover vascular biology

Angiopoietin-2 promotes pathological cardiovascular remodeling after myocardial infarction

α-Globin fine-tunes arteriolar vasodilation with help from α-hemoglobin–stabilizing proteinArteriolar endothelial cells express α-globin at the myoendothelial junction, an interface between endothelial and vascular smooth muscle cells. While α-globin in RBC contributes to oxygen transport, arteriolar α-globin promotes vasoconstriction by binding endothelial NO synthase (eNOS) and degrading NO. β-Globin stabilizes α-globin in RBC, but arterioles lack β-globin. Moreover, free α-globin monomers are unstable and are degraded by cellular protein quality control systems. Noting that α-hemoglobin– stabilizing protein (AHSP) stabilizes α-globin in RBC precursors, Christophe Lechauve and colleagues investigated whether its function is similar in arterioles. They determined that AHSP is a crucial partner for arteriolar α-globin: AHSP promotes α-globin expression and facilitates its reduction by eNOS. They further show that AHSP and α-globin play a key role in maintaining vascular tone and blood pressure. Adam Straub and Mark Gladwin’s accompanying Commentary underscores the relevance of this mechanism in fine-tuning NO regulation.

Endothelial cell α-globin and its molecular chaperone α-hemoglobin–stabilizing protein regulate arteriolar contractilityChristophe Lechauve, Joshua T. Butcher, Abdullah Freiwan, Lauren A. Biwer, Julia M. Keith, Miranda E. Good, Hans Ackerman, Heather S. Tillman, Laurent Kiger, Brant E. Isakson, and Mitchell J. Weiss (ASCI) http://jci.me/99933

Related CommentaryEscorting α-globin to eNOS: α-globin–stabilizing protein paves the wayAdam C. Straub and Mark T. Gladwin (ASCI) http://jci.me/124302

In the aftermath of myocardial infarction, pathological cardiac remodeling sets the stage for ischemic heart disease and heart failure. Dysfunctional endothelial responses to damage contribute to the vascular leakage and inflammation that exacerbate ischemia in the failing heart. Recent studies link elevations in the vascular growth factor angiopoietin-2 with worse cardiovascular outcomes, but its precise functions in cardiac remodeling remain unclear. A study in this issue of the JCI exposes angiopoietin-2’s antagonistic role in heart repair. In a mouse model of myocardial infarction, Lee et al. show increased angio poietin-2 expression in endothelial cells surrounding the infarct. The elevated angiopoietin-2 levels interrupted

endothelium-stabilizing angiopoietin-1/Tie2 signaling, exacerbating vascular leakage and hypoxia. Weeks after myocardial infarction, persistent elevations in angiopoietin-2 were responsible for abnormal vascular remodeling as well as cardiac fibrosis. Blocking angio poietin-2 signaling after ischemic injury mitigated vascular leakage, inflammation, and fibrosis in the murine heart, supporting the concept that angiopoietin-2 inhibition may restrain pathological remodeling following myocar-dial infarction. This issue’s cover illustrates the low level of cardiac fibrosis (green) observed in the infarcted murine heart in the absence of angiopoietin-2 expression. Image credit: Seung-Jun Lee.

Angiopoietin-2 exacerbates cardiac hypoxia and inflammation after myocardial infarctionSeung-Jun Lee, Choong-kun Lee, Seok Kang, Intae Park, Yoo Hyung Kim, Seo Ki Kim, Seon Pyo Hong, Hosung Bae, Yulong He, Yoshiaki Kubota, and Gou Young Koh http://jci.me/99659

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JCI | Research: Editor’s picks

oncology

Reducing tumor hypoxia improves T cell infiltration and response to immunotherapyImmunologically “hot” tumors with preexisting immune infiltration respond well to checkpoint inhibition. For “cold” tumors, which lack T cells and resist immunotherapy, strategies that elicit immune infiltration may restore responsiveness to checkpoint blockade. Priyamvada Jayaprakash, Midan Ai, and colleagues observed that T cell infiltration was impaired within hypoxic regions of multiple prostate cancer models. Treating mice with the cytotoxic, hypoxia-activated prodrug TH-302 reduced the hypoxic area of these tumors over 7-fold. Combining TH-302 with CTLA-4/PD-1 checkpoint blockade eliminated 80% of tumors in a transplantable prostate model and controlled tumor outgrowth in a checkpoint-resistant spontaneous model. Increased T cell infiltration of formerly hypoxic zones drove the success of this therapy (see the accompanying image). Paul Walker’s accompanying Commentary indicates that the sensitization of cold tumors to checkpoint immunotherapy using targeted disruption of hypoxia supports further investigation of this approach in human cancers.

Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapyPriyamvada Jayaprakash, Midan Ai, Arthur Liu, Pratha Budhani, Todd Bartkowiak, Jie Sheng, Casey Ager, Courtney Nicholas, Ashvin R. Jaiswal, Yanqiu Sun, Krishna Shah, Sadhana Balasubramanyam, Nan Li, Guocan Wang, Jing Ning, Anna Zal, Tomasz Zal, and Michael A. Curran http://jci.me/96268

Related CommentaryLet there be oxygen and T cellsPaul R. Walker http://jci.me/124305

metabolism

Nuclear receptor NR4A1 impairs adipogenesis and glucose homeostasis in obesityAdipogenesis slows dramatically in adulthood, and in obese adults, inadequate adipogenesis is associated with impaired glucose and lipid metabolism. Although adipocyte turnover may play an important role in the pathogenesis of metabolic disease and insulin resistance, little is known about the constitutively active regulators of adipocyte progenitor (AP) fate. Yang Zhang and coworkers identified the nuclear receptor NR4A1 as a constitutively expressed negative

regulator of AP fate, demonstrating an inverse relationship between adipogenesis and NR4A1 expression. In NR4A1-deficient mice, adipose tissue displayed higher rates of adipogenesis, and transfer of NR4A1-deficient APs to WT mice attenuated insulin resistance and weight gain induced by high-fat feeding. NR4A1’s role in maintaining AP quiescence suggests that it may be a therapeutic target for mitigating the metabolic consequences of obesity.

Targeting nuclear receptor NR4A1–dependent adipocyte progenitor quiescence promotes metabolic adaptation to obesityYang Zhang, Alexander J. Federation, Soomin Kim, John P. O’Keefe, Mingyue Lun, Dongxi Xiang, Jonathan D. Brown, and Matthew L. Steinhauser http://jci.me/98353

β1-Adrenergic receptor antagonists attenuate human bone resorptionβ-Adrenergic antagonists have been shown to regulate bone metabolism via the sympathetic nervous system (SNS) in animal studies. Prospective studies in humans, however, have failed to demonstrate a clear link between adrenergic signaling and bone turnover. Three lines of investigation conducted by Sundeep Khosla and colleagues now provide evidence that β1-adrenergic receptors (β1-ARs) influence bone density and resorption in adults. Biopsies from 19 younger women and 19 older women revealed that both β1- and β2-ARs are expressed in human bone. In a separate cohort of 248 subjects, use of β-AR antagonists correlated with superior bone microarchitecture. Finally, an interventional study evaluated 155 postmenopausal women randomized to treatment with antagonists that varied in selectivity for β1-ARs. In the accompanying Commentary, Lorenz Hofbauer and Holger Henneicke examine the finding that β1-AR antagonists, but not nonselective β-blockers, reduce bone resorption, indicating a role for the SNS in regulating human bone metabolism.

Sympathetic β1-adrenergic signaling contributes to regulation of human bone metabolismSundeep Khosla (ASCI), Matthew T. Drake, Tammie L. Volkman, Brianne S. Thicke, Sara J. Achenbach, Elizabeth J. Atkinson, Michael J. Joyner, Clifford J. Rosen, David G. Monroe, and Joshua N. Farr http://jci.me/122151

Related Commentaryβ-Blockers and bone healthLorenz C. Hofbauer and Holger Henneicke http://jci.me/122992

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JCI | Research: Editor’s picks

endocrinology

Renin super-enhancer regulates memory of renin phenotype in descendant cellsRenin-expressing cells in the renin-angiotensin-aldosterone axis contribute to modulation of extracellular fluid volume and vasoconstriction. In adults, descendants of renin- expressing cells can revert to a renin-producing phenotype under stress conditions and regain their identity once sufficient renin levels are attained. Maria Florencia Martinez and coworkers characterized renin cell super-enhancers, gene regulatory elements comprising large regions of DNA marked by H3K27 acetylation that are enriched in transcriptional and chromatin regulators. After identifying a super-enhancer at the Renin locus that retains the memory of the renin-producing phenotype in descendant cells, they demon-strated that regions of this super-enhancer are required for maintaining renin cell identity and circulating renin levels in mice. In the accompa-nying Commentary, Steven Crowley unpacks the study’s insights into genomic mechanisms that coordinate the adaptive response of renin-producing cells to physiological stress.

Super-enhancers maintain renin-expressing cell identity and memory to preserve multi-system homeostasisMaria Florencia Martinez, Silvia Medrano, Evan A. Brown, Turan Tufan, Stephen Shang, Nadia Bertoncello, Omar Guessoum, Mazhar Adli, Brian C. Belyea, Maria Luisa S. Sequeira-Lopez, and R. Ariel Gomez (ASCI) http://jci.me/121361

Related CommentaryATAC-ing the mechanisms of renin regulationSteven D. Crowley http://jci.me/124177

immunology

Siglec signaling in tumor-infiltrating T cells enhances immune evasionThough checkpoint inhibitors represent a major advance in anticancer therapies, many tumors exhibit primary resistance or acquire resistance to PD-1–targeting treatments. Michal Stanczack, Shoib Siddiqui, and colleagues investigated sialic acid–binding Ig-like lectins (Siglecs) as potential targets for overcoming resistance to checkpoint inhibition. Recent studies have associated Siglec upregulation with immune evasion in cancer and chronic disease; accordingly, the researchers observed increased Siglec-9 expression on a subset of tumor-infiltrating T cells derived from human lung, colorectal, and ovarian tumors. The Siglec-9+ subset displayed markers of exhaustion, such as PD-1 expression. Moreover, in mice, increased Siglec signaling correlated with enhanced syngeneic tumor growth. These findings indicate that Siglec targeting is a potential strategy for averting treatment failure in tumors that are resistant to checkpoint-targeting therapies.

Self-associated molecular patterns mediate cancer immune evasion by engaging Siglecs on T cellsMichal A. Stanczak, Shoib S. Siddiqui, Marcel P. Trefny, Daniela S. Thommen, Kayluz Frias Boligan, Stephan von Gunten, Alexandar Tzankov, Lothar Tietze, Didier Lardinois, Viola Heinzelmann-Schwarz, Michael von Bergwelt-Baildon, Wu Zhang, Heinz-Josef Lenz, Younghun Han, Christopher I. Amos, Mohammedyaseen Syedbasha, Adrian Egli, Frank Stenner, Daniel E. Speiser, Ajit Varki, Alfred Zippelius, and Heinz Läubli http://jci.me/120612

Species-specific recognition of antigenic sites on the influenza H1 hemagglutininThe influenza virus’s lipid membrane is coated by a surface glycoprotein, a hemagglutinin that contains five classic antigenic sites (Sa, Sb, Ca2, Ca2, and Cb). Antibodies targeting hemagglutinin sites may interfere with virus-host attachment, a function referred to as hemagglutination inhibition (HI). Sean Liu and colleagues adopted previously unutilized reagents to examine HI activity of serum antibodies from influenza virus–infected mice, guinea pigs, ferrets, and humans. They observed that targeting of the major antigenic sites followed species-specific patterns. The murine immune system predominantly targeted sites Sb and Ca2, and the ferret immune system targeted site Sa, whereas immune responses in guinea pigs showed less-specific preferences. HI-active antibodies in adult humans followed yet another pattern, with sites Sb and Sa being immunodominant. Kristien Van Reeth’s accompanying Commentary speculates that these insights may guide more effective influenza vaccine design when coupled with longitudinal studies comparing HI titers and viral protection in humans.

Antigenic sites in influenza H1 hemagglutinin display species-specific immunodominanceSean T. H. Liu, Mohammad Amin Behzadi, Weina Sun, Alec W. Freyn, Wen-Chun Liu, Felix Broecker, Randy A. Albrecht, Nicole M. Bouvier, Viviana Simon, Raffael Nachbagauer, Florian Krammer, and Peter Palese http://jci.me/122895

Related CommentaryThe post-2009 influenza pandemic era: time to revisit antibody immunodominanceKristien Van Reeth http://jci.me/124151

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JCI | Research: Editor’s picks

Genetic susceptibility plus cigarette smoke induce Crohn’s phenotype in mice

gastroenterology

TNK1-driven apoptosis exacerbates intestinal barrier breakdown and systemic inflammationAberrant apoptosis in the gut epithelium is thought to drive increases in intestinal barrier permeability that lead to immune activation, microbiome alterations, and potentially life-threatening systemic inflammation. In this issue, Milena Armacki and colleagues examined how expression of the apoptosis-regulating protein thirty-eight-negative kinase 1 (TNK1) promotes intestinal epithelial dysfunction that may underlie systemic inflammation. TNK1 overexpression dramatically increased intestinal exfoliation, leading to breakdown of the intestinal barrier (see the accompanying image). In TNK1-overexpressing mice, bacterial transloca-tion within epithelial layers and in lymph nodes coincided with systemic inflammation and increased mortality. TNFA blockade attenuated intestinal disturbances associated with TNK1 overexpression, in keeping with prior demonstra-tions that TNK1 promotes apoptosis by inducing this proinflammatory cytokine. In the accompa-nying Commentary, QiQi Zhou and Nicholas Verne discuss the need for further exploration of TNK1 targeting as an intervention in systemic inflammatory responses originating in the gut.

Thirty-eight-negative kinase 1 mediates trauma-induced intestinal injury and multi-organ failureMilena Armacki, Anna Katharina Trugenberger, Ann K. Ellwanger, Tim Eiseler, Christiane Schwerdt, Lucas Bettac, Dominik Langgartner, Ninel Azoitei, Rebecca Halbgebauer, Rüdiger Groß, Tabea Barth, André Lechel, Benjamin M. Walter, Johann M. Kraus, Christoph Wiegreffe, Johannes Grimm, Annika Scheffold, Marlon R. Schneider, Kenneth Peuker, Sebastian Zeißig, Stefan Britsch, Stefan Rose-John, Sabine Vettorazzi, Eckhart Wolf, Andrea Tannapfel, Konrad Steinestel, Stefan O. Reber, Paul Walther, Hans A. Kestler, Peter Radermacher, Thomas F.E. Barth, Markus Huber-Lang, Alexander Kleger, and Thomas Seufferlein http://jci.me/97912

Related CommentaryIntestinal hyperpermeability: a gateway to multi-organ failure?QiQi Zhou and G. Nicholas Verne http://jci.me/124366

Genetic and environmental factors that influence Crohn’s disease (CD) pathogenesis may provide insights into more effective interventions for this complex disease. Ta-Chiang Liu and colleagues

investigated the interaction between a prevalent CD susceptibility allele, ATG16L1T300A, and cigarette smoking in driving CD-associated Paneth cell defects. An analysis of 128 CD patients revealed a high incidence of Paneth cell defects in cigarette smokers carrying the T300A allele (see the accompanying image). Similarly, cigarette smoke triggered Paneth cell defects at a higher rate in Atg16l1T300A mice than in their wild-type littermates. Transcriptome analysis implicated the PPARγ pathway in mediating increased Paneth cell apoptosis, and pre-treatment with a PPARγ inhibitor reduced Paneth cell defects in smoke-exposed T300A-mutant mice. In the accompanying Commentary, Shigeru Oshima and Mamoru Watanabe highlight opportunities to intervene in this pathological gene-environment interaction.

Interaction between smoking and ATG16L1T300A triggers Paneth cell defects in Crohn’s diseaseTa-Chiang Liu, Justin T. Kern, Kelli L. VanDussen, Shanshan Xiong, Gerard E. Kaiko, Craig B. Wilen, Michael W. Rajala, Roberta Caruso, Michael J. Holtzman, Feng Gao, Dermot P.B. McGovern, Gabriel Nunez, Richard D. Head, and Thaddeus S. Stappenbeck (ASCI) http://jci.me/120453

Related CommentaryGenetic and environmental factors drive personalized medicine for Crohn’s diseaseShigeru Oshima and Mamoru Watanabe http://jci.me/124303

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JCI | Research: Editor’s picks

A D V E R T I S E M E N Tconversations with giants in medicine

Carla ShatzDevelopmental neurobiologist Carla Shatz is known both for her discovery of the spontaneous electrical activity that guides the formation of neural connections and for coining the statement, “Neurons that fire together wire together,” a frequently repeated phrasing of a central tenet of neuroscience. Dr. Shatz broke barriers as the first woman to graduate from Harvard’s neurobiology program and navigated new territory as a female faculty member at Stanford and Berkeley and as the chair of neurobiology at Harvard. Currently the director of Stanford University’s Bio-X program, she joined JCI’s Editor-at-Large Ushma Neill to discuss the experiences that influenced her early life and career. The full interview is available as a video on the JCI website. http://jci.me/123942

infectious disease

IFN-γ–induced human tryptophanyl-tRNA synthetase enhances Enterovirus entryHuman enterovirus EV-A71 is one of several Enterovirus serotypes that cause hand, foot, and mouth disease, which can produce life-threatening neurological complications. Functions of known EV-A71 receptors do not fully account for tissue tropism and clinical manifestations of EV-A71 infection. Man Lung Yeung et al. screened an RNAi library and determined that human tryptophanyl-tRNA synthetase (hWARS) functions as an entry factor for EV-A71. hWARS knockdown impaired the entry of multiple human enterovirus serotypes, highlighting its broad relevance to Enterovirus infectivity. Drawing on observations

that IFN-γ upregulates hWARS expression, the researchers showed that IFN-γ stimulation sensitizes semipermissive human neuronal cells to EV-A71 infection. Consistently, sensitization to EV-A71 infection was also observed when hWARS was hyperexpressed in nonpermissive mouse fibroblasts. Moreover, pathological changes in EV-A71–infected, hWARS-transduced mice resembled severe EV-A71 infection in patients. The accompanying Commentary by Stanley Perlman and Tom Gallagher details insights into potential therapeutic options for limiting complications associated with EV-A71 infection.

Human tryptophanyl-tRNA synthetase is an IFN-γ–inducible entry factor for EnterovirusMan Lung Yeung, Lilong Jia, Cyril C. Y. Yip, Jasper F. W. Chan, Jade L. L. Teng, Kwok-Hung Chan, Jian-Piao Cai, Chaoyu Zhang, Anna J. Zhang, Wan-Man Wong, Kin-Hang Kok, Susanna K. P. Lau, Patrick C. Y. Woo, Janice Y. C. Lo, Dong-Yan Jin, Shin-Ru Shih, and Kwok-Yung Yuen http://jci.me/99411

Related CommentaryNot your usual tRNA synthetase: hWARS serves as an enterovirus entry factorStanley Perlman and Tom Gallagher http://jci.me/124582

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Current research articles

aids/hivCycling CD4+ T cells in HIV-infected immune nonresponders have mitochondrial dysfunctionSouheil-Antoine Younes, Aarthi Talla, Susan Pereira Ribeiro, Evgeniya V. Saidakova, Larisa B. Korolevskaya, Konstantin V. Shmagel, Carey L. Shive, Michael L. Freeman, Soumya Panigrahi, Sophia Zweig, Robert Balderas, Leonid Margolis, Daniel C. Douek, Donald D. Anthony, Pushpa Pandiyan, Mark Cameron, Scott F. Sieg, Leonard H. Calabrese, Benigno Rodriguez, and Michael M. Lederman http://jci.me/120245

Neutrophil extracellular trap production contributes to pathogenesis in SIV-infected nonhuman primatesRanjit Sivanandham, Egidio Brocca-Cofano, Noah Krampe, Elizabeth Falwell, Sindhuja Murali Kilapandal Venkatraman, Ruy M. Ribeiro, Cristian Apetrei, and Ivona Pandrea (ASCI) http://jci.me/99420

autoimmunityKidney-infiltrating T cells in murine lupus nephritis are metabolically and functionally exhaustedJeremy S. Tilstra, Lyndsay Avery, Ashley V. Menk, Rachael A. Gordon, Shuchi Smita, Lawrence P. Kane, Maria Chikina, Greg M. Delgoffe, and Mark J. Shlomchik (ASCI) http://jci.me/120859

cardiologyThe two-pore domain potassium channel TREK-1 mediates cardiac fibrosis and diastolic dysfunctionDennis M. Abraham, Teresa E. Lee, Lewis J. Watson, Lan Mao, Gurangad Chandok, Hong-Gang Wang, Stephan Frangakis, Geoffrey S. Pitt, Svati H. Shah, Matthew J. Wolf, and Howard A. Rockman (ASCI) http://jci.me/95945

cell biologyDeletion of Tmtc4 activates the unfolded protein response and causes postnatal hearing lossJiang Li, Omar Akil, Stephanie L. Rouse, Conor W. McLaughlin, Ian R. Matthews, Lawrence R. Lustig, Dylan K. Chan, and Elliott H. Sherr http://jci.me/97498

endocrinologySuper-enhancers maintain renin-expressing cell identity and memory to preserve multi-system homeostasis p. 4Maria Florencia Martinez, Silvia Medrano, Evan A. Brown, Turan Tufan, Stephen Shang, Nadia Bertoncello, Omar Guessoum, Mazhar Adli, Brian C. Belyea, Maria Luisa S. Sequeira-Lopez, and R. Ariel Gomez (ASCI) http://jci.me/121361

gastroenterologyInteraction between smoking and ATG16L1T300A triggers Paneth cell defects in Crohn’s disease p. 5Ta-Chiang Liu, Justin T. Kern, Kelli L. VanDussen, Shanshan Xiong, Gerard E. Kaiko, Craig B. Wilen, Michael W. Rajala, Roberta Caruso, Michael J. Holtzman, Feng Gao, Dermot P.B. McGovern, Gabriel Nunez, Richard D. Head, and Thaddeus S. Stappenbeck (ASCI) http://jci.me/120453

Thirty-eight-negative kinase 1 mediates trauma-induced intestinal injury and multi-organ failure p. 5Milena Armacki, Anna Katharina Trugenberger, Ann K. Ellwanger, Tim Eiseler, Christiane Schwerdt, Lucas Bettac, Dominik Langgartner, Ninel Azoitei, Rebecca Halbgebauer, Rüdiger Groß, Tabea Barth, André Lechel, Benjamin M. Walter, Johann M. Kraus, Christoph Wiegreffe, Johannes Grimm, Annika Scheffold, Marlon R. Schneider, Kenneth Peuker, Sebastian Zeißig, Stefan Britsch, Stefan Rose-John, Sabine Vettorazzi, Eckhart Wolf, Andrea Tannapfel, Konrad Steinestel, Stefan O. Reber, Paul Walther, Hans A. Kestler, Peter Radermacher, Thomas F.E. Barth, Markus Huber-Lang, Alexander Kleger, and Thomas Seufferlein http://jci.me/97912

Lysyl-tRNA synthetase–expressing colon spheroids induce M2 macrophage polarization to promote metastasisSeo Hee Nam, Doyeun Kim, Doohyung Lee, Hye-Mi Lee, Dae-Geun Song, Jae Woo Jung, Ji Eon Kim, Hye-Jin Kim, Nam Hoon Kwon, Eun-Kyeong Jo, Sunghoon Kim, and Jung Weon Lee http://jci.me/99806

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Current research articlesimmunologySelf-associated molecular patterns mediate cancer immune evasion by engaging Siglecs on T cells p. 4Michal A. Stanczak, Shoib S. Siddiqui, Marcel P. Trefny, Daniela S. Thommen, Kayluz Frias Boligan, Stephan von Gunten, Alexandar Tzankov, Lothar Tietze, Didier Lardinois, Viola Heinzelmann-Schwarz, Michael von Bergwelt-Baildon, Wu Zhang, Heinz-Josef Lenz, Younghun Han, Christopher I. Amos, Mohammedyaseen Syedbasha, Adrian Egli, Frank Stenner, Daniel E. Speiser, Ajit Varki, Alfred Zippelius, and Heinz Läubli http://jci.me/120612

Targeted delivery of immune therapeutics to lymph nodes prolongs cardiac allograft survivalBaharak Bahmani, Mayuko Uehara, Liwei Jiang, Farideh Ordikhani, Naima Banouni, Takaharu Ichimura, Zhabiz Solhjou, Georg J. Furtmüller, Gerald Brandacher, David Alvarez, Ulrich H. von Andrian, Kenji Uchimura, Qiaobing Xu, Ishaan Vohra, Osman A. Yilmam, Yousef Haik, Jamil Azzi, Vivek Kasinath, Jonathan S. Bromberg, Martina M. McGrath, and Reza Abdi http:///jci.me/120923

SMAD4 promotes TGF-β–independent NK cell homeostasis and maturation and antitumor immunityYouwei Wang, Jianhong Chu, Ping Yi, Wejuan Dong, Jennifer Saultz, Yufeng Wang, Hongwei Wang, Steven Scoville, Jianying Zhang, Lai-Chu Wu, Youcai Deng, Xiaoming He, Bethany Mundy-Bosse, Aharon G. Freud, Li-Shu Wang, Michael A. Caligiuri (ASCI), and Jianhua Yu http:///jci.me/121227

Transplacental immune modulation with a bacterial-derived agent protects against allergic airway inflammationKyle T. Mincham, Naomi M. Scott, Jean-Francois Lauzon-Joset, Jonatan Leffler, Alexander N. Larcombe, Philip A. Stumbles, Sarah A. Robertson, Christian Pasquali, Patrick G. Holt, and Deborah H. Strickland http:///jci.me/122631

Antigenic sites in influenza H1 hemagglutinin display species-specific immunodominance p. 4Sean T. H. Liu, Mohammad Amin Behzadi, Weina Sun, Alec W. Freyn, Wen-Chun Liu, Felix Broecker, Randy A. Albrecht, Nicole M. Bouvier, Viviana Simon, Raffael Nachbagauer, Florian Krammer, and Peter Palese http:///jci.me/122895

The innate immune receptor TREM-1 promotes liver injury and fibrosisAnh Thu Nguyen-Lefebvre, Ashwin Ajith, Vera Portik-Dobos, Daniel David Horuzsko, Ali Syed Arbab, Amiran Dzutsev, Ramses Sadek, Giorgio Trinchieri, and Anatolij Horuzsko http:///jci.me/98156

infectious diseaseHuman tryptophanyl-tRNA synthetase is an IFN-γ–inducible entry factor for Enterovirus p. 6Man Lung Yeung, Lilong Jia, Cyril C. Y. Yip, Jasper F. W. Chan, Jade L. L. Teng, Kwok-Hung Chan, Jian-Piao Cai, Chaoyu Zhang, Anna J. Zhang, Wan-Man Wong, Kin-Hang Kok, Susanna K. P. Lau, Patrick C. Y. Woo, Janice Y. C. Lo, Dong-Yan Jin, Shin-Ru Shih, and Kwok-Yung Yuen http://jci.me/99411

Peli1 facilitates virus replication and promotes neuroinflammation during West Nile virus infectionHuanle Luo, Evandro R. Winkelmann, Shuang Zhu, Wenjuan Ru, Elizabeth Mays, Jesus A. Silvas, Lauren L. Vollmer, Junling Gao, Bi-Hung Peng, Nathen E. Bopp, Courtney Cromer, Chao Shan, Guorui Xie, Guangyu Li, Robert Tesh, Vsevolod L. Popov, Pei-Yong Shi, Shao-Cong Sun, Ping Wu, Robyn S. Klein, Shao-Jun Tang, Wenbo Zhang, Patricia V. Aguilar, and Tian Wang http://jci.me/99902

metabolismSympathetic β1-adrenergic signaling contributes to regulation of human bone metabolism p. 3Sundeep Khosla (ASCI), Matthew T. Drake, Tammie L. Volkman, Brianne S. Thicke, Sara J. Achenbach, Elizabeth J. Atkinson, Michael J. Joyner, Clifford J. Rosen, David G. Monroe, and Joshua N. Farr http://jci.me/122151

Macrophage migration inhibitory factor mediates metabolic dysfunction induced by atypical antipsychotic therapyDonghong Cui, Yanmin Peng, Chengfang Zhang, Zezhi Li, Yousong Su, Yadan Qi, Mengjuan Xing, Jia Li, Grace E. Kim, Kevin N. Su, Jinjie Xu, Meiti Wang, Wenhua Ding, Marta Piecychna, Lin Leng, Michiru Hirasawa, Kaida Jiang, Lawrence Young, Yifeng Xu, Dake Qi, and Richard Bucala http://jci.me/93090

Targeting nuclear receptor NR4A1–dependent adipocyte progenitor quiescence promotes metabolic adaptation to obesity p. 3Yang Zhang, Alexander J. Federation, Soomin Kim, John P. O’Keefe, Mingyue Lun, Dongxi Xiang, Jonathan D. Brown, and Matthew L. Steinhauser http://jci.me/98353

neuroscienceTuberous sclerosis complex–mediated mTORC1 overactivation promotes age-related hearing lossXiaolong Fu, Xiaoyang Sun, Linqing Zhang, Yecheng Jin, Renjie Chai, Lili Yang, Aizhen Zhang, Xiangguo Liu, Xiaochun Bai, Jianfeng Li, Haibo Wang, and Jiangang Gao http://jci.me/98058

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Flip issue to read JCI Insight content.

Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndromeGal Hacohen-Kleiman, Shlomo Sragovich, Gidon Karmon, Andy Y. L. Gao, Iris Grigg, Metsada Pasmanik-Chor, Albert Le, Vlasta Korenková, R. Anne McKinney, and Illana Gozes http://jci.me/98199

oncologyE-cadherin expression on multiple myeloma cells activates tumor-promoting properties in plasmacytoid DCsEnguang Bi, Rong Li, Laura C. Bover, Haiyan Li, Pan Su, Xingzhe Ma, Chunjian Huang, Qiang Wang, Lintao Liu, Maojie Yang, Zhijuan Lin, Jianfei Qian, Weijun Fu, Yong-Jun Liu, and Qing Yi http://jci.me/121421

Endogenous retroviral signatures predict immunotherapy response in clear cell renal cell carcinomaChristof C. Smith, Kathryn E. Beckermann, Dante S. Bortone, Aguirre A. De Cubas, Lisa M. Bixby, Samuel J. Lee, Anshuman Panda, Shridar Ganesan, Gyan Bhanot, Eric M. Wallen, Matthew I. Milowsky, William Y. Kim, W. Kimryn Rathmell, Ronald Swanstrom, Joel S. Parker, Jonathan S. Serody, Sara R. Selitsky, and Benjamin G. Vincent http://jci.me/121476

O-GlcNAcylation is required for mutant KRAS-induced lung tumorigenesisKekoa Taparra, Hailun Wang, Reem Malek, Audrey Lafargue, Mustafa A. Barbhuiya, Xing Wang, Brian W. Simons, Matthew Ballew, Katriana Nugent, Jennifer Groves, Russell D. Williams, Takumi Shiraishi, James Verdone, Gokben Yildirir, Roger Henry, Bin Zhang, John Wong, Ken Kang-Hsin Wang, Barry D. Nelkin, Kenneth J. Pienta, Dean Felsher, Natasha E. Zachara, and Phuoc T. Tran http://jci.me/94844

Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy p. 3Priyamvada Jayaprakash, Midan Ai, Arthur Liu, Pratha Budhani, Todd Bartkowiak, Jie Sheng, Casey Ager, Courtney Nicholas, Ashvin R. Jaiswal, Yanqiu Sun, Krishna Shah, Sadhana Balasubramanyam, Nan Li, Guocan Wang, Jing Ning, Anna Zal, Tomasz Zal, and Michael A. Curran http://jci.me/96268

ΔNp63-driven recruitment of myeloid-derived suppressor cells promotes metastasis in triple-negative breast cancerSushil Kumar, David W. Wilkes, Nina Samuel, Mario Andres Blanco, Anupma Nayak, Kevin Alicea-Torres, Christian Gluck, Satrajit Sinha, Dmitry Gabrilovich, and Rumela Chakrabarti http://jci.me/99673

reproductive biologyLoss of placental growth factor ameliorates maternal hypertension and preeclampsia in miceJacqueline G. Parchem, Keizo Kanasaki, Megumi Kanasaki, Hikaru Sugimoto, Liang Xie, Yuki Hamano, Soo Bong Lee, Vincent H. Gattone, Samuel Parry, Jerome F. Strauss, Vesna D. Garovic, Thomas F. McElrath, Karen H. Lu, Baha M. Sibai, Valerie S. LeBleu, Peter Carmeliet, and Raghu Kalluri (ASCI) http://jci.me/99026

transplantationSurvival signal REG3α prevents crypt apoptosis to control acute gastrointestinal graft-versus-host diseaseDongchang Zhao, Yeung-Hyen Kim, Seihwan Jeong, Joel K. Greenson, Mohammed S. Chaudhry, Matthias Hoepting, Erik R. Anderson, Marcel R.M. van den Brink, Jonathan U. Peled, Antonio L.C. Gomes, Ann E. Slingerland, Michael J. Donovan, Andrew C. Harris, John E. Levine, Umut Ozbek, Lora V. Hooper, Thaddeus S. Stappenbeck, Aaron Ver Heul, Ta-Chiang Liu, Pavan Reddy, and James L.M. Ferrara (ASCI) http://jci.me/99261

vascular biologyAngiopoietin-2 exacerbates cardiac hypoxia and inflammation after myocardial infarction p. 2Seung-Jun Lee, Choong-kun Lee, Seok Kang, Intae Park, Yoo Hyung Kim, Seo Ki Kim, Seon Pyo Hong, Hosung Bae, Yulong He, Yoshiaki Kubota, and Gou Young Koh http://jci.me/99659

Endothelial cell α-globin and its molecular chaperone α-hemoglobin–stabilizing protein regulate arteriolar contractility p. 2Christophe Lechauve, Joshua T. Butcher, Abdullah Freiwan, Lauren A. Biwer, Julia M. Keith, Miranda E. Good, Hans Ackerman, Heather S. Tillman, Laurent Kiger, Brant E. Isakson, and Mitchell J. Weiss http://jci.me/99933

jci.org/this-month

Gut microbiome protects against kidney injury 11

Platelets mediate retinopathy of prematurity pathogenesis 12

Neoantigen-targeting vaccine reduces murine pancreatic cancer 13

Injury and mutational timing influence sarcoma formation 13

JCI This Month is a summary of the most recent articles in The Journal of Clinical Investigation and JCI Insight

November 2018

Inhibiting SYK ameliorates graft-versus-host disease p. 10

This Month

j c i . o r g / t h i s - m o n t h n o v e m b e r 2 0 1 8

For JCI InsightEditorHoward A. RockmanAssociate EditorsVann Bennett, Rodger A. Liddle, Yiping YangExecutive EditorSarah C. JacksonScience EditorCorinne Williams

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On the JCI Insight cover

This MonthNovember 2018

Make your 18-hour days count.

Submit your work to JCI Insight today.

(ASCI) indicates corresponding authors who are ASCI members.

SYK inhibition after hematopoietic stem cell transplantation prevents murine GVHD

The development of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HCT) is a devastating complication with debilitating and lethal outcomes. Chronic GVHD (cGVHD) commonly manifests as skin rash, mouth sores, and dry eye and can sometimes be controlled with corticosteroid-

based immunosuppression. Unfortunately, in cases in which cGVHD becomes refractory to immunosuppression, manifestations worsen and outcomes are poor. In JCI Insight, Jonathan Poe and colleagues evaluated the potential of the SYK inhibitor entospletinib to prevent GVHD in a murine model of allogeneic HCT. Compared with placebo-treated mice, animals that received entospletinib early after HCT had prolonged survival, along with marked improvements in clinical eye and skin scores. Skin lesions of placebo-treated mice contained infiltrating populations of SYK-expressing B cells and macrophages that were similar to populations observed in skin lesions of cGVHD patients. Notably, these populations were markedly reduced in the skin of entospletinib-treated mice, while blood immune cell numbers were markedly improved. The results of this study support entospletinib as a promising therapeutic to avert or limit cGVHD after allogenic HCT. The cover image shows Masson’s trichrome staining of skin from a representative mouse from the authors’ model of GVHD following entospletinib administration early after transplant.

SYK inhibitor entospletinib prevents ocular and skin GVHD in miceJonathan C. Poe, Wei Jia, Julie A. Di Paolo, Nancy J. Reyes, Ji Yun Kim, Hsuan Su, John S. Sundy, Adela R. Cardones, Victor L. Perez, Benny J. Chen, Nelson J. Chao, Diana M. Cardona, Daniel R. Saban, and Stefanie Sarantopoulos (ASCI) http://jci.me/122430

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Editor’s picks

immunologymicrobiology

Nivolumab-binding kinetics after treatment discontinuationThe PD-1–targeting mAb nivolumab is used to treat a variety of cancers, including non–small cell lung cancer (NSCLC). The effects of nivolumab can persist after treatment cessation; however, the kinetics of nivolumab–PD-1 binding on T cells after discontinuation have not been fully explored. A team led by Shohei Koyama and Atsushi Kumanogoh devised a strategy to monitor nivolumab binding to T cells and used this approach to evaluate T cells from a small cohort of NSCLS patients previously treated with nivolumab. Nivolumab binding was detected more than 20 weeks after the last infusion, regardless of the number of previous infusions or subsequent treatments. Transcriptome analysis of nivolumab-bound T cells revealed upregulation of T cell activation markers and decreased expression of the proliferation marker Ki-67 in nivolumab-bound and -unbound T cells associated with progressive disease. Nivolumab was restarted in 2 of the patients, resulting in increased Ki-67 expression, which correlated to clinical response. These results indicate that monitoring nivolumab binding and Ki-67 expression may help evaluate treatment efficacy.

Clinical implications of monitoring nivolumab immunokinetics in non–small cell lung cancer patientsAkio Osa, Takeshi Uenami, Shohei Koyama, Kosuke Fujimoto, Daisuke Okuzaki, Takayuki Takimoto, Haruhiko Hirata, Yukihiro Yano, Soichiro Yokota, Yuhei Kinehara, Yujiro Naito, Tomoyuki Otsuka, Masaki Kanazu, Muneyoshi Kuroyama, Masanari Hamaguchi, Taro Koba, Yu Futami, Mikako Ishijima, Yasuhiko Suga, Yuki Akazawa, Hirotomo Machiyama, Kota Iwahori, Hyota Takamatsu, Izumi Nagatomo, Yoshito Takeda, Hiroshi Kida, Esra A. Akbay, Peter S. Hammerman, Kwok-kin Wong, Glenn Dranoff, Masahide Mori, Takashi Kijima, and Atsushi Kumanogoh (ASCI) http://jci.me/59125

Microbial-derived D-serine protects mice from acute kidney injury

Disruption of the gut microbiota has been linked to a variety of diseases, and introduction of certain flora can ameliorate some disease phenotypes. Many of the beneficial effects of the gut microbiota are associated with particular microbial metabolites, such as D–amino acids. Yusuke Nakade and colleagues determined that the gut microbiome protects mice from acute kidney injury (AKI) following ischemia/reperfusion (I/R) and that this protection is due to increased generation of microbial D-serine. Animals that were germ free, treated with antibiotics, or depleted of D-serine had worse injury following I/R. Administration of oral D-serine protected mice from I/R-induced injury (see the accompanying image), an effect that was linked to suppression of hypoxia-induced tubular damage and increased tubular cell proliferation after I/R. Finally, circulating D-serine levels were elevated in patients with AKI, supporting D-serine as a potential biomarker and therapeutic target for kidney injury.

Gut microbiota–derived D-serine protects against acute kidney injuryYusuke Nakade, Yasunori Iwata, Kengo Furuichi, Masashi Mita, Kenji Hamase, Ryuichi Konno, Taito Miyake, Norihiko Sakai, Shinji Kitajima, Tadashi Toyama, Yasuyuki Shinozaki, Akihiro Sagara, Taro Miyagawa, Akinori Hara, Miho Shimizu, Yasutaka Kamikawa, Kouichi Sato, Megumi Oshima, Shiori Yoneda-Nakagawa, Yuta Yamamura, Shuichi Kaneko, Tetsuya Miyamoto, Masumi Katane, Hiroshi Homma, Hidetoshi Morita, Wataru Suda, Masahira Hattori, and Takashi Wada http://jci.me/97957

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vascular biology

A D V E R T I S E M E N T

JCI Insight | Editor’s picks

Platelet-released factors limit neovascularization in retinopathy of prematurity

Thrombocytopenia is associated with severe retinopathy of prematurityBertan Cakir, Raffael Liegl, Gunnel Hellgren, Pia Lundgren, Ye Sun, Susanna Klevebro, Chatarina Löfqvist, Clara Mannheimer, Steve Cho, Alexander Poblete, Rubi Duran, Boubou Hallberg, Jorge Canas, Viola Lorenz, Zhi-Jian Liu, Martha C. Sola-Visner, Lois E.H. Smith, and Ann Hellström http://jci.me/99448

Premature infants are at high risk of complica-tions such as retinopathy of prematurity (ROP), which is characterized by abnormal neovascular-ization of the retina and can lead to permanent vision loss. The etiology of ROP and factors that underlie disease severity are poorly understood. A team led by Lois Smith and Ann Hellström longitudinally evaluated thrombyctopenia in a cohort of infants with ROP and found a link between reduced platelet levels and more severe

disease. In a murine ROP model, platelet counts were reduced at the time of peak neovascular-ization, and platelet infusion suppressed (see the accompanying image) — while platelet depletion exacerbated — new vessel formation. In particular, resting, nondegranulated platelets were required to reduce neovascularization, implying that platelet releasate is required for antiangiogenic effects. These results suggest platelet transfusion as a potential strategy for preventing severe ROP.

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JCI Insight | Editor’s picks

inflammation

oncology

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Neoantigen-targeting vaccine combined with checkpoint modulation reduces murine pancreatic cancerThe accumulation of somatic mutations within cancer cells gives rise to neoantigens that are not present on healthy cells and, therefore, represent attractive targets for personalized cancer vaccines. While this approach has been successful for highly mutable cancers, such as melanoma, it has not been fully explored for nonimmunogenic tumors, such as pancreatic adenocarcinoma (PDA). Heather Kinkead and colleagues designed and developed a STING-adjuvanted PDA neoantigen-targeting vaccine (PancVAX) and evaluated the ability of this vaccine to target and eliminate PDA in murine models. PancVAX induced neopeptide-specific responses and promoted tumor regression. Moreover, when combined with immune checkpoint modulators, PancVAX promoted a more durable regression and extended survival. In particular, the addition of agonist OX40 antibodies to PancVAX reduced expression of T cell exhaustion markers and enhanced rejection of tumors following PDA rechallenge. Together, these results support further evaluation of neoantigen-targeting vaccines for nonimmunogenic cancers.

Combining STING-based neoantigen-targeted vaccine with checkpoint modulators enhances antitumor immunity in murine pancreatic cancerHeather L. Kinkead, Alexander Hopkins, Eric Lutz, Annie A. Wu, Mark Yarchoan, Kayla Cruz, Skylar Woolman, Teena Vithayathil, Laura H. Glickman, Chudi O. Ndubaku, Sarah M. McWhirter, Thomas W. Dubensky Jr., Todd D. Armstrong, Elizabeth M. Jaffee, and Neeha Zaidi http://jci.me/122857

Clinical trial supports ketoprofen for reducing lymphedemaLymphedema results from insufficient tissue fluid removal by the lymphatic circulation. Primary lymphedema is characterized by inherent lymphatic abnormalities, while secondary disease occurs as the result of a variety of conditions that lead to lymphatic damage. The nonsteroidal antiinflammatory drug (NSAID) ketoprofen reduced lymphedema in preclinical models but has not been evaluated in humans. Stanley Rockson and colleagues enrolled 21 lymphedema patients in an open-label trial of ketoprofen and showed clinical improvements at 4 months after treatment compared with baseline. The authors enrolled an additional 34 patients in a

Timing matters for injury-induced sarcoma formation

double-blind, randomized, placebo-controlled trial. Compared with the placebo-treated group, ketoprofen- treated subjects had reduced skin thickness, improved histopathology (see accompanying image), and decreased inflammation, as measured by plasma granulocyte CSF (G-CSF). Together, the results of this study indicate that ketoprofen is well tolerated and improves lymphedema.

Pilot studies demonstrate the potential benefits of antiinflammatory therapy in human lymphedemaStanley G. Rockson, Wen Tian, Xinguo Jiang, Tatiana Kuznetsova, Francois Haddad, Jamie Zampell, Babak Mehrara, Joshua P. Sampson, Leslie Roche, Jinah Kim, and Mark R. Nicolls http://jci.me/123775

Sarcomas represent a diverse group of tumors that arise from a variety of tissues, including muscle. Several studies have linked sarcoma development to tissue injury; however, it is not known how sarcoma-associated gene mutations combine with injury to induce disease. Using a murine sarcoma model in which the timing of KrasG12D activation and p53 deletion can be manipulated, David Van Mater and colleagues evaluated the effect of mutation timing and tissue injury on sarcoma development. In this mouse model, 100% of the mice developed a sarcoma if KrasG12D activation and p53 deletion occurred at the same time. In contrast, few sarcomas developed if the same mutations were separated by 3 weeks; however, sarcoma formation could be rescued by cardiotoxin-induced muscle injury. Deletion of p53 with concurrent injury was sufficient for sarcoma formation; however, no sarcomas formed when injury occurred 21 days after p53 deletion. Sarcomas lacking KrasG12D mutations were characterized by amplification of Met- or Yap1-containing chromo-somal regions. Together, these results reveal a complex interplay between mutational timing and injury in sarcoma formation.

Injury promotes sarcoma development in a genetically and temporally restricted mannerDavid Van Mater, Eric Xu, Anupama Reddy, Leonor Añó, Mohit Sachdeva, Wesley Huang, Nerissa Williams, Yan Ma, Cassandra Love, Lanie Happ, Sandeep Dave, and David G. Kirsch (ASCI) http://jci.me/123687

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JCI Insight | Editor’s picks

metabolism

A D V E R T I S E M E N T

Macrophages have distinct functional phenotypes in different vascular inflammatory diseasesMacrophages have a diverse range of functionally relevant phenotypes, with inflammatory M1 and alternatively activated M2 considered the main subtypes. Macrophage infiltration into the vessel wall is a hallmark of vascular diseases, including coronary artery disease (CAD) and giant cell arteritis (GCA); however, it is not clear whether macrophages share common pathogenic mechanisms in these two diseases. Ryu Watanabe and colleagues evaluated and compared functional profiles of macrophages from patients with CAD and GCA.Macrophages from the 2 cohorts had distinct signatures and fundamentally different metabolic

profiles. Compared with healthy macrophages, CAD patient–derived macrophages produced high levels of T cell chemoattractants and inflammatory cytokines (IL-1β, IL-6) and expressed high amounts of the immunoinhibitory ligand PD-L1. In contrast, GCA patient–derived macrophages produced T cell chemoattracts, but generated low amounts of IL-1β or IL-6, and had distinctly low PD-L1 expression. Notably, the CAD macrophage phenotype was associated with excess glucose uptake and glycolytic breakdown. These results reveal that macrophages have distinct and disease-specific phenotypes that influence function in vascular disease.

Glucose metabolism controls disease-specific signatures of macrophage effector functionsRyu Watanabe, Marc Hilhorst, Hui Zhang, Markus Zeisbrich, Gerald J. Berry, Barbara B. Wallis, David G. Harrison, John C. Giacomini, Jörg J. Goronzy, and Cornelia M. Weyand (ASCI) http://jci.me/123047

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Current articles

Clinical implications of monitoring nivolumab immunokinetics in non–small cell lung cancer patients p. 11Akio Osa, Takeshi Uenami, Shohei Koyama, Kosuke Fujimoto, Daisuke Okuzaki, Takayuki Takimoto, Haruhiko Hirata, Yukihiro Yano, Soichiro Yokota, Yuhei Kinehara, Yujiro Naito, Tomoyuki Otsuka, Masaki Kanazu, Muneyoshi Kuroyama, Masanari Hamaguchi, Taro Koba, Yu Futami, Mikako Ishijima, Yasuhiko Suga, Yuki Akazawa, Hirotomo Machiyama, Kota Iwahori, Hyota Takamatsu, Izumi Nagatomo, Yoshito Takeda, Hiroshi Kida, Esra A. Akbay, Peter S. Hammerman, Kwok-kin Wong, Glenn Dranoff, Masahide Mori, Takashi Kijima, and Atsushi Kumanogoh (ASCI) http://jci.me/59125Ex vivo lung perfusion as a human platform for preclinical small molecule testingNathaniel M. Weathington, Diana Álvarez, John Sembrat, Josiah Radder, Nayra Cárdenes, Kentaro Noda, Qiaoke Gong, Hesper Wong, Jay Kolls, Jonathan D’Cunha, Rama K. Mallampalli, Bill B. Chen, and Mauricio Rojas http://jci.me/95515Gut microbiota–derived D-serine protects against acute kidney injury p. 11Yusuke Nakade, Yasunori Iwata, Kengo Furuichi, Masashi Mita, Kenji Hamase, Ryuichi Konno, Taito Miyake, Norihiko Sakai, Shinji Kitajima, Tadashi Toyama, Yasuyuki Shinozaki, Akihiro Sagara, Taro Miyagawa, Akinori Hara, Miho Shimizu, Yasutaka Kamikawa, Kouichi Sato, Megumi Oshima, Shiori Yoneda-Nakagawa, Yuta Yamamura, Shuichi Kaneko, Tetsuya Miyamoto, Masumi Katane, Hiroshi Homma, Hidetoshi Morita, Wataru Suda, Masahira Hattori, and Takashi Wada http://jci.me/97957Maternal high-fat diet results in microbiota-dependent expansion of ILC3s in mice offspringSarah Thomas Babu, Xinying Niu, Megan Raetz, Rashmin C. Savani, Lora V. Hooper, and Julie Mirpuri http://jci.me/99223The DILfrequency study is an adaptive trial to identify optimal IL-2 dosing in patients with type 1 diabetesEleonora Seelig, James Howlett, Linsey Porter, Lucy Truman, James Heywood, Jane Kennet, Emma L. Arbon, Katerina Anselmiova, Neil M. Walker, Ravinder Atkar, Marcin L. Pekalski, Ed Rytina, Mark Evans, Linda S. Wicker, John A. Todd, Adrian P. Mander, Simon Bond, and Frank Waldron-Lynch http://jci.me/99306Arginine vasopressin infusion is sufficient to model clinical features of preeclampsia in miceJeremy A. Sandgren, Guorui Deng, Danny W. Linggonegoro, Sabrina M. Scroggins, Katherine J. Perschbacher, Anand R. Nair, Taryn E. Nishimura, Shao Yang Zhang, Larry N. Agbor, Jing Wu, Henry L. Keen, Meghan C. Naber, Nicole A. Pearson, Kathy A. Zimmerman, Robert M. Weiss, Noelle C. Bowdler, Yuriy M. Usachev, Donna A. Santillan, Matthew J. Potthoff, Gary L. Pierce, Katherine N. Gibson-Corley, Curt D. Sigmund, Mark K. Santillan, and Justin L. Grobe http://jci.me/99403Thrombocytopenia is associated with severe retinopathy of prematurity p. 12Bertan Cakir, Raffael Liegl, Gunnel Hellgren, Pia Lundgren, Ye Sun, Susanna Klevebro, Chatarina Löfqvist, Clara Mannheimer, Steve Cho, Alexander Poblete, Rubi Duran, Boubou Hallberg, Jorge Canas, Viola Lorenz, Zhi-Jian Liu, Martha C. Sola-Visner, Lois E.H. Smith, and Ann Hellström http://jci.me/99448Myeloid HO-1 modulates macrophage polarization and protects against ischemia-reperfusion injuryMin Zhang, Kojiro Nakamura, Shoichi Kageyama, Akeem O. Lawal, Ke Wei Gong, May Bhetraratana, Takehiro Fujii, Dawoud Sulaiman, Hirofumi Hirao, Subhashini Bolisetty, Jerzy W. Kupiec-Weglinski, and Jesus A. Araujo http://jci.me/120596Prelamin A causes aberrant myonuclear arrangement and results in muscle fiber weaknessYotam Levy, Jacob A. Ross, Marili Niglas, Vladimir A. Snetkov, Steven Lynham, Chen-Yu Liao, Megan J. Puckelwartz, Yueh-Mei Hsu, Elizabeth M. McNally, Manfred Alsheimer, Stephen D.R. Harridge, Stephen G. Young, Loren G. Fong, Yaiza Español, Carlos Lopez-Otin, Brian K. Kennedy, Dawn A. Lowe, and Julien Ochala http://jci.me/120920Gut microbiota–dependent modulation of innate immunity and lymph node remodeling affects cardiac allograft outcomesJonathan S. Bromberg, Lauren Hittle, Yanbao Xiong, Vikas Saxena, Eoghan M. Smyth, Lushen Li, Tianshu Zhang, Chelsea Wagner, W. Florian Fricke, Thomas Simon, Colin C. Brinkman, and Emmanuel F. Mongodin http://jci.me/121045Reverse electrical remodeling in rats with heart failure and preserved ejection fractionJae Hyung Cho, Peter J. Kilfoil, Rui Zhang, Ryan E. Solymani, Catherine Bresee, Elliot M. Kang, Kristin Luther, Russell G. Rogers, Geoffrey de Couto, Joshua I. Goldhaber, Eduardo Marbán (ASCI), and Eugenio Cingolani http://jci.me/121123Splicing modulation sensitizes chronic lymphocytic leukemia cells to venetoclax by remodeling mitochondrial apoptotic dependenciesElisa ten Hacken, Rebecca Valentin, Fara Faye D. Regis, Jing Sun, Shanye Yin, Lillian Werner, Jing Deng, Michaela Gruber, Jessica Wong, Mei Zheng, Amy L. Gill, Michael Seiler, Peter Smith, Michael Thomas, Silvia Buonamici, Emanuela M. Ghia, Ekaterina Kim, Laura Z. Rassenti, Jan A. Burger, Thomas J. Kipps, Matthew L. Meyerson, Pavan Bachireddy, Lili Wang, Robin Reed, Donna Neuberg, Ruben D. Carrasco, Angela N. Brooks, Anthony Letai, Matthew S. Davids, and Catherine J. Wu (ASCI) http://jci.me/121438Chronic linaclotide treatment reduces colitis-induced neuroplasticity and reverses persistent bladder dysfunctionLuke Grundy, Andrea M. Harrington, Joel Castro, Sonia Garcia-Caraballo, Annemie Deiteren, Jessica Maddern, Grigori Y. Rychkov, Pei Ge, Stefanie Peters, Robert Feil, Paul Miller, Andre Ghetti, Gerhard Hannig, Caroline B. Kurtz, Inmaculada Silos-Santiago, and Stuart M. Brierley http://jci.me/121841Mucosal-associated invariant and γδ T cell subsets respond to initial Mycobacterium tuberculosis infectionCharles Kyriakos Vorkas, Matthew F. Wipperman, Kelin Li, James Bean, Shakti K. Bhattarai, Matthew Adamow, Phillip Wong, Jeffrey Aubé, Marc Antoine Jean Juste, Vanni Bucci, Daniel W. Fitzgerald, and Michael S. Glickman (ASCI) http://jci.me/121899High-throughput T cell receptor sequencing identifies clonally expanded CD8+ T cell populations in alopecia areataAnnemieke de Jong, Ali Jabbari, Zhenpeng Dai, Luzhou Xing, Dustin Lee, Mei Mei Li, Madeleine Duvic, Maria Hordinsky, David A. Norris, Vera Price, Julian Mackay-Wiggan, Raphael Clynes, and Angela M. Christiano http://jci.me/121949SYK inhibitor entospletinib prevents ocular and skin GVHD in mice p. 10Jonathan C. Poe, Wei Jia, Julie A. Di Paolo, Nancy J. Reyes, Ji Yun Kim, Hsuan Su, John S. Sundy, Adela R. Cardones, Victor L. Perez, Benny J. Chen, Nelson J. Chao, Diana M. Cardona, Daniel R. Saban, and Stefanie Sarantopoulos (ASCI) http://jci.me/122430

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Current articles

Enhanced detection of neoantigen-reactive T cells targeting unique and shared oncogenes for personalized cancer immunotherapyRami Yossef, Eric Tran, Drew C. Deniger, Alena Gros, Anna Pasetto, Maria R. Parkhurst, Jared J. Gartner, Todd D. Prickett, Gal Cafri, Paul F. Robbins, and Steven A. Rosenberg http://jci.me/122467Dual TLR2 and TLR7 agonists as HIV latency-reversing agentsAmanda B. Macedo, Camille L. Novis, Caroline M. De Assis, Eric S. Sorensen, Paula Moszczynski, Szu-han Huang, Yanqin Ren, Adam M. Spivak, R. Brad Jones, Vicente Planelles, and Alberto Bosque http://jci.me/122673Colonic epithelial miR-31 associates with the development of Crohn’s phenotypesBenjamin P. Keith, Jasmine B. Barrow, Takahiko Toyonaga, Nevzat Kazgan, Michelle Hoffner O’Connor, Neil D. Shah, Matthew S. Schaner, Elisabeth A. Wolber, Omar K. Trad, Greg R. Gipson, Wendy A. Pitman, Matthew Kanke, Shruti J. Saxena, Nicole Chaumont, Timothy S. Sadiq, Mark J. Koruda, Paul A. Cotney, Nancy Allbritton, Dimitri G. Trembath, Francisco Sylvester, Terrence S. Furey, Praveen Sethupathy, and Shehzad Z. Sheikh http://jci.me/122788Somatostatin receptor subtype 5 modifies hypothalamic-pituitary-adrenal axis stress functionMasaaki Yamamoto, Anat Ben-Shlomo, Hiraku Kameda, Hidenori Fukuoka, Nan Deng, Yan Ding, and Shlomo Melmed (ASCI) http://jci.me/122932Mast cells and neutrophils mediate peripheral motor pathway degeneration in ALSEmiliano Trias, Peter H. King, Ying Si, Yuri Kwon, Valentina Varela, Sofía Ibarburu, Mariángeles Kovacs, Ivan C. Moura, Joseph S. Beckman, Olivier Hermine, and Luis Barbeito http://jci.me/123249Treatment of Streptococcus pneumoniae otitis media in a chinchilla model by transtympanic delivery of antibioticsRong Yang, Vishakha Sabharwal, Nadya Shlykova, Obiajulu S. Okonkwo, Stephen I. Pelton, and Daniel S. Kohane http://jci.me/123415A sheep model of cystic fibrosis generated by CRISPR/Cas9 disruption of the CFTR geneZhiqiang Fan, Iuri Viotti Perisse, Calvin U. Cotton, Misha Regouski, Qinggang Meng, Chaim Domb, Arnaud J. Van Wettere, Zhongde Wang, Ann Harris, Kenneth L. White, and Irina A. Polejaeva http://jci.me/123529αvβ3 Integrin drives fibroblast contraction and strain stiffening of soft provisional matrix during progressive fibrosisVincent F. Fiore, Simon Wong, Coleen Tran, Chunting Tan, Wenwei Xu, Todd Sulchek, Eric S. White, James S. Hagood, and Thomas H. Barker http://jci.me/97597Homozygous loss-of-function mutations in SLC26A7 cause goitrous congenital hypothyroidismHakan Cangul, Xiao-Hui Liao, Erik Schoenmakers, Jukka Kero, Sharon Barone, Panudda Srichomkwun, Hideyuki Iwayama, Eva G. Serra, Halil Saglam, Erdal Eren, Omer Tarim, Adeline K. Nicholas, Ilona Zvetkova, Carl A. Anderson, Fiona E. Karet Frankl, Kristien Boelaert, Marja Ojaniemi, Jarmo Jääskeläinen, Konrad Patyra, Christoffer Löf, E. Dillwyn Williams, UK10K Consortium, Manoocher Soleimani, Timothy Barrett, Eamonn R. Maher, V. Krishna Chatterjee, Samuel Refetoff, and Nadia Schoenmakers http://jci.me/99631Analysis of leukocyte transepithelial migration using an in vivo murine colonic loop modelSven Flemming, Anny-Claude Luissint, Asma Nusrat, and Charles A. Parkos http://jci.me/99722Transcranial optical imaging reveals a pathway for optimizing the delivery of immunotherapeutics to the brainBenjamin A. Plog, Humberto Mestre, Genaro E. Olveda, Amanda M. Sweeney, H. Mark Kenney, Alexander Cove, Kosha Y. Dholakia, Jeffrey Tithof, Thomas D. Nevins, Iben Lundgaard, Ting Du, Douglas H. Kelley, and Maiken Nedergaard http://jci.me/120922Diabetes with heart failure increases methylglyoxal modifications in the sarcomere, which inhibit functionMaria Papadaki, Ronald J. Holewinski, Samantha Beck Previs, Thomas G. Martin, Marisa J. Stachowski, Amy Li, Cheavar A. Blair, Christine S. Moravec, Jennifer E. Van Eyk, Kenneth S. Campbell, David M. Warshaw, and Jonathan A. Kirk http://jci.me/121264Coordination of ENT2-dependent adenosine transport and signaling dampens mucosal inflammationCarol M. Aherne, Colm B. Collins, Caroline R. Rapp, Kristine E. Olli, Loni Perrenoud, Paul Jedlicka, Jessica L. Bowser, Tingting Weng, Harry Karmouty-Quintana, Michael R. Blackburn, and Holger K. Eltzschig http://jci.me/121521Superior immune reconstitution using Treg-expanded donor cells versus PTCy treatment in preclinical HSCT modelsDietlinde Wolf, Cameron S. Bader, Henry Barreras, Sabrina Copsel, Brent J. Pfeiffer, Casey O. Lightbourn, Norman H. Altman, Krishna V. Komanduri, and Robert B. Levy http://jci.me/121717Stress response protein GJA1-20k promotes mitochondrial biogenesis, metabolic quiescence, and cardioprotection against ischemia/reperfusion injuryWassim A. Basheer, Ying Fu, Daisuke Shimura, Shaohua Xiao, Sosse Agvanian, Diana M. Hernandez, Tara C. Hitzeman, TingTing Hong, and Robin M. Shaw (ASCI) http://jci.me/121900Modulations of human resting brain connectivity by kisspeptin enhance sexual and emotional functionsAlexander N. Comninos, Lysia Demetriou, Matthew B. Wall, Amar J. Shah, Sophie A. Clarke, Shakunthala Narayanaswamy, Alexander Nesbitt, Chioma Izzi-Engbeaya, Julia K. Prague, Ali Abbara, Risheka Ratnasabapathy, Lisa Yang, Victoria Salem, Gurjinder M. Nijher, Channa N. Jayasena, Mark Tanner, Paul Bassett, Amrish Mehta, John McGonigle, Eugenii A. Rabiner, Stephen R. Bloom, and Waljit S. Dhillo http://jci.me/121958Cytokine and chemokine signatures associated with hepatitis B surface antigen loss in hepatitis B patientsSachiyo Yoshio, Yohei Mano, Hiroyoshi Doi, Hirotaka Shoji, Tomonari Shimagaki, Yuzuru Sakamoto, Hironari Kawai, Michitaka Matsuda, Taizo Mori, Yosuke Osawa, Masaaki Korenaga, Masaya Sugiyama, Masashi Mizokami, Eiji Mita, Keiko Katayama, Junko Tanaka, and Tatsuya Kanto http://jci.me/122268

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Molecular mechanisms of IL-33–mediated stromal interactions in cancer metastasisPatrik Andersson, Yunlong Yang, Kayoko Hosaka, Yin Zhang, Carina Fischer, Harald Braun, Shuzhen Liu, Guohua Yu, Shihai Liu, Rudi Beyaert, Mayland Chang, Qi Li, and Yihai Cao http://jci.me/122375LNK deficiency promotes acute aortic dissection and ruptureFanny Laroumanie, Arina Korneva, Matthew R. Bersi, Matthew R. Alexander, Liang Xiao, Xue Zhong, Justin P. Van Beusecum, Yuhan Chen, Mohamed A. Saleh, William G. McMaster, Kyle A. Gavulic, Bethany L. Dale, Shilin Zhao, Yan Guo, Yu Shyr, Daniel S. Perrien, Nancy J. Cox, John A. Curci, Jay D. Humphrey, and Meena S. Madhur http://jci.me/122558Integrin αvβ8–expressing tumor cells evade host immunity by regulating TGF-β activation in immune cellsNaoki Takasaka, Robert I. Seed, Anthony Cormier, Andrew J. Bondesson, Jianlong Lou, Ahmed Elattma, Saburo Ito, Haruhiko Yanigasawa, Mitsuo Hashimoto, Royce Ma, Michelle D. Levine, Jean Publicover, Rashaun Potts, Jillian M. Jespersen, Melody G. Campbell, Fraser Conrad, James D. Marks, Yifan Cheng, Jody L. Baron, and Stephen L. Nishimura http://jci.me/122591Targeting antigen-presenting cells by anti–PD-1 nanoparticles augments antitumor immunityFarideh Ordikhani, Mayuko Uehara, Vivek Kasinath, Li Dai, Siawosh K. Eskandari, Baharak Bahmani, Merve Yonar, Jamil R. Azzi, Yousef Haik, Peter T. Sage, George F. Murphy, Nasim Annabi, Tobias Schatton, Indira Guleria, and Reza Abdi http://jci.me/122700Combining STING-based neoantigen-targeted vaccine with checkpoint modulators enhances antitumor immunity in murine pancreatic cancer p. 13Heather L. Kinkead, Alexander Hopkins, Eric Lutz, Annie A. Wu, Mark Yarchoan, Kayla Cruz, Skylar Woolman, Teena Vithayathil, Laura H. Glickman, Chudi O. Ndubaku, Sarah M. McWhirter, Thomas W. Dubensky Jr., Todd D. Armstrong, Elizabeth M. Jaffee, and Neeha Zaidi http://jci.me/122857Glucose metabolism controls disease-specific signatures of macrophage effector functions p. 14Ryu Watanabe, Marc Hilhorst, Hui Zhang, Markus Zeisbrich, Gerald J. Berry, Barbara B. Wallis, David G. Harrison, John C. Giacomini, Jörg J. Goronzy, and Cornelia M. Weyand (ASCI) http://jci.me/123047Determinants of the efficacy of HIV latency-reversing agents and implications for drug and treatment designRuian Ke, Jessica M. Conway, David M. Margolis, and Alan S. Perelson http://jci.me/123052Histone H2A monoubiquitylation and p38-MAPKs regulate immediate-early gene-like reactivation of latent retrovirus HTLV-1Anurag Kulkarni, Graham P. Taylor, Robert J. Klose, Christopher J. Schofield, and Charles R.M. Bangham http://jci.me/123196Human IgE mAbs define variability in commercial Aspergillus extract allergen compositionMark A. Wurth, Azadeh Hadadianpour, Dennis J. Horvath, Jacob Daniel, Olivia Bogdan, Kasia Goleniewska, Anna Pomés, Robert G. Hamilton, R. Stokes Peebles Jr., and Scott A. Smith http://jci.me/123387Influenza-mediated reduction of lung epithelial ion channel activity leads to dysregulated pulmonary fluid homeostasisJeffrey D. Brand, Ahmed Lazrak, John E. Trombley, Ren-Jay Shei, A. Timothy Adewale, Jennifer L. Tipper, Zhihong Yu, Amit R. Ashtekar, Steven M. Rowe, Sadis Matalon, and Kevin S. Harrod http://jci.me/123467Increased expression of ATP12A proton pump in cystic fibrosis airwaysPaolo Scudieri, Ilaria Musante, Emanuela Caci, Arianna Venturini, Patrizia Morelli, Christine Walter, Davide Tosi, Alessandro Palleschi, Pablo Martin-Vasallo, Isabelle Sermet-Gaudelus, Gabrielle Planelles, Gilles Crambert, and Luis J.V. Galietta http://jci.me/123616Exploring the cardiac response to injury in heart transplant biopsiesPhilip F. Halloran (ASCI), Jeff Reeve, Arezu Z. Aliabadi, Martin Cadeiras, Marisa G. Crespo-Leiro, Mario Deng, Eugene C. Depasquale, Johannes Goekler, Xavier Jouven, Daniel H. Kim, Jon Kobashigawa, Alexandre Loupy, Peter Macdonald, Luciano Potena, Andreas Zuckermann, and Michael D. Parkes http://jci.me/123674Injury promotes sarcoma development in a genetically and temporally restricted manner p. 13David Van Mater, Eric Xu, Anupama Reddy, Leonor Añó, Mohit Sachdeva, Wesley Huang, Nerissa Williams, Yan Ma, Cassandra Love, Lanie Happ, Sandeep Dave, and David G. Kirsch (ASCI) http://jci.me/123687Pilot studies demonstrate the potential benefits of antiinflammatory therapy in human lymphedema p. 13Stanley G. Rockson, Wen Tian, Xinguo Jiang, Tatiana Kuznetsova, Francois Haddad, Jamie Zampell, Babak Mehrara, Joshua P. Sampson, Leslie Roche, Jinah Kim, and Mark R. Nicolls http://jci.me/123775

reviewsFat fibrosis: friend or foe?Ritwik Datta, Michael J. Podolsky, and Kamran Atabai (ASCI) http://jci.me/122289Emerging functions of DNA transposases and oncogenic mutators in childhood cancer developmentAnton G. Henssen and Alex Kentsis (ASCI) http://jci.me/123172

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