this month...benny j. chen ju chen jun chen marie-françoise chesselet vivian g. cheung raymond...
TRANSCRIPT
jci.org/this-month
Self-reactive T cells contribute to cardiac healing 2
Peptide modification improves intramuscular ASO delivery 3
DNA damage response protein coordinates kidney repair 4
Rethinking weight and diet guidelines in pregnancy 5
Vaccination-induced correlates of decreased HIV-1 risk 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.
November 2019
This Month
ANGPTL4 destabilizes the retinal vasculature in diabetic macular edema p. 2
Journal of Clinical Investigation Consulting Editors
Soman N. Abraham
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Jun Chen
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Gianpietro Dotti
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Connie J. Eaves
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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.
Sharon Gerecht
Stanton L. Gerson
Robert E. Gerszten
Todd Golde
Sherita Golden
Stanley Goldfarb
Larry B. Goldstein
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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
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
David A. Kass
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
Shelby Kutty
Chulan Kwon
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
Kieren A. Marr
Jack Martin
Steven O. Marx
Rodger P. McEver
Elizabeth McNally
Cornelis J. Melief
Shlomo Melmed
George Michalopoulos
Jeffrey H. Miner
Peter J. Mohler
Jeffery 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
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. Ptáček
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
Ryan Riddle
Sarah A. Robertson
Howard A. Rockman
Paul B. Rosenberg
Theodora S. Ross
Marc E. Rothenberg
Anil Rustgi
Scheherazade Sadegh-Nasseri
J. Evan Sadler
Junichi Sadoshima
Akira Sawa
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
Mingzhao Xing
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 n o v e m b e r 2 0 1 9 1
For the JCIEditorRexford S. Ahima
Deputy EditorsArturo Casadevall, Gregg L. Semenza, Gordon F. Tomaselli
Associate EditorsMark E. Anderson, Mary Y. Armanios, Nilofer S. Azad, Joel N. Blankson, William R. Bishai, Robert A. Brodsky, Peter A. Calabresi, Thomas L. Clemens, Franco R. D’Alessio, Ted M. Dawson, Angelo M. DeMarzo, Stephen Desiderio, Mark Donowitz, Andrew P. Feinberg, Paul M. Hassoun, Maureen R. Horton, Elizabeth M. Jaffee, Mariana J. Kaplan, Marikki Laiho, Leo Luznik, Marcela V. Maus, Timothy H. Moran, Laszlo Nagy, William Nelson, Brian O’Rourke, Ben Ho Park, Jonathan D. Powell, Thomas C. Quinn, Hamid Rabb, Jean-Pierre Raufman, Stuart C. Ray, Linda Smith Resar, Jeffrey D. Rothstein, Jonathan Schneck, Akrit S. Sodhi, Charlotte J. Sumner, Simeon I. Taylor, Robert G. Weiss, Sarah J. Wheelan, Marsha Wills-Karp
Editorial Advisory GroupPeter Agre, Carol W. Grieder, Diane E. Griffin, Paul B. Rothman, David Valle
BiostatisticianEliseo Guallar
Computational BiologistPatrick Cahan
JCI ScholarsJ. David Peske, Laura Sena
Staff EditorsExecutive EditorSarah C. Jackson
Senior Science EditorCorinne Williams
Science EditorElyse Dankoski
Assistant Science EditorLisa Conti
Editor at LargeUshma S. Neill
Editorial InternBouchra Taib
JCI This Month ISSN 2324-7703 (print);ISSN 2325-4556 (online)
For the full JCI online: jci.me/129/11
This MonthNovember 2019
Contact the JCI and JCI Insight2015 Manchester Road, Ann 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.
(ASCI) indicates corresponding authors who are ASCI members.
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
Nilofer S. Azad, MD, Associate Editor, is an Associate Professor of Oncology and a mem-ber of the Gastrointestinal Oncology Program within the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University. Dr. Azad is the principal investigator of numerous early-phase clinical trials in solid tumors and gastrointestinal cancers. She has been a member of the National Cancer Insti-tute’s Colon Cancer Task Force and the advi-sory boards of the Biden Cancer Initiative and the Cholangiocarcinoma Foundation, among others. Her laboratory is currently investigating
drugs that work through epigenetic mechanisms, as well as epigenetic molec-ular differences in tumors that may change the efficacy of treatment, and the intersection of these agents with immunotherapy.
Publication highlights
Kurzrock R, Ball DW, Zahurak ML, Nelkin BD, Subbiah V, Ahmed S, O’Connor A, Karunsena E, Parkinson RM, Bishop JA, Ha Y, Sharma R, Gocke CD, Zinner R, Rudek MA, Sherman SI, Azad NS. A phase I trial of the VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced solid tumors and differentiated thyroid cancers. Clin Cancer Res. 2019;25(18):5475–5484.
Lee V, Wang J, Zahurak M, Gootjes E, Verheul HM, Parkinson R, Kerner Z, Sharma A, Rosner G, De Jesus-Acosta A, Laheru D, Le DT, Oganesian A, Lilly E, Brown T, Jones P, Baylin S, Ahuja N, Azad N. A Phase I trial of a guadecitabine (SGI-110) and irinotecan in metastatic colorectal cancer patients previously exposed to irinotecan. Clin Cancer Res. 2018;24(24):6160–6167.
Shroff RT, Yarchoan M, O’Connor A, Gallagher D, Zahurak ML, Rosner G, Ohaji C, Sartorius-Mergenthaler S, Parkinson R, Subbiah V, Zinner R, Azad NS. The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma. Br J Cancer. 2017;116(11):1402–1407.
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research
Editor’s picks
ophthalmologyon the jci cover
cardiology
Autoreactive T cells assume pro-repair roles in the infarcted heart
Elevated ANGPTL4 contributes to vascular destabilization in diabetic macular edemaAnti-VEGF treatments have become a standard of care for patients with diabetic macular edema (DME), a complication of diabetes characterized by progressive damage to the retinal vasculature, leading to vascular leakage and visual impairment. The goal of anti-VEGF therapies is to prevent the leakage of fluid from the injured blood vessels that produces edema; however, in many DME patients, anti-VEGF therapy does not substantially improve vision. In this issue of the JCI, Akrit Sodhi et al. draw upon recent observations linking angiopoietin-like 4 (ANGPTL4) to retinal hyperpermeability to explore this protein’s role in DME. Their work reveals that ANGPTL4 and VEGF work in concert to destabilize the retina’s vasculature. The researchers report that ANGPTL4 levels are increased in the aqueous fluid of DME patients and diabetic mouse models. Further, they determined that ANGPTL4’s binding to neuropilin 1 and 2 on endothelial cells disrupts vascular barriers via activation of RhoA/ROCK signaling, a mechanism that occurs in parallel to VEGF’s effects on vascular permeability. Treatment with a soluble fragment of neuropilin 1 blocked ANGPTL4-induced vascular leakage in diabetic animals, supporting a potential therapeutic avenue for interfering in ANGPTL4- mediated mechanisms in DME. This issue’s cover depicts the pathological leakage of the retinal vasculature in a patient with diabetic eye disease. Image courtesy of Wilmer Photography; modified by Isabella and Adriana Sodhi.
Angiopoietin-like 4 binds neuropilins and cooperates with VEGF to induce diabetic macular edemaAkrit Sodhi, Tao Ma, Deepak Menon, Monika Deshpande, Kathleen Jee, Aumreetam Dinabandhu, Jordan Vancel, Daoyuan Lu, and Silvia Montaner http://jci.me/120879
Myocardial infarction (MI) drives T cell priming and proliferation in the heart-draining lymph nodes. These MI-induced T cells include both inflammation-resolving FOXP3+ Tregs and conventional T cells, though their specific functions in cardiac repair remain unclear. Max Rieckmann and colleagues identified myosin heavy chain α (MYHCA) as a cardiac self-antigen that activates CD4+ Th cells following experimental MI. MYHCA-specific Th cells accumulated in the infarct zone and acquired Treg-like features, indicating that the injured myocardium recruits autoreactive Th cells and facilitates the conversion to pro-repair phenotypes. Hearts enriched in MYHCA-specific T cells had improved outcomes one week after experimental MI, and adoptive transfer of these cells into healthy mice did not produce pathogenic effects. The researchers further revealed the presence of CD4+ and FOXP3+ T cells in infarcted postmortem hearts. In the related Commentary, Ziad Mallat calls for further investigation of the cells’ therapeutic potential to aid in recovery from cardiac injury.
Myocardial infarction triggers cardioprotective antigen-specific T helper cell responsesMax Rieckmann, Murilo Delgobo, Chiara Gaal, Lotte Büchner, Philipp Steinau, Dan Reshef, Cristina Gil-Cruz, Ellis N. ter Horst, Malte Kircher, Theresa Reiter, Katrin G. Heinze, Hans W.M. Niessen, Paul A.J. Krijnen, Anja M. van der Laan, Jan J. Piek, Charlotte Koch, Hans-Jürgen Wester, Constantin Lapa, Wolfgang R. Bauer, Burkhard Ludewig, Nir Friedman, Stefan Frantz, Ulrich Hofmann, and Gustavo Campos Ramos http://jci.me/123859
Related CommentaryRegulating heart repair with cardiac-specific T lymphocytesZiad Mallat http://jci.me/132441
j c i . o r g / t h i s - m o n t h n o v e m b e r 2 0 1 9 3
JCI | Research: Editor’s picks
oncology
Reversing diphthamide pathway impairment restores efficacy of CD123-targeted cancer therapyTagraxofusp, a CD123-targeting therapy fused to a truncated diphtheria toxin payload, is approved for blastic plasmacytoid dendritic cell neoplasm (BPDCN) and under investigation for other hematologic cancers. The factors contributing to tagraxofusp treatment response remain unclear. Katsuhiro Togami, Timothy Pastika, Jason Stephansky, et al., determined that tagraxofusp resistance in patient-derived BPDCN and acute myeloid leukemia (AML) cells was not driven by CD123 loss. Rather, cells displayed resistance to diphtheria toxin due to methylation and downregulation
of DPH1, a critical enzyme in the diphthamide synthesis pathway. In tagraxofusp-resistant AML cells, inhibiting DNA methyltransferase rescued DPH1 expression and restored response to tagraxofusp. Further, cotreating BPDCN patient-derived xenograft models with the DNA methyltransferase inhibitor azacitidine and tagraxofusp prolonged survival relative to either treatment alone. In the related Commentary, Lukasz Gondek puts these data into clinical context, highlighting an upcoming phase I trial of azacitidine/tagraxofusp combination treatment in myeloid malignancies.
DNA methyltransferase inhibition overcomes diphthamide pathway deficiencies underlying CD123-targeted treatment resistanceKatsuhiro Togami, Timothy Pastika, Jason Stephansky, Mahmoud Ghandi, Amanda L. Christie, Kristen L. Jones, Carl A. Johnson, Ross W. Lindsay, Christopher L. Brooks, Anthony Letai, Jeffrey W. Craig, Olga Pozdnyakova, David M. Weinstock, Joan Montero, Jon C. Aster, Cory M. Johannessen, and Andrew A. Lane http://jci.me/128571
Related CommentaryHitting the bullseye with a nonlethal payload: resistance in CD123-positive malignanciesLukasz P. Gondek http://jci.me/132443
muscle biology
Cell-penetrating peptides improve ASO delivery and myotonic dystrophy correctionMyotonic dystrophy (DM1) is caused by CUG repeats in the DM1 protein kinase (DMPK) transcript that sequester CUG-targeting RNA binding factors within nuclear foci and lead to abnormal splicing in multiple genes. Antisense oligonucleotide (ASO) strategies have successfully reversed DM1 phenotypes in mouse models, but ASO delivery and uptake in muscle tissue remains an obstacle to clinical success. To improve drug distribution, teams led by Denis Furling and Matthew Wood collaborated to test a DM1-reversing ASO conjugated to the cell-penetrating peptide Pip6a. Low doses of the
Peptide-conjugated oligonucleotides evoke long-lasting myotonic dystrophy correction in patient-derived cells and miceArnaud F. Klein, Miguel A. Varela, Ludovic Arandel, Ashling Holland, Naira Naouar, Andrey Arzumanov, David Seoane, Lucile Revillod, Guillaume Bassez, Arnaud Ferry, Dominic Jauvin, Genevieve Gourdon, Jack Puymirat, Michael J. Gait, Denis Furling, and Matthew J.A. Wood http://jci.me/128205
Related CommentaryBetter living through peptide-conjugated chemistry: next-generation antisense oligonucleotidesElizabeth M. McNally (ASCI) and Brian D. Leverson http://jci.me/131933
ASO-peptide conjugate produced long-lasting reversal of splicing defects, transcriptional alterations, and myotonia in mouse models. The conjugated ASO also corrected splicing defects and other molecular alterations present in patient-derived DM1 muscle cells (compare ASO-treated cells, left, with DM1-derived cells, right, in the associated image). In the accompanying Commentary, Elizabeth McNally and Brian Leverson outline opportunities to use peptide-conjugated ASOs in DM1 and other diseases where tissue penetration remains a barrier to successful ASO therapy.
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JCI | Research: Editor’s picks
nephrology
ATR-mediated DNA repair reduces pathological remodeling after kidney injuryMany forms of kidney injury lead to activation of the DNA damage response (DDR), which detects and mends breaks in DNA strands in coordination with the cell cycle. Following up on recent work associating kidney fibrosis with G2/M cell-cycle arrest, Seiji Kishi, Craig Brooks, Joseph Bonventre and colleagues interrogated the role of the DDR kinase ATR in pathogenic responses to kidney injury. In patients with chronic kidney disease and in cisplatin-exposed human kidney organoids, renal damage was associated with increased ATR activation (see the associated image). Ablation of ATR in renal proximal tubule cells (RPTCs) exacerbated cisplatin- or ischemia-induced kidney injury in mouse models. Following cisplatin injury, the researchers observed more RPTCs in the G2/M phase in ATR-deficient mice compared with WT mice. The accompanying Commentary by Bruce Molitoris discusses the implications of ATR’s critical role in protecting against maladaptive repair of kidney injuries.
Proximal tubule ATR regulates DNA repair to prevent maladaptive renal injury responsesSeiji Kishi, Craig R. Brooks, Kensei Taguchi, Takaharu Ichimura, Yutaro Mori, Akinwande Akinfolarin, Navin Gupta, Pierre Galichon, Bertha C. Elias, Tomohisa Suzuki, Qian Wang, Leslie Gewin, Ryuji Morizane, and Joseph V. Bonventre (ASCI) http://jci.me/122313
Related CommentaryDNA damage response protects against progressive kidney diseaseBruce A. Molitoris (ASCI) http://jci.me/131171
Calcium channel Orai1 enhances Th17 cell–mediated progressive kidney injuryIL-17–expressing T helper cells (Th17 cells) contribute to delayed recovery from acute kidney injury (AKI) and its progression to chronic kidney disease. High-salt diet has been shown to reactivate Th17 cells following ischemic renal injury, driving increased fibrosis and neutrophil infiltration. Purvi Mehrotra and colleagues determined that the store-operated calcium entry channel Orai1 contributes to Th17 cell activation and maladaptive renal repair. They observed that both Orai1-expressing and Th17 cells were elevated in the peripheral blood of AKI
patients. Orai1 activity enhanced intracellular calcium flux and IL-17 expression in salt-stimulated T cells isolated from post-AKI rats. In contrast, when rats were fed a high-salt diet following AKI, Orai1 inhibition attenuated the severity of progressive renal impairment. Together, the results suggest that Orai1 expression mediates salt-driven Th17 cell activation. Sanjeev Noel’s accompanying Commentary describes the potential of Orai1 inhibitors to become interventions for the AKI–to–chronic kidney disease transition.
Calcium channel Orai1 promotes lymphocyte IL-17 expression and progressive kidney injuryPurvi Mehrotra, Michael Sturek, Javier A. Neyra, and David P. Basile http://jci.me/126108
Related CommentaryOrai1: CRACing the Th17 response in AKISanjeev Noel http://jci.me/131935
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JCI | Research: Editor’s picks
clinical medicine
Optimizing the immunogenicity of a prime-boost HIV vaccine regimenThe most effective demonstration of an HIV vaccine to date was RV144, which combined four injections of canarypox-vectored vaccine with two injections of recombinant gp120 protein (AIDSVAX B/E). Although RV144 achieved only moderate efficacy, the trial provided clues for optimizing prime-boost HIV vaccine regimens. In a phase I trial of 104 HIV-negative participants, Nadine Rouphael and colleagues investigated the safety and immunogenicity of regimens combining AIDSVAX B/E with a DNA-HIV vaccine, an immunogenic alternative to the original vectored vaccine. Whereas RV144 induced potentially protective antibody responses six months after the final injection, the DNA-HIV/protein combinations induced higher-magnitude and persistent anti-HIV antibody responses within six weeks of the initial treatment. The study also determined that immunologic responses to regimens with DNA priming/protein boosting were superior to protein priming/DNA boosting. In the accompanying Commentary, Nelson Michael supports the study’s conclusion that these regimens are safe and immunogenic, providing a rationale for a modified strategy for HIV vaccine efficacy trials.
DNA priming and gp120 boosting induces HIV-specific antibodies in a randomized clinical trialNadine G. Rouphael, Cecilia Morgan, Shuying S. Li, Ryan Jensen, Brittany Sanchez, Shelly Karuna, Edith Swann, Magdalena E. Sobieszczyk, Ian Frank, Gregory J. Wilson, Hong-Van Tieu, Janine Maenza, Aliza Norwood, James Kobie, Faruk Sinangil, Giuseppe Pantaleo, Song Ding, M. Juliana McElrath, Stephen C. De Rosa, David C. Montefiori, Guido Ferrari, Georgia D. Tomaras, Michael C. Keefer, and the HVTN 105 Protocol Team and the NIAID HIV Vaccine Trials Network http://jci.me/128699
Related CommentarySimplified steps to heterologous prime-boost HIV vaccine development?Nelson L. Michael http://jci.me/132440
Evidence to improve nutritional and weight gain guidelines in pregnancyThe Institute of Medicine’s guidelines for weight gain and nutrition during pregnancy are not tailored to women with obesity, two-thirds of whom gain excess weight during pregnancy that poses a risk to mother and child. To improve recommendations for this group, Jasper Most and colleagues studied weight gain, caloric intake, and energy expenditure in 54 pregnant women with obesity. Their report indicates that increased caloric intake is not required to support a healthy pregnancy in the setting of obesity, contradicting current recommendations. The researchers also observed that gestational weight gain due to increased blood volume, expansion of breast tissue, and fetal mass accounted for the 5–9 kg of weight gain that is currently recommended. Thus, for women in the study, even modest increases in daily calorie consumption led to excess weight gain. Sarah Comstock’s accompanying Commentary supports using this evidence as a step toward improving maternal health guidelines.
Evidence-based recommendations for energy intake in pregnant women with obesityJasper Most, Marshall St Amant, Daniel S. Hsia, Abby D. Altazan, Diana M. Thomas, L. Anne Gilmore, Porsha M. Vallo, Robbie A. Beyl, Eric Ravussin, and Leanne M. Redman http://jci.me/130341
Related CommentaryTime to change weight gain recommendations for pregnant women with obesitySarah S. Comstock http://jci.me/131932
aids/hiv
Vaccine-induced Fcγ receptor recruitment and IgG3 linked to lower HIV-1 riskThe most recently completed HIV-1 efficacy trial, HVTN 505, did not demonstrate overall efficacy; however, there was evidence that vaccination exerted selective pressure on the infecting viruses. Led by Peter Gilbert and Georgia Tomaras, Scott Neidich, Youyi Fong, Shuying Li, et al. investigated the immune correlates of HIV-1 risk in this trial to improve the design of future vaccine regimens, focusing on antibody-mediated Fcγ receptor recruitment, antibody-dependent cellular phagocytosis, and anti-Env IgG3. Their analyses indicate that increases in all three variables were inversely correlated with HIV-1 acquisition, with antibody-mediated Fcγ receptor binding also correlating with decreased viral load. A computational analysis revealed that combined measurements of antibody and CD8+ T cells best predicted HIV-1 acquisition. In the related Commentary, Tysheena Charles and Cynthia Derdeyn highlight how insights into antibody and immune system interactions may improve the study and design of future vaccines.
Antibody Fc effector functions and IgG3 associate with decreased HIV-1 riskScott D. Neidich, Youyi Fong, Shuying S. Li, Daniel E. Geraghty, Brian D. Williamson, William Chad Young, Derrick Goodman, Kelly E. Seaton, Xiaoying Shen, Sheetal Sawant, Lu Zhang, Allan C. deCamp, Bryan S. Blette, Mengshu Shao, Nicole L. Yates, Frederick Feely, Chul-Woo Pyo, Guido Ferrari, HVTN 505 Team, Ian Frank, Shelly T. Karuna, Edith M. Swann, John R. Mascola, Barney S. Graham, Scott M. Hammer, Magdalena E. Sobieszczyk, Lawrence Corey, Holly E. Janes, M. Juliana McElrath, Raphael Gottardo, Peter B. Gilbert, and Georgia D. Tomaras http://jci.me/126391
Related CommentaryStriking a balance in an antibody network: a roadmap for HIV-1 vaccinesTysheena P. Charles and Cynthia A. Derdeyn http://jci.me/132535
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JCI | Features
viewpoint
How to fight skyrocketing prescription drug pricing in AmericaHealth care costs — including the prices of medical treatments, lab tests, hospital stays, and doctor visits — are greater in the United States than in any of the countries considered its economic peers. The staggering prices of prescription drugs command particular attention in discussions about improving US health policies. In a Viewpoint, Arthur Caplan emphasizes Americans’ right to affordably access life-saving treatments and offers serious solutions to America’s drug-pricing problems. He argues that rather than relying on piecemeal efforts to curb out-of-control prices, a consolidated federal agency should do the bargaining for drug pricing in the United States. The accompanying image, based on Leslie Thrasher’s Tipping the Scales, suggests that government has a role in moderating prescription drug costs.
Obtaining prescription drugs in America: it’s no bargainArthur L. Caplan http://jci.me/132977
A D V E R T I S E M E N T
j c i . o r g / t h i s - m o n t h n o v e m b e r 2 0 1 9 7
Current research articles
aids/hivGlycan-dependent HIV-specific neutralizing antibodies bind to cells of uninfected individualsJana Blazkova, Eric W. Refsland, Katherine E. Clarridge, Victoria Shi, J. Shawn Justement, Erin D. Huiting, Kathleen R. Gittens, Xuejun Chen, Stephen D. Schmidt, Cuiping Liu, Nicole Doria-Rose, John R. Mascola, Alonso Heredia, Susan Moir, and Tae-Wook Chun http://jci.me/125955
Antibody Fc effector functions and IgG3 associate with decreased HIV-1 risk p. 5Scott D. Neidich, Youyi Fong, Shuying S. Li, Daniel E. Geraghty, Brian D. Williamson, William Chad Young, Derrick Goodman, Kelly E. Seaton, Xiaoying Shen, Sheetal Sawant, Lu Zhang, Allan C. deCamp, Bryan S. Blette, Mengshu Shao, Nicole L. Yates, Frederick Feely, Chul-Woo Pyo, Guido Ferrari, HVTN 505 Team, Ian Frank, Shelly T. Karuna, Edith M. Swann, John R. Mascola, Barney S. Graham, Scott M. Hammer, Magdalena E. Sobieszczyk, Lawrence Corey, Holly E. Janes, M. Juliana McElrath, Raphael Gottardo, Peter B. Gilbert, and Georgia D. Tomaras http://jci.me/126391
HIV-1 in lymph nodes is maintained by cellular proliferation during antiretroviral therapyWilliam R. McManus, Michael J. Bale, Jonathan Spindler, Ann Wiegand, Andrew Musick, Sean C. Patro, Michele D. Sobolewski, Victoria K. Musick, Elizabeth M. Anderson, Joshua C. Cyktor, Elias K. Halvas, Wei Shao, Daria Wells, Xiaolin Wu, Brandon F. Keele, Jeffrey M. Milush, Rebecca Hoh, John W. Mellors, Stephen H. Hughes, Steven G. Deeks, John M. Coffin, and Mary F. Kearney http://jci.me/126714
cardiologyMyocardial infarction triggers cardioprotective antigen-specific T helper cell responses p. 2Max Rieckmann, Murilo Delgobo, Chiara Gaal, Lotte Büchner, Philipp Steinau, Dan Reshef, Cristina Gil-Cruz, Ellis N. ter Horst, Malte Kircher, Theresa Reiter, Katrin G. Heinze, Hans W.M. Niessen, Paul A.J. Krijnen, Anja M. van der Laan, Jan J. Piek, Charlotte Koch, Hans-Jürgen Wester, Constantin Lapa, Wolfgang R. Bauer, Burkhard Ludewig, Nir Friedman, Stefan Frantz, Ulrich Hofmann, and Gustavo Campos Ramos http://jci.me/123859
Atrial fibrillation risk loci interact to modulate Ca2+-dependent atrial rhythm homeostasisBrigitte Laforest, Wenli Dai, Leonid Tyan, Sonja Lazarevic, Kaitlyn M. Shen, Margaret Gadek, Michael T. Broman, Christopher R. Weber, and Ivan P. Moskowitz (ASCI) http://jci.me/124231
clinical medicineAge-dependent SMN expression in disease-relevant tissue and implications for SMA treatmentDaniel M. Ramos, Constantin d’Ydewalle, Vijayalakshmi Gabbeta, Amal Dakka, Stephanie K. Klein, Daniel A. Norris, John Matson, Shannon J. Taylor, Phillip G. Zaworski, Thomas W. Prior, Pamela J. Snyder, David Valdivia, Christine L. Hatem, Ian Waters, Nikhil Gupte, Kathryn J. Swoboda, Frank Rigo, C. Frank Bennett, Nikolai Naryshkin, Sergey Paushkin, Thomas O. Crawford, and Charlotte J. Sumner (ASCI) http://jci.me/124120
T cell repertoire remodeling following post-transplant T cell therapy coincides with clinical responseCorey Smith, Dillon Corvino, Leone Beagley, Sweera Rehan, Michelle A. Neller, Pauline Crooks, Katherine K. Matthews, Matthew Solomon, Laetitia Le Texier, Scott Campbell, Ross S. Francis, Daniel Chambers, and Rajiv Khanna http://jci.me/128323
DNA priming and gp120 boosting induces HIV-specific antibodies in a randomized clinical trial p. 5Nadine G. Rouphael, Cecilia Morgan, Shuying S. Li, Ryan Jensen, Brittany Sanchez, Shelly Karuna, Edith Swann, Magdalena E. Sobieszczyk, Ian Frank, Gregory J. Wilson, Hong-Van Tieu, Janine Maenza, Aliza Norwood, James Kobie, Faruk Sinangil, Giuseppe Pantaleo, Song Ding, M. Juliana McElrath, Stephen C. De Rosa, David C. Montefiori, Guido Ferrari, Georgia D. Tomaras, Michael C. Keefer, and the HVTN 105 Protocol Team and the NIAID HIV Vaccine Trials Network http://jci.me/128699
Evidence-based recommendations for energy intake in pregnant women with obesity p. 5Jasper Most, Marshall St Amant, Daniel S. Hsia, Abby D. Altazan, Diana M. Thomas, L. Anne Gilmore, Porsha M. Vallo, Robbie A. Beyl, Eric Ravussin, and Leanne M. Redman http://jci.me/130341
gastroenterologyIFN-γ drives inflammatory bowel disease pathogenesis through VE-cadherin–directed vascular barrier disruptionVictoria Langer, Eugenia Vivi, Daniela Regensburger, Thomas H. Winkler, Maximilian J. Waldner, Timo Rath, Benjamin Schmid, Lisa Skottke, Somin Lee, Noo Li Jeon, Thomas Wohlfahrt, Viktoria Kramer, Philipp Tripal, Michael Schumann, Stephan Kersting, Claudia Handtrack, Carol I. Geppert, Karina Suchowski, Ralf H. Adams, Christoph Becker, Andreas Ramming, Elisabeth Naschberger, Nathalie Britzen-Laurent, and Michael Stürzl http://jci.me/124884
Elastase 3B mutation links to familial pancreatitis with diabetes and pancreatic adenocarcinomaPaul C. Moore, Jessica T. Cortez, Chester E. Chamberlain, Diana Alba, Amy C. Berger, Zoe Quandt, Alice Chan, Mickie H. Cheng, Jhoanne L. Bautista, Justin Peng, Michael S. German, Mark S. Anderson, and Scott A. Oakes (ASCI) http://jci.me/129961
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Current research articles
immunologyFOXN1 compound heterozygous mutations cause selective thymic hypoplasia in humans Qiumei Du, Larry K. Huynh, Fatma Coskun, Erika Molina, Matthew A. King, Prithvi Raj, Shaheen Khan, Igor Dozmorov, Christine M. Seroogy, Christian A. Wysocki, Grace T. Padron, Tyler R. Yates, M. Louise Markert, M. Teresa de la Morena, and Nicolai S.C. van Oers http://jci.me/127565
Increased flux through the mevalonate pathway mediates fibrotic repair without injuryJennifer L. Larson-Casey, Mudit Vaid, Linlin Gu, Chao He, Guo-Qiang Cai, Qiang Ding, Dana Davis, Taylor F. Berryhill, Landon S. Wilson, Stephen Barnes, Jeffrey D. Neighbors, Raymond J. Hohl, Kurt A. Zimmerman, Bradley K. Yoder, Ana Leda F. Longhini, Vidya Sagar Hanumanthu, Ranu Surolia, Veena B. Antony, and A. Brent Carter (ASCI) http://jci.me/127959
JMJD3 regulates CD4+ T cell trafficking by targeting actin cytoskeleton regulatory gene Pdlim4Chuntang Fu, Qingtian Li, Jia Zou, Changsheng Xing, Mei Luo, Bingnan Yin, Junjun Chu, Jiaming Yu, Xin Liu, Helen Y. Wang, and Rong-Fu Wang http://jci.me/128293
Early adaptive immune activation detected in monozygotic twins with prodromal multiple sclerosisEduardo Beltrán, Lisa Ann Gerdes, Julia Hansen, Andrea Flierl-Hecht, Stefan Krebs, Helmut Blum, Birgit Ertl-Wagner, Frederik Barkhof, Tania Kümpfel, Reinhard Hohlfeld, and Klaus Dornmair http://jci.me/128475
infectious diseasePeritoneal GATA6+ macrophages function as a portal for Staphylococcus aureus disseminationSelina K. Jorch, Bas G.J. Surewaard, Mokarram Hossain, Moritz Peiseler, Carsten Deppermann, Jennifer Deng, Ania Bogoslowski, Fardau van der Wal, Abdelwahab Omri, Michael J. Hickey, and Paul Kubes http://jci.me/127286
p53-responsive TLR8 SNP enhances human innate immune response to respiratory syncytial virusDaniel Menendez, Joyce Snipe, Jacqui Marzec, Cynthia L. Innes, Fernando P. Polack, Mauricio T. Caballero, Shepherd H. Schurman, Steven R. Kleeberger, and Michael A. Resnick http://jci.me/128626
Plasma deconvolution identifies broadly neutralizing antibodies associated with hepatitis C virus clearanceValerie J. Kinchen, Guido Massaccesi, Andrew I. Flyak, Madeleine C. Mankowski, Michelle D. Colbert, William O. Osburn, Stuart C. Ray, Andrea L. Cox, James E. Crowe Jr., and Justin R. Bailey http://jci.me/130720
metabolismHotspot SF3B1 mutations induce metabolic reprogramming and vulnerability to serine deprivationW. Brian Dalton, Eric Helmenstine, Noel Walsh, Lukasz P. Gondek, Dhanashree S. Kelkar, Abigail Read, Rachael Natrajan, Eric S. Christenson, Barbara Roman, Samarjit Das, Liang Zhao, Robert D. Leone, Daniel Shinn, Taylor Groginski, Anil K. Madugundu, Arun Patil, Daniel J. Zabransky, Arielle Medford, Justin Lee, Alex J. Cole, Marc Rosen, Maya Thakar, Alexander Ambinder, Joshua Donaldson, Amy E. DeZern, Karen Cravero, David Chu, Rafael Madero-Marroquin, Akhilesh Pandey, Paula J. Hurley, Josh Lauring, and Ben Ho Park (ASCI) http://jci.me/125022
Nuclear envelope–localized torsinA-LAP1 complex regulates hepatic VLDL secretion and steatosisJi-Yeon Shin, Antonio Hernandez-Ono, Tatyana Fedotova, Cecilia Östlund, Michael J. Lee, Sarah B. Gibeley, Chun-Chi Liang, William T. Dauer, Henry N. Ginsberg, and Howard J. Worman (ASCI) http://jci.me/129769
Regulation of hepatic mitochondrial oxidation by glucose-alanine cycling during starvation in humansKitt Falk Petersen, Sylvie Dufour, Gary W. Cline, and Gerald I. Shulman (ASCI) http://jci.me/129913
muscle biologyPeptide-conjugated oligonucleotides evoke long-lasting myotonic dystrophy correction in patient-derived cells and mice p. 3Arnaud F. Klein, Miguel A. Varela, Ludovic Arandel, Ashling Holland, Naira Naouar, Andrey Arzumanov, David Seoane, Lucile Revillod, Guillaume Bassez, Arnaud Ferry, Dominic Jauvin, Genevieve Gourdon, Jack Puymirat, Michael J. Gait, Denis Furling, and Matthew J.A. Wood http://jci.me/128205
Recombinant annexin A6 promotes membrane repair and protects against muscle injuryAlexis R. Demonbreun, Katherine S. Fallon, Claire C. Oosterbaan, Elena Bogdanovic, James L. Warner, Jordan J. Sell, Patrick G. Page, Mattia Quattrocelli, David Y. Barefield, and Elizabeth M. McNally (ASCI) http://jci.me/128840
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nephrologyProximal tubule ATR regulates DNA repair to prevent maladaptive renal injury responses p. 4Seiji Kishi, Craig R. Brooks, Kensei Taguchi, Takaharu Ichimura, Yutaro Mori, Akinwande Akinfolarin, Navin Gupta, Pierre Galichon, Bertha C. Elias, Tomohisa Suzuki, Qian Wang, Leslie Gewin, Ryuji Morizane, and Joseph V. Bonventre (ASCI) http://jci.me/122313
Calcium channel Orai1 promotes lymphocyte IL-17 expression and progressive kidney injury p. 4Purvi Mehrotra, Michael Sturek, Javier A. Neyra, and David P. Basile http://jci.me/126108
Myo-inositol oxygenase expression profile modulates pathogenic ferroptosis in the renal proximal tubuleFei Deng, Isha Sharma, Yingbo Dai, Ming Yang, and Yashpal S. Kanwar http://jci.me/129903
oncologyStromal integrin α11 regulates PDGFRβ signaling and promotes breast cancer progressionIrina Primac, Erik Maquoi, Silvia Blacher, Ritva Heljasvaara, Jan Van Deun, Hilde Y.H. Smeland, Annalisa Canale, Thomas Louis, Linda Stuhr, Nor Eddine Sounni, Didier Cataldo, Taina Pihlajaniemi, Christel Pequeux, Olivier De Wever, Donald Gullberg, and Agnès Noel http://jci.me/125890
cGAS/STING axis mediates a topoisomerase II inhibitor–induced tumor immunogenicityZining Wang, Jiemin Chen, Jie Hu, Hongxia Zhang, Feifei Xu, Wenzhuo He, Xiaojuan Wang, Mengyun Li, Wenhua Lu, Gucheng Zeng, Penghui Zhou, Peng Huang, Siyu Chen, Wende Li, Liang-ping Xia, and Xiaojun Xia http://jci.me/127471
Recognition of human gastrointestinal cancer neoantigens by circulating PD-1+ lymphocytesAlena Gros, Eric Tran, Maria R. Parkhurst, Sadia Ilyas, Anna Pasetto, Eric M. Groh, Paul F. Robbins, Rami Yossef, Andrea Garcia-Garijo, Carlos A. Fajardo, Todd D. Prickett, Li Jia, Jared J. Gartner, Satyajit Ray, Lien Ngo, John R. Wunderllich, James C. Yang, and Steven A. Rosenberg http://jci.me/127967
DNA methyltransferase inhibition overcomes diphthamide pathway deficiencies underlying CD123-targeted treatment resistance p. 3Katsuhiro Togami, Timothy Pastika, Jason Stephansky, Mahmoud Ghandi, Amanda L. Christie, Kristen L. Jones, Carl A. Johnson, Ross W. Lindsay, Christopher L. Brooks, Anthony Letai, Jeffrey W. Craig, Olga Pozdnyakova, David M. Weinstock, Joan Montero, Jon C. Aster, Cory M. Johannessen, and Andrew A. Lane http://jci.me/128571
ophthalmologyAngiopoietin-like 4 binds neuropilins and cooperates with VEGF to induce diabetic macular edema p. 2Akrit Sodhi, Tao Ma, Deepak Menon, Monika Deshpande, Kathleen Jee, Aumreetam Dinabandhu, Jordan Vancel, Daoyuan Lu, and Silvia Montaner http://jci.me/120879
AAV8-vectored suprachoroidal gene transfer produces widespread ocular transgene expressionKun Ding, Jikui Shen, Zibran Hafiz, Sean F. Hackett, Raquel Lima e Silva, Mahmood Khan, Valeria E. Lorenc, Daiqin Chen, Rishi Chadha, Minie Zhang, Sherri Van Everen, Nicholas Buss, Michele Fiscella, Olivier Danos, and Peter A. Campochiaro http://jci.me/129085
pulmonologyAirway epithelium–shifted mast cell infiltration regulates asthmatic inflammation via IL-33 signalingMatthew C. Altman, Ying Lai, James D. Nolin, Sydney Long, Chien-Chang Chen, Adrian M. Piliponsky, William A. Altemeier, Megan Larmore, Charles W. Frevert, Michael S. Mulligan, Steven F. Ziegler, Jason S. Debley, Michael C. Peters, and Teal S. Hallstrand http://jci.me/126402
reproductive biologyLymphatic mimicry in maternal endothelial cells promotes placental spiral artery remodelingJohn B. Pawlak, László Bálint, Lillian Lim, Wanshu Ma, Reema B. Davis, Zoltán Benyó, Michael J. Soares, Guillermo Oliver, Mark L. Kahn, Zoltán Jakus, and Kathleen M. Caron http://jci.me/120446
vascular biologyIntegrin α5β1 regulates PP2A complex assembly through PDE4D in atherosclerosisSanguk Yun, Rui Hu, Melanie E. Schwaemmle, Alexander N. Scherer, Zhenwu Zhuang, Anthony J. Koleske, David C. Pallas, and Martin A. Schwartz http://jci.me/127692
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jci.org/this-month
Tumor-resident mast cells promote anti-melanoma response 12
Fecal microbiota transplantation may introduce carcinogenic bacteria 12
Immune dysfunction underlies diabetes-associated MERS-CoV severity 12
Gene correction improves healing in recessive skin disease 13
JCI This Month is a summary of the most recent articles in The Journal of Clinical Investigation and JCI Insight
November 2019
Viral oncogene drives bone loss in T cell leukemia p. 11
This Month
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Pilar Alcaide
John F. Alcorn
Maria-Luisa Alegre
Ravi K. Amaravadi
Cristian Apetrei
Rajendra S. Apte
Zoltan Arany
Hossein Ardehali
Julio Ayala
Sami J. Barmada
Alexander G. Bassuk
Vann Bennett
Sudha B. Biddinger
Jonathan S. Bogan
Laura M. Bohn
Nunzio Bottini
Sebastien G. Bouret
Jason Brenchley
Renier J. Brentjens
G.R. Scott Budinger
George A. Calin
Stephen Y. Chan
Timothy A. Chan
Yuan Chang
Benjamin K. Chen
Kang Chen
Zhou-Feng Chen
Wendy Chung
Matthew Ciorba
Janice E. Clements
Craig M. Coopersmith
George Cotsarelis
Peter A. Crawford
Lisa L. Cunningham
Jennifer Davis
Ronald P. DeMatteo
Madhav V. Dhodapkar
Elia J. Duh
Sarah K. England
Carmella Evans-Molina
Robert L. Fairchild
Eric R. Fearon
Brian Finck
John H. Fingert
Robert Flaumenhaft
Edward A. Fon
Lawrence Fong
Nikolaos G. Frangogiannis
Anthony R. French
Katherine A. Gallagher
Terrence L. Geiger
Raphaela Goldbach-Mansky
Daniel R. Goldstein
Douglas K. Graham
Johann E. Gudjonsson
Kirk Habegger
Khalid A. Hanafy
Eric B. Haura
John Cijiang He
Adam Steven Helms
Robert O. Heuckeroth
Cory M. Hogaboam
Young-Kwon Hong
Eric J. Huang
Benjamin D. Humphreys
Ken Inoki
Rajan Jain
Daniel P. Judge
J. Michelle Kahlenberg
Shingo Kajimura
Pawel Kalinski
Nobuhiko Kamada
Thomas W.H. Kay
Barbara I. Kazmierczak
Catherine E. Keegan
Hans-Peter Kiem
William Y. Kim
Frank Kirchhoff
David G. Kirsch
Jason S. Knight
Donald E. Kohan
Maria Kontaridis
Laura A. Kresty
Jongsoon Lee
Michael Lehrke
Claire E. Lewis
Mathias Lichterfeld
Rodger A. Liddle
André Lieber
Michail S. Lionakis
Ivan Maillard
Ziad Mallat
Peter Mannon
Eric Martens
Franck Mauvais-Jarvis
Linda McAllister-Lucas
Dermot P.B. McGovern
Borna Mehrad
Ingo K. Mellinghoff
David K. Meyerholz
Jason C. Mills
Joshua D. Milner
Satdarshan Paul Monga
Hidayatullah G. Munshi
William J. Murphy
Matthias Nahrendorf
Mary C. Nakamura
Lisa F.P. Ng
Mark Nicolls
Laura J. Niedernhofer
Una O’Doherty
S. Tiong Ong
Akira Ono
Puneet Opal
Olabisi Opeyemi
Daniel Ory
Sophie Paczesny
Rulan Parekh
Victoria N. Parikh
Mary-Elizabeth Patti
Janos Peti-Peterdi
Fernando P. Polack
Benjamin Prosser
Ling Qi
Dominic Raj
Jalees Rehman
Florian Rieder
Matthew D. Ringel
Howard A. Rockman
Steven M. Rowe
Linda C. Samuelson
Victoria L. Seewaldt
Svati H. Shah
Vijay H. Shah
Yatrik M. Shah
Vikram Shakkottai
Guo-Ping Shi
Kanakadurga Singer
Scott Soleimanpour
Rhonda F. Souza
Fayyaz S. Sutterwala
Shu Takeda
James E. Talmadge
Muneesh Tewari
John P. Thyfault
Natalie J. Torok
Stephen H. Tsang
Hubert M. Tse
Fumihiko Urano
Jolanda van der Velden
Deborah J. Veis
Charles P. Venditti
Claudio J. Villanueva
Joseph Vinetz
Stephanie M. Ware
Sing Sing Way
Kevin W. Williams
Minna Woo
Prescott G. Woodruff
Jing Yang
Tianxin Yang
Yiping Yang
Vincent B. Young
Lori M. Zeltser
Zhen Zhang
Yutong Zhao
Binhua P. Zhou
JCI Insight Consulting Editors
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For JCI InsightEditorKathleen CollinsDeputy EditorsAndrew Lieberman, Donna Martin, Pavan ReddyAssociate EditorsSharlene M. Day, Gregory R. Dressler, David A. Fox, Santhi Ganesh, John Y. Kao, Celina G. Kleer, Carey Lumeng, Lona Mody, Bethany B. Moore, Alexey Nesvizhskii, Marina Pasca di Magliano, Darleen Sandoval, Andrew Tai, Weiping ZouExecutive EditorSarah C. JacksonSenior Science EditorCorinne Williams
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This MonthNovember 2019
For JCI Insight online: jci.me/insight/4/19jci.me/insight/4/20
JCI Insight’s first Impact Factor: 6.014Read more about JCI Insight’s Impact Factor, reported in the 2018 Journal Citation Reports (June 2019): http://jci.me/muhtx
Andrew Lieberman, MD, PhD, Deputy Editor, is the Gerald D. Abrams Professor of Pathology and Director of Neuropathology at the University of Michigan Medical School. His research focuses on the mechanisms of neurodegeneration in inherited neurological disorders, including Niemann-Pick type C disease and spinal and bulbar muscular atrophy. He is a member of the American Society for Clinical Investigation.
Publication highlights
Nath SR, Yu Z, Gipson TA, Marsh GB, Yoshidome E, Robins DM, Todi SV, Housman DE, Lieberman AP. Androgen receptor polyglutamine expansion drives age-dependent quality control defects and muscle dysfunction. J Clin Invest. 2018;128(8):3630–3641.
Schultz ML, Krus KL, Kaushik S, Dang D, Chopra R, Qi L, Shakkottai VG, Cuervo AM, Lieberman AP. Coordinate regulation of mutant NPC1 degradation by selective ER autophagy and MARCH6-dependent ERAD. Nat Commun. 2018;9(1):3671.
Chua JP, Reddy SL, Yu Z, Giorgetti E, Montie HL, Mukherjee S, Higgins J, McEachin RC, Robins DM, Merry DE, Iñiguez-Lluhí JA, Lieberman AP. Disrupting SUMOylation enhances transcriptional function and ameliorates polyglutamine androgen receptor-mediated disease. J Clin Invest. 2015;125(2):831–845.
Wang AM, Miyata Y, Klinedinst S, Peng HM, Chua JP, Komiyama T, Li X, Morishima Y, Merry DE, Pratt WB, Osawa Y, Collins CA, Gestwicki JE, Lieberman AP. Activation of Hsp70 reduces neurotoxicity by promoting polyglutamine protein degradation. Nat Chem Biol. 2013;9(2):112–118.
JCI Insight’s Editorial Board is composed of peer scientists at the University of Michigan and the University of Pennsylvania. Members of the Editorial Board review and oversee the peer review process of manuscripts directly submitted to JCI Insight, evaluate all transferred manuscripts, and meet weekly to discuss manuscripts under review.
Featured Editor
j c i . o r g / t h i s - m o n t h n o v e m b e r 2 0 1 911
Editor’s picks
on the jci insight cover bone biology
Understanding bone loss in adult T cell leukemia/lymphomaBone loss is a serious complication of adult T cell leukemia/lymphoma (ATL), an aggressive cancer caused by human T cell leukemia virus type 1 (HTLV-1). Jingyu Xiang, Daniel Rauch, Devra Huey, and colleagues investigated the role of HTLV-1 oncogenes in driving bone loss. In a humanized mouse model of ATL, the oncogene HBZ played only a minor role in the lympho proliferative disorder, but it was required for disease- induced bone loss. In human cell lines, HBZ indirectly drove overexpression of RANKL, a key factor known to regulate the development and
function of bone-resorbing osteoclasts. Furthermore, in the mouse model, treatment with denosumab, a monoclonal antibody targeting RANKL, prevented bone loss. These findings clarify the mechanism controlling bone loss in ATL and demonstrate the potential of denosumab to protect ATL patients from this compli cation. The cover image shows tartrate-resistant acid phosphatase (TRAP, pink) staining of osteo-clasts in the tibia of an HTLV-1 ΔHBZ–infected humanized mouse, which lacks the HBZ protein.
HTLV-1 viral oncogene HBZ drives bone destruction in adult T cell leukemiaJingyu Xiang, Daniel A. Rauch, Devra D. Huey, Amanda R. Panfil, Xiaogang Cheng, Alison K. Esser, Xinming Su, John C. Harding, Yalin Xu, Gregory C. Fox, Francesca Fontana, Takayuki Kobayashi, Junyi Su, Hemalatha Sundaramoorthi, Wing Hing Wong, Yizhen Jia, Thomas J. Rosol, Deborah J. Veis, Patrick L. Green, Stefan Niewiesk, Lee Ratner, and Katherine N. Weilbaecher (ASCI) http://jci.me/128713
metabolism
Intestinal GLP-1 does not account for improved glycemia after bariatric surgeryGlucagon-like peptide–1 (GLP-1), a hormone encoded by the preprogluca-gon (Gcg) gene, modulates systemic glucose homeostasis. The hormone is secreted from intestinal L cells in response to feeding and is believed to promote insulin secretion. Following vertical sleeve gastrectomy (VSG), a commonly performed weight-loss surgery, postprandial levels of GLP-1 rise, which may contribute to VSG-induced weight loss and improved glucose tolerance. However, recent research suggests that GLP-1 production from pancreatic islet cells, not the intestine, plays a dominant role in the effect of GLP-1 on glucose homeostasis. Ki-Suk Kim and colleagues used multiple mouse models to investigate the relevant source of GLP-1. Reactivation of Gcg specifically within the intestine normalized circulating GLP-1 in response
to a variety of nutrients and in response to VSG, supporting that the intestine is the source of systemic GLP-1 following VSG. However, intes-tine-derived GLP-1 was dispensable for glycemic improvements following the surgery. Thus, islet-derived GLP-1 may act in a paracrine manner to regulate glucose homeostasis even after bariatric surgery.
Glycemic effect of pancreatic preproglucagon in mouse sleeve gastrectomyKi-Suk Kim, Chelsea R. Hutch, Landon Wood, Irwin J. Magrisso, Randy J. Seeley, and Darleen A. Sandoval http://jci.me/129452
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JCI Insight | Editor’s picks
12
microbiology infectious disease
Unintended consequences of fecal transplantsFecal microbiota transplantation (FMT) is a life-saving treatment for individuals with recurrent C. difficile infection and is being explored as a treatment for other disorders, including ulcerative colitis. However, the long-term consequences of FMT are understudied, and FMT donors are not currently screened for all potentially carcinogenic bacterial species. Julia Drewes and colleagues collected samples from 11 pediatric patients with recurrent C. difficile infection and their FMT donors, and followed the patients for up to six months after FMT. In four cases, transmission of potentially carcinogenic bacterial species from donor to recipient was observed. Whole genome sequencing of the bacterial isolates from one patient confirmed that transmission occurred from donor to recipient, rather than from an environmental source. Conversely, two other patients demonstrated reduction or clearance of carcinogenic species after transplant. This study indicates that additional studies of the long-term outcomes of FMT are needed and that more extensive screening of FMT donors could be beneficial.
Transmission and clearance of potential procarcinogenic bacteria during fecal microbiota transplantation for recurrent Clostridioides difficileJulia L. Drewes, Alina Corona, Uriel Sanchez, Yunfan Fan, Suchitra K. Hourigan, Melissa Weidner, Sarah D. Sidhu, Patricia J. Simner, Hao Wang, Winston Timp, Maria Oliva-Hemker, and Cynthia L. Sears http://jci.me/130848
Diabetes worsens respiratory illness due to a dysregulated immune responseMiddle East respiratory syndrome coronavirus (MERS-CoV) is a severe respiratory infection that emerged in Saudi Arabia in 2012 and caused more than 800 deaths. Epidemiological studies identified comorbid illnesses, particularly diabetes, as risk factors for more severe or lethal outcome of MERS-CoV infection. Kristen Kulcsar and colleagues investigated the connection between diabetes and MERS-CoV in a mouse model, and discovered that although viral replication did not differ between diabetic and control mice, diabetic mice exhibited a delayed and prolonged inflammatory response in the lung. Diabetic mice had lower levels of inflammatory cytokines and fewer inflammatory macrophages and T cells. These results indicate that the increased severity of MERS-CoV infection in patients with comorbid diabetes is due to immune dysregulation.
Comorbid diabetes results in immune dysregulation and enhanced disease severity following MERS-CoV infectionKirsten A. Kulcsar, Christopher M. Coleman, Sarah E. Beck, and Matthew B. Frieman http://jci.me/131774
immunology
Tumor-resident mast cells have potential as melanoma treatment targetImmune checkpoint inhibitors, such as anti–CTLA-4 and anti–PD-1, have emerged as powerful tools in the fight against cancer. However, a paradox predicts patient responses: those who develop adverse events related to the immunotherapy, such as colitis, are more likely to experience tumor regression. Susanne Kaesler and colleagues discovered that in patients with colitis, LPS leakage from the intestine activated a proinflammatory program. In a mouse model of melanoma, LPS activated mast cells in the tumor micro environment, which in turn secreted CXCL10 to recruit tumor-infiltrating T cells (TILs) to mediate regression of the tumor. TIL recruitment and melanoma control required CXCL10 expression in mast cells. In humans, spontaneous tumor regression correlated with mast cell infiltration (see the accompanying image),
and CXCL10 was a biomarker of improved patient survival. These data indicate the potential of targeting immune cells in the tumor microenvironment, such as mast cells, to improve current cancer therapies.
Targeting tumor-resident mast cells for effective anti-melanoma immune responsesSusanne Kaesler, Florian Wölbing, Wolfgang Eberhard Kempf, Yuliya Skabytska, Martin Köberle, Thomas Volz, Tobias Sinnberg, Teresa Amaral, Sigrid Möckel, Amir Yazdi, Gisela Metzler, Martin Schaller, Karin Hartmann, Benjamin Weide, Claus Garbe, Hans-Georg Rammensee, Martin Röcken, and Tilo Biederman http://jci.me/125057
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JCI Insight | Editor’s picks
dermatology
cardiology
Gene correction therapy shows promise for genetic skin disease
Coronary artery disease is not linked to increased epicardial adipose inflammationEpicardial adipose tissue (EAT) is a visceral fat deposit around the heart that increases in size proportionally with obesity. Previous studies in patients with coronary artery disease (CAD) reported that EAT exhibits higher expression of inflammatory genes and a denser inflammatory cell infiltrate than subcutaneous adipose tissue, leading to the hypothesis that inflammation of EAT may contribute to CAD. To determine whether this is the case, Timothy Fitzgibbons and colleagues compared the gene expression profile of EAT isolated from 13 patients with CAD to that of 13 patients without CAD. Although EAT had higher levels of inflammatory gene expression than subcutaneous adipose tissue as expected, there was no difference in inflammatory gene expression or macrophage infiltration between the EAT of cases and controls (see the accompanying image). In contrast, CAD was associated with decreased antiinflammatory gene expression in EAT. This indicates that the adipose tissue depot, rather than disease status, is the greatest determinant of gene expression pattern.
Coronary disease is not associated with robust alterations in inflammatory gene expression in human epicardial fatTimothy P. Fitzgibbons, Nancy Lee, Khanh-Van Tran, Sara Nicoloro, Mark Kelly, Stanley K.C. Tam, and Michael P. Czech http://jci.me/124859
Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable skin disorder character-ized by recurrent and chronic wounds. It is caused by loss of function of COL7A1, which results in a lack of type VII collagen (C7). A team led by Jean Tang performed a phase 1/2a clinical trial to test the safety and efficacy of gene-corrected cell therapy for RDEB patients. Keratinocytes were isolated from seven patients, and then transduced with a retrovirus carrying full-length human COL7A1. The cells
were grown into epidermal sheets, grafted onto six wound sites on each patient, and followed over several years. Treated wounds showed markedly improved healing compared with untreated wounds (see accompanying image), and patients experienced less pain at treated sites with healing. Moreover, C7 expression persisted for at least two years. The approach was safe, with no serious adverse effects reported. This study supports the use of gene-corrected cell therapy for RDEB.
Phase 1/2a clinical trial of gene-corrected autologous cell therapy for recessive dystrophic epidermolysis bullosaShaundra Eichstadt, Melissa Barriga, Anusha Ponakala, Claudia Teng, Ngon T. Nguyen, Zurab Siprashvili, Jaron Nazaroff, Emily S. Gorell, Albert S. Chiou, Lisa Taylor, Phuong Khuu, Douglas R. Keene, Kerri Rieger, Rohit K. Khosla, Louise K. Furukawa, H. Peter Lorenz, M. Peter Marinkovich, and Jean Y. Tang http://jci.me/130554
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