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

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Weihong Song

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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

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Staff EditorsExecutive EditorSarah C. Jackson

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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: 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.

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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

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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

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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

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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

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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

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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

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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

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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

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For JCI InsightEditorHoward A. RockmanAssociate EditorsRodger A. Liddle, Yiping YangExecutive EditorSarah C. JacksonScience EditorCorinne Williams

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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

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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

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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

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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

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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

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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

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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

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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

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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,

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Rodent eye fundus

Undifferentiated cardiomyocytes

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