Upload
duongdien
View
217
Download
0
Embed Size (px)
Citation preview
jci.org/this-month
TNF blockade overcomes resistance to EGFR inhibitors 2
Mosaic brain mutations in DEPDC5 underlie focal epilepsy 3
Deacetylation refines the effects of PPARγ agonists 4
Connecting chronic liver injury and cancer 5
Liver-repopulating cells upregulate glutathione metabolism 5
JCI This Month is a summary of the most recent articles in The Journal of Clinical Investigation and JCI Insight
Scan for the digital version of JCI This Month.
June 2018
Copy number variations contribute to breast cancer spread p. 2
This Month
Journal of Clinical Investigation Consulting Editors
Soman N. Abraham
John S. Adams
Qais Al-Awqati
Kari Alitalo
Dario C. Altieri
Masayuki Amagai
Brian H. Annex
M. Amin Arnaout
Alan Attie
Jane E. Aubin
Michael F. Beers
Vann Bennett
Gregory K. Bergey
Nina Bhardwaj
Morris J. Birnbaum
Joyce Bischoff
Craig Blackstone
Bruce R. Blazar
Gerard C. Blobe
William A. Boisvert
Nancy Bonini
Brendan Boyce
Jonathan Bromberg
Frank C. Brosius
Hal E. Broxmeyer
Michael J. Caplan
Diego H. Castrillon
Harold Chapman
Ajay Chawla
Benjamin K. Chen
Benny J. Chen
Ju Chen
Jun Chen
Marie-Françoise Chesselet
Vivian G. Cheung
Raymond Chung
Jeanne M. Clark
Sheila Collins
Ronald G. Collman
Marco Colonna
Shaun R. Coughlin
Tyler J. Curiel
David D'Alessio
Richard T. D'Aquila
Alan Daugherty
Sudhansu Dey
Anna Mae Diehl
Harry C. Dietz III
Gianpietro Dotti
Michael Dustin
Connie J. Eaves
Dominique Eladari
Joel K. Elmquist
Stephen G. Emerson
Jonathan A. Epstein
Adrian Erlebacher
Joel D. Ernst
James M. Ervasti
Robert V. Farese Jr.
Eric R. Fearon
Anthony W. Ferrante Jr.
Edward A. Fisher
Richard A. Flavell
Alessia Fornoni
Tatiana Foroud
Martin Friedlander
Stephen J. Galli
J. Victor Garcia-Martinez
Alfred L. George Jr.
Stanton L. Gerson
Robert E. Gerszten
Todd Golde
Sherita Golden
Stanley Goldfarb
Larry B. Goldstein
Fred Sanford Gorelick
Kathleen J. Green
Steven K. Grinspoon
David Hafler
Jonathan J. Hansen
Raymond Clement Harris
Stanley L. Hazen
Peter Heeringa
Meenhard Herlyn
Joachim Herz
Katherine A. High
Helen H. Hobbs
Ronald Hoffman
V. Michael Holers
Steven Holland
David Holtzman
Michael J. Holtzman
Lawrence B. Holzman
Maureen Horton
Tamas L. Horvath
Gokhan S. Hotamisligil
Steven R. Houser
Ralph H. Hruban
Christopher A. Hunter
David James
Richard J. Jones
William G. Kaelin Jr.
Klaus Kaestner
Mark L. Kahn
Raghu Kalluri
S. Ananth Karumanchi
Robert S. Kass
Masato Kasuga
Daniel P. Kelly
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
Stavroula Kousteni
John W. Krakauer
Rohit N. Kulkarni
Antonio La Cava
Fadi G. Lakkis
Terri Laufer
Mitchell A. Lazar
Brendan Lee
William M.F. Lee
Rudolph L. Leibel
Wayne I. Lencer
Jon D. Levine
Ross L. Levine
Klaus Ley
Rodger A. Liddle
Richard Locksley
Fanxin Long
Gary Lopaschuk
Nigel Mackman
Richard B. Mailman
Rama K. Mallampalli
Jack Martin
Steven O. Marx
Rodger P. McEver
Elizabeth McNally
Cornelis J. Melief
Shlomo Melmed
George Michalopoulos
Jeffrey H. Miner
Peter J. Mohler
Jeffrey D. Molkentin
David D. Moore
Edward E. Morrisey
James H. Morrissey
Deborah M. Muoio
Anthony J. Muslin
Martin G. Myers Jr.
Benjamin G. Neel
Paul W. Noble
Guillermo Oliver
Eric N. Olson
Harry T. Orr
Leo E. Otterbein
Roberto Pacifici
Akhilesh Pandey
William C. Parks
Warren S. Pear
Sallie R. Permar
David J. Pinsky
Edward Plow
Catherine Postic
Alice S. Prince
Louis J. Ptacek
Luigi Puglielli
Pere Puigserver
Bali Pulendran
Ellen Puré
Susan E. Quaggin
Marlene Rabinovitch
Daniel J. Rader
Shahin Rafii
Gwendalyn J. Randolph
Jeffrey C. Rathmell
W. Kimryn Rathmell
Barbara Rehermann
Muredach P. Reilly
Linda Resar
Ryan Riddle
Sarah A. Robertson
Howard A. Rockman
Paul B. Rosenberg
Theodora S. Ross
Marc E. Rothenberg
Anil Rustgi
J. Evan Sadler
Junichi Sadoshima
Jose-Alain Sahel
Jean E. Schaffer
Philipp E. Scherer
Michael D. Schneider
Detlef Schuppan
Amita Sehgal
Clay Semenkovich
Jonathan S. Serody
John Seykora
Theresa A. Shapiro
Mari Shinohara
Steven E. Shoelson
Gerald I. Shulman
Roy L. Silverstein
M. Celeste Simon
Mihaela Skobe
Donald Small
Lois Smith
Akrit Sodhi
Weihong Song
Ashley L. St. John
Jonathan Stamler
Colin L. Stewart
Doris Stoffers
Warren Strober
Maureen A. Su
D. James Surmeier
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
Marcel R.M. van den Brink
Luc Van Kaer
David M. Virshup
Matthias von Herrath
Kathryn R. Wagner
Yisong Y. Wan
Bart O. Williams
Allan W. Wolkoff
Joseph C. Wu
Thomas A. Wynn
Ramnik J. Xavier
Yiping Yang
Srinivasan Yegnasubramanian
Mone Zaidi
Kang Zhang
Len Zon
Weiping Zou
R. Suzanne Zukin
j c i . o r g / t h i s - m o n t h j u n e 2 0 1 8 1
For the JCI EditorGordon F. Tomaselli
Deputy EditorsRexford S. Ahima, Arturo Casadevall
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, Sharon Gerecht, Paul M. Hassoun, Elizabeth M. Jaffe, Mariana J. Kaplan, David A. Kass, Leo Luznik, Kieren A. Marr, Timothy H. Moran, William Nelson, Brian O’Rourke, Ben Ho Park, Jonathan D. Powell, Thomas C. Quinn, Hamid Rabb, Stuart C. Ray, Jeffrey D. Rothstein, Scheherazade Sadegh-Nasseri, Jonathan Schneck, Gregg L. Semenza, Robert F. Siliciano, Charlotte Sumner, Simeon I. Taylor, David L. Thomas, Robert G. Weiss, Sarah J. Wheeler, Marsha Wills-Karp
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/128/6
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
Charlotte Sumner, MD, Associate Editor, is Professor of Neurology and Neuroscience at Johns Hopkins University School of Medicine. In addition to her clinical care for adult patients with spinal muscular atrophy, Dr. Sumner heads a research laboratory focused on the genetic and cellular pathogenesis of spinal muscular atrophies, with particular attention to identification of disease genes, characterization of molecular and cellular mechanisms underlying disease pathogenesis, and preclinical development
of therapeutics. She is the coeditor of the only comprehensive book on spinal muscular atrophy, Spinal Muscular Atrophy: Disease Mechanisms and Therapy. In April 2018, Dr. Sumner was inducted as a new member to the American Society for Clinical Investigation.
Publication highlights
d’Ydewalle C, Ramos DM, Pyles NJ, Ng SY, Gorz M, Pilato CM, Ling K, Kong L, Ward AJ, Rubin LL, Rigo F, Bennett CF, Sumner CJ. The antisense transcript SMN-AS1 regulates SMN expression and is a novel therapeutic target for spinal muscular atrophy. Neuron. 2017;93(1):66–79.
Martinez TL, Kong L, Wang X, Osborne MA, Crowder ME, Van Meerbeke JP, Xu X, Davis C, Wooley J, Goldhamer DJ, Lutz CM, Rich MM, Sumner CJ. Survival motor neuron protein in motor neurons determines synaptic integrity in spinal muscular atrophy. J Neurosci. 2012;32(25):8703–8715.
Landouré G, Zdebik AA, Martinez TL, Burnett BG, Stanescu HC, Inada H, Shi Y, Taye AA, Kong L, Munns CH, Choo SS, Phelps CB, Paudel R, Houlden H, Ludlow CL, Caterina MJ, Gaudet R, Kleta R, Fischbeck KH, Sumner CJ. Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C. Nat Genet. 2010;42(2):170–174.
This MonthJune 2018
Contact the JCI and JCI Insight2015 Manchester RoadAnn Arbor, Michigan 48104, USAPhone: 734.222.6050Email: [email protected] (JCI); [email protected] (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.
Get noticed.Submit your workto the JCI today. jci.org
j c i . o r g / t h i s - m o n t h j u n e 2 0 1 82
research
Editor’s picks
on the jci cover
Subclonal copy number variations contribute to breast cancer metastasisMetastasis remains a frequent cause of breast cancer mortality, and considerable effort has been devoted to understanding the drivers of metastasis. Single-cell genomic analyses offer an opportunity to examine tumor heterogeneity and clonal evolution of mutations within primary tumors and correspond-ing metastases. In this issue of the JCI, Bao et al. report on their implementation of laser-capture microdissection techniques to perform single-cell sequencing on over 100 cells from morphologically distinct regions of primary breast tumor paired with lymph node metastases. Their analyses traced aberrations present in metastases to a subclone located in an invasive region of the primary tumor. While no metastasis-specific mutations in known driver genes could be identified, copy number alterations in chromosome regions harboring metastasis-associated genes were consistently observed in several data sets of multiple primary tumors from patients with or without lymph node metastasis. Although a larger number of patient samples are needed to draw definitive conclusions about the precise metastasis-promoting genomic aberrations, these findings emphasize the power of single-cell analyses for interpreting heterogeneity and clonal evolution in cancer. The cover image visualizes the sequencing of single cells, a technique enabling analyses of clonal evolution that account for cell type, spatial location, and within-tumor genetic variation. Image credit: Henrik Ditzel and Li Bao.
Coexisting genomic aberrations associated with lymph node metastasis in breast cancerLi Bao, Zhaoyang Qian, Maria B. Lyng, Ling Wang, Yuan Yu, Ting Wang, Xiuqing Zhang, Huanming Yang, Nils Brünner, Jun Wang, and Henrik J. Ditzel http://jci.me/97449
oncology
TNF blockade may undermine EGFR inhibitor resistance in lung cancerA subset of non–small cell lung cancers (NSCLCs) are driven by activating mutations in EGFR. These cancers initially respond well to EGFR tyrosine kinase inhibitors (TKIs) but eventually develop secondary resistance mechanisms. Ke Gong, Gao Guo, and coworkers report that TKI treatment induces an adaptive upregulation of TNF that enhances tumor cell survival in both EGFR-mutant and EGFR WT NSCLCs. TKI treatment decreased the expression of microRNA-21, leading to stabilization of TNF-encoding mRNA. Initial increases in TNF activated an NF-κB– mediated feed-forward mechanism that further exacerbated TNF overexpression. TNF blockade enhanced the efficacy of TKI treatment in EGFR-mutant cells compared with TKI treatment alone. Moreover, it produced treatment sensitivity in TKI-resistant, EGFR-mutant and EGFR
WT NSCLCs, suggesting that this combinatorial approach may produce beneficial responses in a broad population of patients with lung cancer and circumvent treatment resistance.
TNF-driven adaptive response mediates resistance to EGFR inhibition in lung cancerKe Gong, Gao Guo, David E. Gerber, Boning Gao, Michael Peyton, Chun Huang, John D. Minna, Kimmo J. Hatanpaa, Kemp Kernstine, Ling Cai, Yang Xie, Hong Zhu, Farjana J. Fattah, Shanrong Zhang, Masaya Takahashi, Bipasha Mukherjee, Sandeep Burma, Jonathan Dowell, Kathryn Dao, Vassiliki A. Papadimitrakopoulou, Victor Olivas, Trever G. Bivona, Dawen Zhao, and Amyn A. Habib http://jci.me/96148
j c i . o r g / t h i s - m o n t h j u n e 2 0 1 8 3
JCI | Research: Editor’s picks
neuroscienceCD155 deficiency in host or tumor impairs cancer development
Immunotherapy strategies targeting PD-1, PD-L1, and CTLA-4 have demonstrated success in treating cancer but are not a universal cure, highlighting the need to identify additional targetable mechanisms of immune resistance. CD155, a nectin-like ligand for the immune checkpoint receptors TIGIT and CD96, is overexpressed in tumors and has been linked to poor prognosis in cancer patients. Xian-Yang Li and colleagues reveal that loss of CD155 in syngeneic tumors, host cells, or both impaired tumor growth and metastasis, demonstrating its tumor- and host-intrinsic roles in cancer development. Mechanis-tically, host CD155 loss upregulated DNAM-1, a costimulatory molecule for NK and T cells, producing enhanced effector function. CD155 deficiency also improved the antitumor effect of PD-1, PD-L1, and CTLA-4 blockade. In the associated Commentary, Vincenzo Bronte indicates that CD155 blockade may be a beneficial addition to cancer immunotherapy. The accompanying image shows the coexpression of CD155 and HMB45 in a human melanoma sample.
CD155 loss enhances tumor suppression via combined host and tumor-intrinsic mechanismsXian-Yang Li, Indrajit Das, Ailin Lepletier, Venkateswar Addala, Tobias Bald, Kimberley Stannard, Deborah Barkauskas, Jing Liu, Amelia Roman Aguilera, Kazuyoshi Takeda, Matthias Braun, Kyohei Nakamura, Sebastien Jacquelin, Steven W. Lane, Michele W.L. Teng, William C. Dougall, and Mark J. Smyth http://jci.me/98769
Related CommentaryThe expanding constellation of immune checkpoints: a DNAMic control by CD155Vincenzo Bronte http://jci.me/121229
Second-hit inactivation of DEPDC5 underlies brain cortical malformation with focal epilepsyFamilial focal epilepsy is caused by loss-of-function mutations in DEPDC5, encoding a repressor in the mTORC1 amino acid–sensing pathway. Some individuals expressing this DEPDC5 mutation develop focal cortical dysplasia (FCD), a malformation of cortical development, suggesting that a second-hit mutation may drive the neurodevelopmental disorder. Théo Ribierre and coworkers provide evidence of this second hit in a patient with a maternally inherited DEPDC5 mutation, focal epilepsy, and FCD. The patient’s resected cortical tissue revealed a mosaic variant with a somatic loss-of-function mutation in the second DEPDC5 allele, producing biallelic DEPDC5 inactivation. Brain mosaic Depdc5 inactivation in a mouse faithfully recapitulated the patient’s focal epilepsy and cortical malformation. This model also provided insights into the role of Depdc5 in the development of excitatory cortical neurons (see the associated image). Matthew Anderson’s accompanying Commentary highlights these insights and the resulting model as promising steps toward identifying potential therapies for neurodevelopmental seizure disorders.
Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia–associated epilepsyThéo Ribierre, Charlotte Deleuze, Alexandre Bacq, Sara Baldassari, Elise Marsan, Mathilde Chipaux, Giuseppe Muraca, Delphine Roussel, Vincent Navarro, Eric Leguern, Richard Miles, and Stéphanie Baulac http://jci.me/99384
Related CommentaryDEPDC5 takes a second hit in familial focal epilepsyMatthew P. Anderson http://jci.me/121052
oncology
j c i . o r g / t h i s - m o n t h j u n e 2 0 1 84
JCI | Research: Editor’s picks
metabolism
virology
Modifications may slim down the side-effect profile of PPARγ agonists
KSHV viral protein kinase expression promotes B cell lymphomas in miceKaposi’s sarcoma–associated herpesvirus (KSHV) causes the eponymous endothelial cancer Kaposi’s sarcoma and two B cell–associated lymphoproliferative disorders in immunocompromised individuals. Although antiviral strategies can reduce the spread of KSHV to uninfected cells, these treatments are unable to prevent reactivation and replication of the latent virus within infected cells. Penny Anders and colleagues explored the in vivo functions of the KSHV viral protein kinase (vPK, also known as KSHV ORF36), which was previously implicated in promoting cancer-like protein synthesis and growth in cultured cells. Ubiquitous expression of vPK in mice produced increases in B cell activation and, over time, led to hyperproliferation of B cells and B cell lymphoma. Richard Ambinder points to vPK as a potential target for preventing disease in KSHV-infected individuals in an accompanying Commentary.
Human herpesvirus–encoded kinase induces B cell lymphomas in vivoPenny M. Anders, Nathan D. Montgomery, Stephanie A. Montgomery, Aadra P. Bhatt, Dirk P. Dittmer, and Blossom Damania http://jci.me/97053
Related CommentaryA viral protein kinase drug target for tumors?Richard F. Ambinder http://jci.me/121080
Bispecific antibody takes promising steps toward HIV prevention and immunotherapyThe numerous and diverse subtypes of HIV-1 present an enormous challenge to vaccine development. Infected individuals develop broadly neutralizing antibodies (bnAbs) to the variable regions of HIV-1’s viral envelope that provide a basis for structure-guided HIV-1 vaccine design. However, resistant strains hinder the success of bnAb monotherapies, and bispecific bnAbs have encountered technical setbacks. A team led by Zhiwei Chen engineered a bispecific bnAb encoded by a single gene that preserves each antibody’s single-chain variable fragment (scFv) binding domains. This bispecific bnAb demonstrated the ability to neutralize a large number of HIV-1 pseudotypes and protected humanized mice from HIV-1 infection by multiple strains. Moreover, prolonged expression of the bnAb in HIV-1–infected humanized mice eliminated the detectable viral load. In an accompanying Commentary, Guido Ferrari stresses the need for further clinical development of this approach, which may produce an effective method of reducing global rates of HIV-1 infection.
Tandem bispecific neutralizing antibody eliminates HIV-1 infection in humanized miceXilin Wu, Jia Guo, Mengyue Niu, Minghui An, Li Liu, Hui Wang, Xia Jin, Qi Zhang, Ka Shing Lam, Tongjin Wu, Hua Wang, Qian Wang, Yanhua Du, Jingjing Li, Lin Cheng, Hang Ying Tang, Hong Shang, Linqi Zhang, Paul Zhou, and Zhiwei Chen http://jci.me/96764
Related CommentaryTandem bispecific broadly neutralizing antibody — a novel approach to HIV-1 treatmentGuido Ferrari http://jci.me/121078
Thiazolidinediones (TZDs) are PPARγ agonists that potently increase insulin sensitivity and induce adipocyte browning. They also pose significant health risks that limit their clinical use. Recent work revealed that deacetylation of the PPARγ lysine residues K268 and K293 is responsible for TZD-induced brown adipocyte gene expression in white adipocytes. Michael Kraakman, Qiongming Liu, and colleagues developed a mouse model of constitutive PPARγ deacetylation (2KR mice) by mutating K268 and K293 residues to arginines. The mutations enhanced adipocyte browning in 2KR mice and conferred protection against diet-induced obesity. TZD treatment evoked insulin sensitivity in 2KR mice in the absence of the adverse effects that were observed in TZD-treated control mice, including decreased bone density. The accompanying Commentary by Mitchell Lazar outlines the evidence that promoting PPARγ deacetylation may be the key to harnessing the beneficial effects of TZDs.
PPARγ deacetylation dissociates thiazolidinedione’s metabolic benefits from its adverse effectsMichael J. Kraakman, Qiongming Liu, Jorge Postigo-Fernandez, Ruiping Ji, Ning Kon, Delfina Larrea, Maria Namwanje, Lihong Fan, Michelle Chan, Estela Area-Gomez, Wenxian Fu, Remi J. Creusot, and Li Qiang http://jci.me/98709
Related CommentaryReversing the curse on PPARγMitchell A. Lazar http://jci.me/121392
j c i . o r g / t h i s - m o n t h j u n e 2 0 1 8 5
JCI | Research: Editor’s picks
HMGB1 promotes progenitor cell expansion and exacerbates hepatic tumorigenesis
hepatology
The liver’s ability to regenerate is unique among visceral organs, but damage does not occur without consequences. Chronic insults induce repair responses accompanied by fibrosis and inflammation, which are eventually followed by cirrhosis and hepatocellular carcinoma (HCC). While the mechanisms linking liver injury to HCC are unclear, it is thought that a cycle of injury-driven inflammation and cell death contributes to pathogenesis. Two studies in this issue investigate the role of the damage-associated molecular pattern HMGB1 in the transition to hepatic tumors. Celine Hernandez, Peter Huebener, and colleagues observed that loss of HMGB1 did not impact inflammation, fibrosis, or regeneration in multiple models of chronic liver injury. Rather, hepatocyte-derived HMGB1 promoted the expansion of hepatic progenitor cells as well as hepatocyte metaplasia and HCC development as a response to chronic insults. Complementary work performed by Bilon Khambu and labmates demonstrated a role for inflammasome-dependent HMGB1 in progenitor cell expansion and tumor development in autophagy-deficient hepatocytes, indicating a contribution of defective autophagy processes to
liver tumorigenesis. Together, these studies link HMGB1 signaling with chronic liver pathologies that promote carcinogenesis, providing insight into the pathways upstream of hepatic tumors.
Related ResearchHMGB1 links chronic liver injury to progenitor responses and hepatocarcinogenesisCeline Hernandez, Peter Huebener, Jean-Philippe Pradere, Daniel J. Antoine, Richard A. Friedman, and Robert F. Schwabe http://jci.me/91786
HMGB1 promotes ductular reaction and tumorigenesis in autophagy-deficient liversBilon Khambu, Nazmul Huda, Xiaoyun Chen, Daniel J. Antoine, Yong Li, Guoli Dai, Ulrike A. Köhler, Wei-Xing Zong, Satoshi Waguri, Sabine Werner, Tim D. Oury, Zheng Dong, and Xiao-Ming Yin http://jci.me/91814
Maintaining glutathione metabolism bolsters regeneration after acute liver injuryThe liver can recover from loss of up to 75% of its volume by activating proliferation in remaining hepatocytes. In a model of acute toxic liver injury, Amber Wang, Kirk Wangensteen, and colleagues isolated mRNAs specific to repopulating hepatocytes. They observed a dramatic upregulation of genes that regulate glutathione metabolism, specifically Slc7a11, encoding xCT, a cystine/glutamate antiporter that imports a rate-limiting substrate in glutathione synthesis. Activating Slc7a11 expression in regenerative hepatocytes enhanced repopulation and recovery following toxic liver injury. An accompanying Commentary by Kai-Yuan Chen, Xiling Shen, and Anna Mae Diehl discusses the importance of glutathione-mediated antioxidant pathways during liver regeneration and the need for further investigation into xCT as a therapeutic target in acute liver injury. The accompanying images show impaired proliferation of Slc7a11-silenced hepatocytes (right) compared with controls (left).
TRAP-seq identifies cystine/glutamate antiporter as a driver of recovery from liver injuryAmber W. Wang, Kirk J. Wangensteen, Yue J. Wang, Adam M. Zahm, Nicholas G. Moss, Noam Erez, and Klaus H. Kaestner http://jci.me/95120
Related CommentaryPrometheus revisitedKai-Yuan Chen, Xiling Shen, and Anna Mae Diehl http://jci.me/120933
j c i . o r g / t h i s - m o n t h j u n e 2 0 1 86
JCI | Features
Gene therapies for inherited retinal diseases are within our sights
Circadian rhythms make your heart tick
reviews
In December 2017, the FDA approved Luxturna for the treatment of Leber congenital amaurosis, an inherited form of progressive blindness. Although Luxturna is the first FDA-approved gene therapy treatment for an eye disease, multiple gene-targeting therapies for retinal conditions are in the pipeline. James DiCarlo, Vinit Mahajan, and Stephen Tsang provide a comprehensive overview of the genetic strategies for ophthalmologic disorders that are currently under preclinical investigation or in clinical development. Recent advances in gene-editing techniques, such as CRISPR-Cas, provide new opportunities to correct diseases driven by dominant-negative alleles. Given the rate of recent progress in gene therapy, the authors speculate that we are likely to see more successful gene-targeting therapeutics in the near future.
Gene therapy and genome surgery in the retinaJames E. DiCarlo, Vinit B. Mahajan, and Stephen H. Tsang http://jci.me/120429
Get noticed.Submit your workto the JCI today.
jci.org
Endogenous 24-hour molecular rhythms drive predictable fluctuations in cardiovascular physiology that parallel daily activity patterns. In the morning, increases in heart rate, blood pressure, and thrombus formation support the onset of activity in most healthy individuals. However, these fluctuations can also precipitate adverse cardiovascular events, as evidenced by the elevated incidence of myocardial infarction, stroke, and sudden cardiac death in early-morning hours. In this Review, Saurabh Thosar, Matthew Butler, and Steven Shea describe how daily patterns in cardiovas-cular physiology, individual risk factors, and behavior interact to influence cardiovascular function. In addition to cardiovascular disease, sleep disruptions such as night-shift work, daylight savings time, and jet lag are associated with increased risk for adverse cardiovascular events. The authors argue that increased research into the circadian patterns of the cardiovascu-lar system may help tailor medication dosing times to achieve maximum benefits in patients.
Role of the circadian system in cardiovascular diseaseSaurabh S. Thosar, Matthew P. Butler, and Steven A. Shea http://jci.me/80590
j c i . o r g / t h i s - m o n t h j u n e 2 0 1 8 7
Current research articles
autoimmunityMicroRNA-210 overexpression promotes psoriasis-like inflammation by inducing Th1 and Th17 cell differentiationRuifang Wu, Jinrong Zeng, Jin Yuan, Xinjie Deng, Yi Huang, Lina Chen, Peng Zhang, Huan Feng, Zixin Liu, Zijun Wang, Xiaofei Gao, Haijing Wu, Honglin Wang, Yuwen Su, Ming Zhao, and Qianjin Lu http://jci.me/97426
Disease-driving CD4+ T cell clonotypes persist for decades in celiac diseaseLouise F. Risnes, Asbjørn Christophersen, Shiva Dahal-Koirala, Ralf S. Neumann, Geir K. Sandve,
Vikas K. Sarna, Knut E.A. Lundin, Shuo-Wang Qiao, and Ludvig M. Sollid http://jci.me/98819
hepatologyHMGB1 links chronic liver injury to progenitor responses and hepatocarcinogenesis p. 5Celine Hernandez, Peter Huebener, Jean-Philippe Pradere, Daniel J. Antoine, Richard A. Friedman, and Robert F. Schwabe http://jci.me/91786
HMGB1 promotes ductular reaction and tumorigenesis in autophagy-deficient livers p. 5Bilon Khambu, Nazmul Huda, Xiaoyun Chen, Daniel J. Antoine, Yong Li, Guoli Dai, Ulrike A. Köhler, Wei-Xing Zong, Satoshi Waguri, Sabine Werner, Tim D. Oury, Zheng Dong, and Xiao-Ming Yin http://jci.me/91814
TRAP-seq identifies cystine/glutamate antiporter as a driver of recovery from liver injury p. 5Amber W. Wang, Kirk J. Wangensteen, Yue J. Wang, Adam M. Zahm, Nicholas G. Moss, Noam Erez, and Klaus H. Kaestner http://jci.me/95120
immunologyBlocking IFNAR1 inhibits multiple myeloma–driven Treg expansion and immunosuppressionYawara Kawano, Oksana Zavidij, Jihye Park, Michele Moschetta, Katsutoshi Kokubun, Tarek H. Mouhieddine, Salomon Manier, Yuji Mishima, Naoka Murakami, Mark Bustoros, Romanos Sklavenitis Pistofidis, Mairead Reidy, Yu J. Shen, Mahshid Rahmat, Pavlo Lukyanchykov, Esilida Sula Karreci, Shokichi Tsukamoto, Jiantao Shi, Satoshi Takagi, Daisy Huynh, Antonio Sacco, Yu-Tzu Tai, Marta Chesi, P. Leif Bergsagel, Aldo M. Roccaro, Jamil Azzi, and Irene M. Ghobrial http://jci.me/88169
Tumor-secreted Pros1 inhibits macrophage M1 polarization to reduce antitumor immune responseEric Ubil, Laura Caskey, Alisha Holtzhausen, Debra Hunter, Charlotte Story, and H. Shelton Earp http://jci.me/97354
sNASP inhibits TLR signaling to regulate immune response in sepsisFeng-Ming Yang, Yong Zuo, Wei Zhou, Chuan Xia, Bumsuk Hahm, Mark Sullivan, Jinke Cheng, Hui-Ming Chang, and Edward T.H. Yeh http://jci.me/95720
Hypercholesterolemia induces T cell expansion in humanized immune miceJonathan D. Proto, Amanda C. Doran, Manikandan Subramanian, Hui Wang, Mingyou Zhang, Erdi Sozen, Christina C. Rymond, George Kuriakose, Vivette D’Agati, Robert Winchester, Megan Sykes, Yong-Guang Yang, and Ira Tabas http://jci.me/97785
metabolismKetohexokinase C blockade ameliorates fructose-induced metabolic dysfunction in fructose-sensitive miceMiguel A. Lanaspa, Ana Andres-Hernando, David J. Orlicky, Christina Cicerchi, Cholsoon Jang, Nanxing Li, Tamara Milagres, Masanari Kuwabara, Michael F. Wempe, Joshua D. Rabinowitz, Richard J. Johnson, and Dean R. Tolan http://jci.me/94427
Neuronal hypothalamic regulation of body metabolism and bone density is galanin dependentAnna Idelevich, Kazusa Sato, Kenichi Nagano, Glenn Rowe, Francesca Gori, and Roland Baron http://jci.me/99350
Pros1 expression in tumor cells
Psoriasis-like lesions
j c i . o r g / t h i s - m o n t h j u n e 2 0 1 88
Current research articles
metabolismPPARγ deacetylation dissociates thiazolidinedione’s metabolic benefits from its adverse effects p. 4Michael J. Kraakman, Qiongming Liu, Jorge Postigo-Fernandez, Ruiping Ji, Ning Kon, Delfina Larrea, Maria Namwanje, Lihong Fan, Michelle Chan, Estela Area-Gomez, Wenxian Fu, Remi J. Creusot, and Li Qiang http://jci.me/98709
muscle biologyTransient HIF2A inhibition promotes satellite cell proliferation and muscle regenerationLiwei Xie, Amelia Yin, Anna S. Nichenko, Aaron M. Beedle, Jarrod A. Call, and Hang Yin http://jci.me/96208
neuroscienceReducing CXCR4-mediated nociceptor hyperexcitability reverses painful diabetic neuropathyNirupa D. Jayaraj, Bula J. Bhattacharyya, Abdelhak A. Belmadani, Dongjun Ren, Craig A. Rathwell, Sandra Heckelberg, Brittany E. Hopkins, Herschel R. Gupta, Richard J. Miller, and Daniela M. Menichella http://jci.me/92117
Mutant ataxin1 disrupts cerebellar development in spinocerebellar ataxia type 1Chandrakanth Reddy Edamakanti, Jeehaeh Do, Alessandro Didonna, Marco Martina, and Puneet Opal http://jci.me/96765
Systemic isradipine treatment diminishes calcium-dependent mitochondrial oxidant stressJaime N. Guzman, Ema Ilijic, Ben Yang, Javier Sanchez-Padilla, David Wokosin, Dan Galtieri, Jyothisri Kondapalli, Paul T. Schumacker, and D. James Surmeier http://jci.me/95898
Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia–associated epilepsy p. 3Théo Ribierre, Charlotte Deleuze, Alexandre Bacq, Sara Baldassari, Elisa Marsan, Mathilde Chipaux,
Giuseppe Muraca, Delphine Roussel, Vincent Navarro, Eric Leguern, Richard Miles, and Stéphanie Baulac http://jci.me/99384
oncologyTNF-driven adaptive response mediates resistance to EGFR inhibition in lung cancer p. 2Ke Gong, Gao Guo, David E. Gerber, Boning Gao, Michael Peyton, Chun Huang, John D. Minna, Kimmo J. Hatanpaa, Kemp Kernstine, Ling Cai, Yang Xie, Hong Zhu, Farjana J. Fattah, Shanrong Zhang, Masaya Takahashi, Bipasha Mukherjee, Sandeep Burma, Jonathan Dowell, Kathryn Dao, Vassiliki A. Papadimitrakopoulou, Victor Olivas, Trever G. Bivona, Dawen Zhao, and Amyn A. Habib http://jci.me/96148
Dose intensification of TRAIL-inducing ONC201 inhibits metastasis and promotes intratumoral NK cell recruitmentJessica Wagner, C. Leah Kline, Lanlan Zhou, Kerry S. Campbell, Alexander W. MacFarlane, Anthony J. Olszanski, Kathy Q. Cai, Harvey H. Hensley, Eric A. Ross, Marie D. Ralff, Andrew Zloza, Charles B. Chesson, Jenna H. Newman, Howard Kaufman, Joseph Bertino, Mark Stein, and Wafik S. El-Deiry http://jci.me/96711
Eya3 promotes breast tumor–associated immune suppression via threonine phosphatase–mediated PD-L1 upregulationRebecca L. Vartuli, Hengbo Zhou, Lingdi Zhang, Rani K. Powers, Jared Klarquist, Pratyaydipta Rudra, Melanie Y. Vincent, Debashis Ghosh, James C. Costello, Ross M. Kedl, Jill E. Slansky, Rui Zhao, and Heide L. Ford http://jci.me/96784
Notch-effector CSL promotes squamous cell carcinoma by repressing histone demethylase KDM6BDania Al Labban, Seung-Hee Jo, Paola Ostano, Chiara Saglietti, Massimo Bongiovanni, Renato Panizzon, and G. Paolo Dotto http://jci.me/96915
Regeneration in injured muscle
Probing a dopaminergic neuron
j c i . o r g / t h i s - m o n t h j u n e 2 0 1 8 9
Coexisting genomic aberrations associated with lymph node metastasis in breast cancer p. 2Li Bao, Zhaoyang Qian, Maria B. Lyng, Ling Wang, Yuan Yu, Ting Wang, Xiuqing Zhang, Huanming Yang, Nils Brünner, Jun Wang, and Henrik J. Ditzel http://jci.me/97449
Imaging activated T cells predicts response to cancer vaccinesIsrat S. Alam, Aaron T. Mayer, Idit Sagiv-Barfi, Kezheng Wang, Ophir Vermesh, Debra K. Czerwinski, Emily M. Johnson, Michelle L. James, Ronald Levy, and Sanjiv S. Gambhir http://jci.me/98509
DNA methyltransferase expression in triple-negative breast cancer predicts sensitivity to decitabineJia Yu, Bo Qin, Ann M. Moyer, Somaira Nowsheen, Tongzheng Liu, Sisi Qin, Yongxian Zhuang, Duan Liu, Shijia W. Lu, Krishna R. Kalari, Daniel W. Visscher, John A. Copland, Sarah A. McLaughlin, Alvaro Moreno-Aspitia, Donald W. Northfelt, Richard J. Gray, Zhenkun Lou, Vera J. Suman, Richard Weinshilboum, Judy C. Boughey, Matthew P. Goetz, and Liewei Wang http://jci.me/97924
CD155 loss enhances tumor suppression via combined host and tumor-intrinsic mechanisms p. 3Xian-Yang Li, Indrajit Das, Ailin Lepletier, Venkateswar Addala, Tobias Bald, Kimberley Stannard, Deborah Barkauskas, Jing Liu, Amelia Roman Aguilera, Kazuyoshi Takeda, Matthias Braun, Kyohei Nakamura, Sebastien Jacquelin, Steven W. Lane, Michele W.L. Teng, William C. Dougall, and Mark J. Smyth http://jci.me/98769
pulmonologyFOXM1 is a critical driver of lung fibroblast activation and fibrogenesisLoka R. Penke, Jennifer M. Speth, Vijaya L. Dommeti, Eric S. White, Ingrid L. Bergin, and Marc Peters-Golden http://jci.me/87631
Circadian clock component REV-ERBα controls homeostatic regulation of pulmonary inflammationMarie Pariollaud, Julie E. Gibbs, Thomas W. Hopwood, Sheila Brown, Nicola Begley, Ryan Vonslow, Toryn Poolman, Baoqiang Guo, Ben Saer, D. Heylyn Jones, James P. Tellam, Stefano Bresciani, Nicholas C.O. Tomkinson, Justyna Wonjo-Picon, Anthony W.J. Cooper, Dion A. Daniels, Ryan P. Trump, Daniel Grant, William Zuercher, Timothy M. Willson, Andrew S. MacDonal, Brian Bolognese, Patricia L. Podolin, Yolanda Sanchez, Andrew S.I. Loudon, and David W. Ray http://jci.me/93910
Granulocyte-CSF links destructive inflammation and comorbidities in obstructive lung diseaseEvelyn Tsantikos, Maverick Lau, Cassandra M.N. Castelino, Mhairi J. Maxwell, Samantha L. Passey, Michelle J. Hansend, Narelle E. McGregor, Natalie A. Sims, Daniel P. Steinfort, Louis B. Irving, Gary P. Anderson, and Margaret L. Hibbs http://jci.me/98224
vascular biologyUHRF1 epigenetically orchestrates smooth muscle cell plasticity in arterial diseaseLeonardo Elia, Paolo Kunderfranco, Pierluigi Carullo, Marco Vacchiano, Floriana Maria Farina, Ignacio Fernando Hall, Stefano Mantero, Cristina Panico, Roberto Papait, Gianluigi Condorelli, and Manuela Quintavalle http://jci.me/96121
virologyTandem bispecific neutralizing antibody eliminates HIV-1 infection in humanized mice p. 4Xilin Wu, Jia Guo, Mengyue Niu, Minghui An, Li Liu, Hui Wang, Xia Jin, Qi Zhang, Ka Shing Lam, Tongjin Wu, Hua Wang, Qian Wang, Yanhua Du, Jingjing Li, Lin Cheng, Hang Ying Tang, Hong Shang, Linqi Zhang, Paul Zhou, and Zhiwei Chen http://jci.me/96764
Human herpesvirus–encoded kinase induces B cell lymphomas in vivo p. 4Penny M. Anders, Nathan D. Montgomery, Stephanie A. Montgomery, Aadra P. Bhatt, Dirk P. Dittmer, and Blossom Damania http://jci.me/97053
Normal breast tissue
Carotid artery segment
Flip issue to read JCI Insight content.
jci.org/this-month
Markers improve acute myeloid leukemia monitoring 11
Metabolite ratio predicts acute graft-versus-host disease 11
Acute HIV infection markers associate with viral reservoir 12
Hypertrophy-associated alterations in cardiac metabolism 13
JCI This Month is a summary of the most recent articles in The Journal of Clinical Investigation and JCI Insight
June 2018
Identification of a myeloid-derived myofibroblast population p. 10
This Month
Christopher M. Adams
Maria-Luisa Alegre
Ravi K. Amaravadi
John K. Amory
Jennifer H. Anolik
Cristian Apetrei
Rajendra S. Apte
Zoltan Arany
Hossein Ardehali
Kenneth I. Ataga
Joseph Bass
Alexander G. Bassuk
Antonio C. Bianco
Jonathan S. Bogan
Laura M. Bohn
Nunzio Bottini
Sebastien G. Bouret
Jason Brenchley
Renier J. Brentjens
G.R. Scott Budinger
George A. Calin
Stephen Chan
Timothy Chan
Yuan Chang
Zhou-Feng Chen
Keith A. Choate
Wendy Chung
Craig M. Coopersmith
George Cotsarelis
Peter Crawford
Lisa L. Cunningham
Ronald P. DeMatteo
Elia J. Duh
Sarah K. England
Mark W. Feinberg
John H. Fingert
Robert Flaumenhaft
Edward A. Fon
Lawrence Fong
Nikolaos G. Frangogiannis
Anthony R. French
Terrence L. Geiger
Noyan Gokce
Raphaela Goldbach-Mansky
Daniel R. Goldstein
Douglas K. Graham
Khalid A. Hanafy
Eric B. Haura
John Cijiang He
Robert O. Heuckeroth
Cory M. Hogaboam
Young-Kwon Hong
Benjamin D. Humphreys
Ken Inoki
Shingo Kajimura
Pawel Kalinski
John Y. Kao
Michael G. Kaplitt
Thomas W.H. Kay
Barbara I. Kazmierczak
Hans-Peter Kiem
William Y. Kim
David G. Kirsch
Claire E. Lewis
Mathias Lichterfeld
André Lieber
Michail S. Lionakis
Carey N. Lumeng
Ivan Maillard
Ziad Mallat
Peter Mannon
Franck Mauvais-Jarvis
Dermot P.B. McGovern
Borna Mehrad
Ingo K. Mellinghoff
David K. Meyerholz
Jason C. Mills
Joshua D. Milner
Satdarshan (Paul) Singh Monga
Hidayatullah G. Munshi
Matthias Nahrendorf
Mary Nakamura
Lisa F.P. Ng
Mark Nicolls
Laura J. Niedernhofer
S. Tiong Ong
Puneet Opal
Daniel Ory
Sophie Paczesny
Stephanie T. Page
Mary-Elizabeth Patti
Janos Peti-Peterdi
Fernando P. Polack
Matthew D. Ringel
Steven M. Rowe
Svati H. Shah
Vijay H. Shah
Alice T. Shaw
Rhonda F. Souza
Fayyaz S. Sutterwala
Shu Takeda
Natalie J. Torok
Stephen H. Tsang
Ellie Tzima
Fumihiko Urano
Deborah J. Veis
Charles P. Venditti
Joseph M. Vinetz
Sing Sing Way
Bernd Wollnik
Minna Woo
Prescott G. Woodruff
Lori M. Zeltser
Yutong Zhao
Binhua P. Zhou
JCI Insight Consulting Editors
j c i . o r g / t h i s - m o n t h j u n e 2 0 1 8 10
For JCI InsightEditorHoward A. RockmanAssociate EditorsRodger A. Liddle, Yiping YangExecutive EditorSarah C. JacksonScience EditorCorinne Williams
ASCI StaffExecutive DirectorJohn B. HawleyManaging DirectorKaren D. GuthAssociate DirectorMaya HoptmanAssociate Director, TechnologyShawn PyleProduction EditorsCatherine Ahmann, Ken Beauchamp, Molly Jean, Lara L. McCarronScientific IllustratorBruce WordenCopy EditorsClare Cross, Meredith Dimick, Barbara Fabyan, Rachel Nelson, Chet ProvodaAssociate Copy EditorsRachel Bullen, Megan O'ReillyPublications CoordinatorMegan JenkinsSystem Administrator and DeveloperBryan EnglishWeb DeveloperAustin BrewerScience Communications SpecialistNeha AggarwalAccounts ManagerPaula KremidasAdministrative AssistantTheresa KaiserFigures CoordinatorKeith Kalinowski
For JCI Insight online: jci.me/insight/3/9jci.me/insight/3/10
Limited contribution of myeloid- derived myofibroblasts in kidney fibrosis
On the JCI Insight cover
Chronic kidney disease is char-acterized by progressive loss of function due to the development of fibrosis. Myofibroblasts are the cells responsible for fibrosis devel-opment and progression. While about half of all myofibroblasts are derived from the pericyte lineage, the cellular origin of the remain-ing myofibroblasts is unclear. In JCI Insight, Rafael Kramann and colleagues developed genetic lineage-tracing experiments to evaluate the contribution of the
proximal tubule epithelium and circulating cells to the myofibroblast popula-tion in murine models of renal fibrosis. Myofibroblasts were not derived from proximal tubular epithelial cells. Parabiosis experiments, in which circulating cells of one animal were labeled and kidney fibrosis was induced in the other, revealed that a small fraction of myofibroblasts are derived from circulat-ing cells. RNA sequencing of these cells indicated that they are of monocyte origin; however, circulation-derived myofibroblasts expressed very few ECM-encoding genes but had high expression of proinflammatory cytokines, suggesting that this population does not secrete matrix but may regulate inflammation. The cover image shows the accumulation of myofibroblasts (green, α–smooth muscle actin) and myeloid-derived myofibroblasts (red and blue, CD45) in the kidney after induction of fibrosis. Nuclei were stained with DAPI (white).
Parabiosis and single-cell RNA sequencing reveal a limited contribution of monocytes to myofibroblasts in kidney fibrosisRafael Kramann, Flavia Machado, Haojia Wu, Tetsuro Kusaba, Konrad Hoeft, Rebekka K. Schneider, and Benjamin D. Humphreys http://jci.me/99561
This MonthJune 2018
Make your 18-hour days count.
Submit your work to JCI Insight today.
j c i . o r g / t h i s - m o n t h j u n e 2 0 1 811
Editor’s picks
Improved monitoring of residual disease in acute myeloid leukemiaFor many patients with acute myeloid leukemia (AML), chemotherapy results in nondetectable disease and long-term remission. Unfortunately, in some cases the disease will relapse due to the presence of a small population of chemoresistant leukemia cells. Strategies to better detect this minimal residual disease (MRD) are needed to more accurately identify patients at risk of relapse. Elaine Coustan-Smith and colleagues compared gene expression profiles of patient AML cells with those of normal myeloblasts and identified several aberrantly expressed genes, including leukemia stem cell–associated genes, that could be detected by flow cytometry. Moreover, these markers were consistently expressed during treatment, able to identify MRD, and could be used to monitor disease progres-sion. In combination with conventional methods, these markers have potential to improve the detection of MRD.
Universal monitoring of minimal residual disease in acute myeloid leukemiaElaine Coustan-Smith, Guangchun Song, Sheila Shurtleff, Allen Eng-Juh Yeoh, Wee Joo Chng, Siew Peng Chen, Jeffrey E. Rubnitz, Ching-Hon Pui, James R. Downing, and Dario Campana http://jci.me/98561
The ratio of stearic acid to palmitic acid predicts acute GVHD after HSCTThe development of acute graft-versus-host disease (aGVHD) has hindered the use of hematopoietic stem cell transplantation (HSCT) for a variety of diseases, and current techniques to accurately predict and monitor aGVHD are limited. Xiaojin Wu et al. analyzed serum metabolites in patients with hematological malignancies prior to, at the time of, and at 7 and 14 days after HSCT. There was a marked fluctuation of serum metabolites after HSCT, and, in particular, the ratio of stearic acid to palmitic acid (SA/PA) was predictive of aGVHD. Patients with a high SA/PA ratio at day 7 after HSCT were less likely to develop aGVHD than those with a low SA/PA ratio. These results support the SA/PA ratio as a marker of aGVHD.
Prediction of acute GVHD and relapse by metabolic biomarkers after allogeneic hematopoietic stem cell transplantationXiaojin Wu, Yiyu Xie, Chang Wang, Yue Han, Xiebing Bao, Shoubao Ma, Ahmet Yilmaz, Bingyu Yang, Yuhan Ji, Jinge Xu, Hong Liu, Suning Chen, Jianying Zhang, Jianhua Yu, and Depei Wu http://jci.me/99672
hematology
immunology
CSFR1 inhibition–dependent reduction of NK cells promotes metastasisMetastasis of cancer cells from the primary tumor remains a leading cause of cancer-related death. Different immune cell subsets are attractive targets for boosting cancer immunity, and recent studies have shown that depleting tumor-associated macrophages by inhibiting CSF1 receptor (CSF1R) is beneficial in preclinical models and nonmetastasizing human cancers. Michal Beffinger and colleagues evaluated the effect of CSFR1 inhibition on metastasis development in multiple models and revealed that CSFR1 inhibition exacer-bated metastasis to the lungs without affecting progression of the primary tumor. Increased metastasis was linked to decreased NK cell numbers, an indirect effect of CSF1R inhibition–induced loss of myeloid cells that transpresent IL-15 — an essential NK cell survival factor. While loss of NK cells increased seeding of metastases, it did not affect progression of established metastases. Addition of IL-15 to CSFR1 inhibition rescued NK cell numbers and reduced metastatic disease (see the accompanying image), suggesting that CSF1R inhibition should be combined with IL-15 to maintain normal NK cell numbers for prevention of metastatic disease.
CSF1R-dependent myeloid cells are required for NK-mediated control of metastasisMichal Beffinger, Paulino Tallón de Lara, Sònia Tugues, Marijne Vermeer, Yannick Montagnolo, Isabel Ohs, Virginia Cecconi, Giulia Lucchiari, Aron Gagliardi, Nikola Misljencevic, James Sutton, Roman Spörri, Burkhard Becher, Anurag Gupta, and Maries van den Broek http://jci.me/97792
j c i . o r g / t h i s - m o n t h j u n e 2 0 1 8 12
JCI Insight | Editor’s picks
neuroscience
Inflammatory monocytes linked to sepsis-associated cognitive dysfunctionSepsis is a life-threatening condition that accounts for substantial morbidity and mortality in hospitalized patients. A majority of those who survive will exhibit long-term cognitive dysfunction, the etiology of which is unknown and for which treatment options are limited. Graciela Andonegui, Erin Zelinski, and colleagues evaluated cognitive function in patients recovered from sepsis- associated delirium approximately one year after hospital discharge. Compared with control subjects, those who had sepsis-associated delirium scored lower on spatial and pattern recognition memory-associated tests. In mice, pneumonia-induced sepsis recapitulated human phenotypes, including multiorgan dysfunction, encephalopathy, and spatial memory defects. In both humans and mice, sepsis promoted increased expression of myeloid cell–recruiting chemokines, with murine models showing a notable increase in neutrophil and inflammatory CCR2+ monocytes (see the accompanying images) and microglia activation. Importantly, prevention of inflammatory monocyte recruitment in septic mice markedly reduced neuroinflammation and prevented cognitive impairment, suggesting that CCR2+ monocytes should be further explored as a therapeutic target.
Targeting inflammatory monocytes in sepsis-associated encephalopathy and long-term cognitive impairmentGraciela Andonegui, Erin L. Zelinski, Courtney L. Schubert, Derrice Knight, Laura A. Craig, Brent W. Winston, Simon C. Spanswick, Björn Petri, Craig N. Jenne, Janice C. Sutherland, Rita Nguyen, Natalie Jayawardena, Margaret M. Kelly, Christopher J. Doig, Robert J. Sutherland, and Paul Kubes http://jci.me/99364
aids/hiv
Serum biomarkers during early infection associate with viral reservoirStrategies to estimate, target, and eradicate the viral reservoir remain a major challenge for an HIV cure. The viral reservoir is established early in infection, and the cells harboring latent virus are variable among infected individuals. Jeffrey Teigler and colleagues collected and analyzed sera during acute and chronic phases of disease from antiretroviral therapy–naive (ART-naive) subjects and subjects who began ART early after HIV infection. Distinct inflammatory pathways were induced early after infection, and the levels of these markers correlated with viral load and the frequency of HIV-harboring peripheral blood mononuclear cells (PBMCs). Moreover, the levels of certain markers prior to ART associated with HIV levels after treatment, suggesting a link to the early HIV response and reservoir persistence. Together, these results identify markers with potential to predict viral reservoir and risk of disease resurgence after stopping ART.
Distinct biomarker signatures in HIV acute infection associate with viral dynamics and reservoir sizeJeffrey E. Teigler, Louise Leyre, Nicolas Chomont, Bonnie Slike, Ningbo Jian, Michael A. Eller, Nittaya Phanuphak, Eugène Kroon, Suteeraporn Pinyakorn, Leigh Anne Eller, Merlin L. Robb, Jintanat Ananworanich, Nelson L. Michael, Hendrik Streeck, Shelly J. Krebs, and RV254/RV217 study groups http://jci.me/98420
dermatology
Roseomonas mucosa is safe and improves atopic dermatitis in initial clinical trialAtopic dermatitis is an inflammatory skin disease characterized by decreased epidermal barrier function, susceptibility to Staphylococcus aureus infection, and immune dysfunction. The skin microbiome is altered in atopic dermatitis patients, and recently, the commensal Roseomonas mucosa was shown to improve atopic dermatitis–like phenotypes in murine models. Now, Ian Myles and colleagues have evaluated the effect and safety of topical administration of R. mucosa in a small cohort of adults and children with atopic dermatitis. Overall, in both adults and children, R. mucosa treatment was considered safe and reduced disease severity (see the accompanying image), the requirement for topical steroids, and S. aureus levels. This initial study supports further evaluation of topical R. mucosa for treating atopic dermatitis.
First-in-human topical microbiome transplantation with Roseomonas mucosa for atopic dermatitisIan A. Myles, Noah J. Earland, Erik D. Anderson, Ian N. Moore, Mark D. Kieh, Kelli W. Williams, Arhum Saleem, Natalia M. Fontecilla, Pamela A. Welch, Dirk A. Darnell, Lisa A. Barnhart, Ashleigh A. Sun, Gulbu Uzel, and Sandip K. Datta http://jci.me/120608
j c i . o r g / t h i s - m o n t h j u n e 2 0 1 813
JCI Insight | Editor’s picks
review
cardiology
Ubiquitination and deubiquitination regulate pulmonary fibrosis–associated pathways
Hypertrophy perturbs lysine acetylation and alters maturation of cardiac metabolismPatients with congenital heart disease (CHD) have a higher risk of heart failure, even when defects were surgically corrected during infancy. The factors that underlie CHD-associated heart failure are not fully understood, though metabolic alterations that are secondary to cardiac hypertrophy have been proposed. Arata Fukushima and colleagues analyzed right ventricular biopsies from patients with CHD for the presence of hypertrophy and lysine acetylation, which promotes a developmental shift from glycolysis to fatty acid oxidation for
cardiac energy after birth. Compared with those from nonhypertrophied hearts, biopsies from hypertrophic hearts had reduced acetylation and activation of key fatty acid β-oxidation enzymes. In a neonatal rabbit model, cardiac hypertrophy similarly decreased cardiac fatty acid oxidation and acetylation. These alterations associated with a decrease in expression of mitochondrial acetyltransferase GCN5L1 but had no effect on expression of deacetylase SIRT1. Gcn5l1 silencing in cardiomyocytes promoted hypertrophy and reduced acetylation of fatty oxidation enzymes,
supporting GCN5L1 as a key regulator of fatty acid oxidation in the heart.
Acetylation contributes to hypertrophy-caused maturational delay of cardiac energy metabolismArata Fukushima, Liyan Zhang, Alda Huqi, Victoria H. Lam, Sonia Rawat, Tariq Altamimi, Cory S. Wagg, Khushmol K. Dhaliwal, Lisa K. Hornberger, Paul F. Kantor, Ivan M. Rebeyka, and Gary D. Lopaschuk http://jci.me/99239
Idiopathic pulmonary fibrosis (IPF) is characterized by progressive fibroblast differentiation and extracellular matrix accumulation, ultimately resulting in irreversible damage to the lung and loss of function. Aberrant TGF-β activation is a known driver of the disease; however, many aspects of IPF pathogenesis and regulation are poorly defined. In this Review, Shuang Li et al. discuss the role of ubiquitin E3 ligases and deubiquitinating enzymes (DUBs) in the regulation of both TGF-β–dependent and –independent pathways that are associated with lung
fibrosis. Several small molecules are available to target IPF-associated E3 ligases, and DUBs and have potential to be used as a therapeutic approach for IPF.
Ubiquitination and deubiquitination emerge as players in idiopathic pulmonary fibrosis pathogenesis and treatmentShuang Li, Jing Zhao, Dong Shang, Daniel J. Kass, and Yutong Zhao http://jci.me/120362
j c i . o r g / t h i s - m o n t h j u n e 2 0 1 8 14
Current articles
RIPK3 mediates pathogenesis of experimental ventilator-induced lung injuryIlias I. Siempos, Kevin C. Ma, Mitsuru Imamura, Rebecca M. Baron, Laura E. Fredenburgh, Jin-Wong Huh, Jong-Seok Moon, Eli J. Finkelsztein, Daniel S. Jones, Michael Torres Lizardi, Edward J. Schenck, Stefan W. Ryter, Kiichi Nakahira, and Augustine M.K. Choi http://jci.me/97102
Endospanin-2 enhances skeletal muscle energy metabolism and running endurance capacitySteve Lancel, Matthijs K.C. Hesselink, Estelle Woldt, Yves Rouillé ,Emilie Dorchies, Stephane Delhaye, Christian Duhem, Quentin Thorel, Alicia Mayeuf-Louchart, Benoint Pourcet, Valérie Montel, Gert Schaart, Nicolas Beton, Florence Picquet, Olivier Briand, Jean Pierre Salles, Hélène Duez, Patrick Schrauewen, Bruno Bastide, Bernard Bailleul, Bart Staels, and Yasmine Sebti http://jci.me/98081
Neutrophils are essential for induction of vaccine-like effects by antiviral monoclonal antibody immunotherapiesMar Naranjo-Gomez, Jennifer Lambour, March Piechaczyk, and Mireia Pelegrin http://jci.me/97339
Unexpected kidney-restricted role for IL-17 receptor signaling in defense against systemic Candida albicans infectionKritika Ramani, Chetan V. Jawale, Akash H. Verma, Bianca M. Coleman, Jay K. Kolls, and Partha S. Biswas http://jci.me/98241
Selection of phage-displayed accessible recombinant targeted antibodies (SPARTA): methodology and applicationsSara D’Angelo, Fernanda I. Staquicini, Fortunato Ferrara, Daniela I. Staquicini, Geetanjali Sharma, Christy A. Tarleton, Huynh Nguyen, Leslie A. Naranjo, Richard L. Sidman, Wadih Arap, Andrew R.M. Bradbury, and Renata Pasqualini http://jci.me/98305
pDCs in lung and skin fibrosis in a bleomycin-induced model and patients with systemic sclerosisSuzanne Kafaja, Isela Valera, Anagha A. Divekar, Rajan Saggar, Fereidoun Abtin, Daniel E. Furst, Dinesh Khanna, and Ram Raj Singh http://jci.me/98380
Universal monitoring of minimal residual disease in acute myeloid leukemia p. 11Elaine Coustan-Smith, Guangchun Song, Sheila Shurtleff, Allen Eng-Juh Yeoh, Wee Joo Chng, Siew Peng Chen,
Jeffrey E. Rubnitz, Ching-Hon Pui, James R. Downing, and Dario Campana http://jci.me/98561
Phosphodiesterase 2A as a therapeutic target to restore cardiac neurotransmission during sympathetic hyperactivityKun Liu, Dan Li, Guoliang Hao, David McCaffary, Oliver Neely, Lavinia Woodward, Demetris Ioannides, Chieh-Ju Lu, Marcella Brescia, Manuela Zaccolo, Harikrishna Tandri, Olujimi A. Ajijola, Jeffrey L. Ardell, Kalyanam Shivkumar, and David J. Paterson http://jci.me/98694
Efficient exon skipping of SGCG mutations mediated by phosphorodiamidate morpholino oligomersEugene J. Wyatt, Alexis R. Demonbreun, Ellis Y. Kim, Megan J. Puckelwartz, Andy H. Vo, Lisa M. Dellefave-Castillo, Quan Q. Gao, Mariz Vainzof, Rita C.M. Pavanello, Mayana Zatz, and Elizabeth M. McNally http://jci.me/99357
Targeting inflammatory monocytes in sepsis-associated encephalopathy and long-term cognitive impairment p. 12
Graciela Andonegui, Erin L. Zelinski, Courtney L. Schubert, Derrice Knight, Laura A. Craig, Brent W. Winston, Simon C. Spanswick, Björn Petri, Craig N. Jenne, Janice C. Sutherland, Rita Nguyen, Natalie Jayawardena, Margaret M. Kelly, Christopher J. Doig, Robert J. Sutherland, and Paul Kubes http://jci.me/99364
Collagen content of normal skin
Myosin fiber types in muscle
SGCG-mutant myotubes and nuclei
j c i . o r g / t h i s - m o n t h j u n e 2 0 1 815
Current articles
Parabiosis and single-cell RNA sequencing reveal a limited contribution of monocytes to myofibroblasts in kidney fibrosis p. 10Rafael Kramann, Flavia Machado, Haojia Wu, Tetsuro Kusaba, Konrad Hoeft, Rebekka K. Schneider, and Benjamin D. Humphreys http://jci.me/99561
Prediction of acute GVHD and relapse by metabolic biomarkers after allogeneic hematopoietic stem cell transplantation p. 11Xiaojin Wu, Yiyu Xie, Chang Wang, Yue Han, Xiebing Bao, Shoubao Ma, Ahmet Yilmaz, Bingyu Yang, Yuhan Ji,
Jinge Xu, Hong Liu, Suning Chen, Jianying Zhang, Jianhua Yu, and Depei Wu http://jci.me/99672
First-in-human topical microbiome transplantation with Roseomonas mucosa for atopic dermatitis p. 12Ian A. Myles, Noah J. Earland, Erik D. Anderson, Ian N. Moore, Mark D. Kieh, Kelli W. Williams, Arhum Saleem, Natalia M. Fontecilla, Pamela A. Welch, Dirk A. Darnell, Lisa A. Barnhart, Ashleigh A. Sun, Gulbu Uzel, and Sandip K. Datta http://jci.me/120608
Implementation of a cardiac PET stress program: comparison of outcomes to the preceding SPECT eraStacey Knight, David B. Min, Viet T. Le, Kent G. Meredith, Ritesh Dhar, Santanu Biswas, Kurt R. Jensen, Steven M. Mason, Jon-David Ethington, Donald L. Lappe, Joseph B. Muhlestein, Jeffrey L. Anderson, and Kirk U. Knowlton http://jci.me/120949
Unique features and clinical importance of acute alloreactive immune responsesCharlotte F. Inman, Suzy A. Eldershaw, Joanne E. Croudace, Nathaniel J. Davies, Archana Sharma-Oates, Tanuja Rai, Hayden Pearce, Mirjana Sirovica, Y.L. Tracey Chan, Kriti Verma, Jianmin Zuo, Sandeep Nagra, Francesca Kinsella, Jane Nunnick, Rasoul Amel-Kashipaz, Charles Craddock, Ram Malladi, and Paul Moss http://jci.me/97219
CSF1R-dependent myeloid cells are required for NK-mediated control of metastasis p. 11Michal Beffinger, Paulino Tallón de Lara, Sònia Tugues, Marijne Vermeer, Yannick Montagnolo, Isabel Ohs, Virginia Cecconi, Giulia Lucchiari, Aron Gagliardi, Nikola Misljencevic, James Sutton, Roman Spörri, Burkhard Becher, Anurag Gupta, and Maries van den Broek http://jci.me/97792
Distinct biomarker signatures in HIV acute infection associate with viral dynamics and reservoir size p. 12Jeffrey E. Teigler, Louise Leyre, Nicolas Chomont, Bonnie Slike, Ningbo Jian, Michael A. Eller, Nittaya Phanuphak, Eugène Kroon, Suteeraporn Pinyakorn, Leigh Anne Eller, Merlin L. Robb, Jintanat Ananworanich, Nelson L. Michael, Hendrik Streeck, Shelly J. Krebs, and RV254/RV217 study groups http://jci.me/98420
Glioblastoma-targeted CD4+ CAR T cells mediate superior antitumor activityDongrui Wang, Brenda Aguilar, Renate Starr, Darya Alizadeh, Alfonso Brito, Aniee Sarkissian, Julie R. Ostberg, Stephen J. Forman, and Christine E. Brown http://jci.me/99048
Exosome-delivered microRNAs promote IFN-α secretion by human plasmacytoid DCs via TLR7Valentina Salvi, Veronica Gianello, Sara Busatto, Paolo Bergese, Laura Andreoli, Ugo D’Oro, Alessandra Zingoni, Angela Tincani, Silvano Sozzani, and Daniela Bosisio http://jci.me/98204
Relapsed glioblastoma
Proximal tubular epithelial cells
Bile duct epithelium
j c i . o r g / t h i s - m o n t h j u n e 2 0 1 8 16
Flip issue to read JCI content.
Acetylation contributes to hypertrophy-caused maturational delay of cardiac energy metabolism p. 13Arata Fukushima, Liyan Zhang, Alda Huqi, Victoria H. Lam, Sonia Rawat, Tariq Altamimi, Cory S. Wagg, Khushmol K. Dhaliwal, Lisa K. Hornberger, Paul F. Kantor, Ivan M. Rebeyka, and Gary D. Lopaschuk http://jci.me/99239
Aquaporin-1 regulates platelet procoagulant membrane dynamics and in vivo thrombosisEjaife O. Agbani, Christopher M. Williams, Yong Li, Marion T.J. van den Bosch, Samantha F. Moore, Adele Mauroux, Lorna Hodgson, Alan S. Verkman, Ingeborg Hers, and Alastair W. Poole http://jci.me/99062
Heat shock protein peptide complex-96 vaccination for newly diagnosed glioblastoma: a phase I, single-arm trialNan Ji, Yang Zhang, Yunpeng Liu, Jian Xie, Yi Wang, Shuyu Hao, and Zhixian Gao http://jci.me/99145
VEGF/VEGFR2 blockade does not cause retinal atrophy in AMD-relevant modelsDa Long, Yogita Kanan, Jikui Shen, Sean F. Hackett, Yuanyuan Liu, Zibran Hafiz, Mahmood Kahn, Lili Lu, and Peter A. Campochiaro http://jci.me/120231
Cytometry TOF identifies alveolar macrophage subtypes in acute respiratory distress syndromeEric D. Morrell, Alice Wiedeman, S. Alice Long, Sina A. Gharib, T. Eoin West, Shawn J. Skerrett, Mark M. Wurfel, and Carmen Mikacenic http://jci.me/99281
Elevated hepatic expression of H19 long noncoding RNA contributes to diabetic hyperglycemiaNa Zhang, Tingting Geng, Zhangsheng Wang, Ruling Zhang, Tiefeng Cao, Joao Paulo Camporez, Shi-Ying Cai, Ya Liu, Luisa Dandolo, Gerald I. Shulman, Gordon G. Carmichael, Hugh S. Taylor, and Yingqun Huang http://jci.me/120304
Fatty acid receptor modulator PBI-4050 inhibits kidney fibrosis and improves glycemic controlYan Li, Sungjin Chung, Zhilian Li, Jessica Overstreet, Lyne Gagnon, Brigitte Grouix, Martin Leduc, Pierre Laurin, Ming-Zhi Zhang, and Raymond C. Harris http://jci.me/120365
TLR-adjuvanted nanoparticle vaccines differentially imprint the quality and longevity of responses to malaria antigen Pfs25Elizabeth A Thompson, Sebastian Ols, Kazutoyo Miura, Kelly Rausch, David L. Narum, Mats Spångberg,
Michal Juraska, Ulrike Wille-Reece, Amy Weiner, Randall F. Howard, Carole A. Long, Patrick E. Duffy, Lloyd Johnston, Conlin P. O’Neil, and Karin Loré http://jci.me/120692
ReviewUbiquitination and deubiquitination emerge as players in idiopathic pulmonary fibrosis pathogenesis and treatment p. 13Shuang Li, Jing Zhao, Dong Shang, Daniel J. Kass, and Yutong Zhao http://jci.me/120362
Rodent eye fundus
Undifferentiated cardiomyocytes
Renal interstitial fibrosis