Embed Size (px)
Citation preview
jci.org/this-month
Also in this issue:
Epigenetic regulation of erythropoietin 7
A humanized Morris water maze 9
Review series: hiV edited by Robert F. Siliciano 10
Introducing JCI Insight 13
A summary of the most recent articles in the Journal of Clinical investigation and JCi insight
Scan with your mobile device for the digital version of JCI This Month.
This Month
Metabolic reprogramming in
the metastatic niche p. 6
February 2016
The JCI welcomes submissions in the following categories:
Research: Substantial new mechanistic insights into biology and disease.
Brief report: Discrete, highly significant findings in a short format.
Sample article: Hepatic stellate cells contribute to progenitor cells and liver regenerationClaus Kordes, Iris Sawitza, Silke Götze, Diran Herebian, and Dieter Häussinger
Published November 2014 http://jci.me/74119
Times cited: 21
Sample article: Early microbial translocation blockade reduces SIV-mediated inflammation and viral replicationJan Kristoff, George Haret-Richter, Dongzhu Ma, Ruy M. Ribeiro, Cuiling Xu, Elaine Cornell, Jennifer L. Stock, Tianyu He, Adam D. Mobley, Samantha Ross, Anita Trichel, Cara Wilson, Russell Tracy, Alan Landay, Cristian Apetrei, and Ivona Pandrea
Published May 2014 http://jci.me/75090 Times cited: 18
Clinical medicine:Research that reports early-stage, effective new therapies that impact disease outcomes in patients.
Sample article: Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftmentMitchell E. Horwitz, Nelson J. Chao, David A. Rizzieri, Gwynn D. Long, Keith M. Sullivan, Cristina Gasparetto, John P. Chute, Ashley Morris, Carolyn McDonald, Barbara Waters-Pick, Patrick Stiff, Steven Wease, Amnon Peled, David Snyder, Einat Galamidi Cohen, Hadas Shoham, Efrat Landau, Etty Friend, Iddo Peleg, Dorit Aschengrau, Dima Yackoubov, Joanne Kurtzberg, and Tony Peled
Published June 2014 http://jci.me/74556 Times cited: 23
jci.org
Submit your work to the JCI
The Journal of Clinical Investigation
Citation information is from Web of Science and Scopus as of December 2015.
More information: http://jci.me/aqcqs or [email protected]
j c i . o r g / t h i s - m o n t h F e b r u a r y 2 0 1 6 1
For the JCi and JCi insighteditorHoward A. Rockman
executive editorSarah C. Jackson
science editorsJillian Hurst, Corinne Williams
For the JCiDeputy editorsGarnett Kelsoe, Bryan L. Roth
Associate editorsSoman N. Abraham, Vann Bennett,Gerard C. Blobe, Kathleen M. Caron,Marc G. Caron, John P. Chute,Thomas M. Coffman, Anna Mae Diehl,Ronald J. Falk, Michael B. Kastan, Daniel P. Kelly, Mary E. Klotman, Rodger A. Liddle, Nigel Mackman, Larry G. Moss, Deborah M. Muoio, Christopher B. Newgard, Paul W. Noble, Geoffrey S. Pitt, Jeffrey C. Rathmell, W. Kimryn Rathmell, Jonathan S. Serody, Norman Sharpless, Yiping Yang
Clinical Medicine Associate editorsMichael A. Morse, Andrew J. Muir,Scott M. Palmer, Mark A. Stacy
Asia editorDavid M. Virshup
Chair, executive CouncilRobert J. Lefkowitz
BiostatisticiansCynthia Coffman, Barry Moser, Maren Olsen
BioethicistArthur L. Caplan
editor at largeUshma S. Neill
issn 2380-3029 (print)issn 2380-3037 (online)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.
Contact the JCi and JCi insight2015 Manchester RoadAnn Arbor, Michigan 48104, USAPhone: 734.222.6050E-mail: [email protected] (JCI); [email protected] (JCI Insight)
For the full JCI online: jci.me/126/2 For JCI Insight: jci.me/insight/1/1
This MonthFebruary 2016
We are delighted to publish the first set of articles in JCI Insight, the newest peer-reviewed publication of the American Society for Clinical Investigation (ASCI). In creating this journal, we sought to provide an expanded forum for a wide range of preclinical, translational, and clinical research that uncovers new insights into the basis of disease and therapeutic approaches. In selecting articles for JCI Insight, we place a strong emphasis on rigorous experimental methods and data reporting, which are truly the hallmark of publications in the JCI family.
In January 2016, JCI Insight opened to new submissions. Manuscripts that meet our editorial bar for quality and interest to our readership are sent for external peer review by our professional editors. We are indebted to our esteemed board of consulting editors, who have agreed to provide advice on manuscripts in their area of expertise. We have also implemented a transfer process for manuscripts previously considered at the JCI that we believe are better suited for JCI Insight. For manuscripts that have been previously reviewed at the JCI, the submission and reviewer comments are transferred to JCI Insight, allowing our editors to come to a rapid decision based on the original evaluation.
In the first batch of articles, we are extremely proud to publish an outstanding collection of preclinical and clinical research from around the globe (see page 13 for a listing of the articles). We are pleased to provide this new venue for the publication of well-executed human and preclinical model-based research, and we encourage you to consider JCI Insight for your work within this scope.
For more information about submitting manuscripts to JCI Insight, please visit our website: www.insight.jci.org.
Sarah JacksonExecutive EditorThe Journal of Clinical Investigation and JCI Insight
To read Dr. Jackson’s complete editorial, see http://jci.me/86444.
The inaugural issue of JCI Insight
From the Editor
j c i . o r g / t h i s - m o n t h F e b r u a r y 2 0 1 62
Research articles in the current issue of the JCI
Bone biologyOsteoblast-derived VEGF regulates osteoblast differentiation and bone formation during bone repairKai Hu and Bjorn R. Olsen http://jci.me/82585
EndocrinologyCYP24 inhibition as a therapeutic target in FGF23-mediated renal phosphate wasting disordersXiuying Bai, Dengshun Miao, Sophia Xiao, Dinghong Qiu, René St-Arnaud, Martin Petkovich, Ajay Gupta, David Goltzman, and Andrew C. Karaplis http://jci.me/81928
With related Commentary by Valentin David and Myles Wolf More, p. 8
GastroenterologyToll-like receptor 4–mediated lymphocyte influx induces neonatal necrotizing enterocolitisCharlotte E. Egan, Chhinder P. Sodhi, Misty Good, Joyce Lin, Hongpeng Jia, Yukihiro Yamaguchi, Peng Lu, Congrong Ma, Maria F. Branca, Samantha Weyandt, William B. Fulton, Diego F. Niño, Thomas Prindle Jr., John A. Ozolek, and David J. Hackam http://jci.me/83356
Rho-A prenylation and signaling link epithelial homeostasis to intestinal inflammationRocío López-Posadas, Christoph Becker, Claudia Günther, Stefan Tenzer, Kerstin Amann, Ulrike Billmeier, Raja Atreya, Gionata Fiorino, Stefania Vetrano, Silvio Danese, Arif B. Ekici, Stefan Wirtz, Veronika Thonn, Alastair J.M. Watson, Cord Brakebusch, Martin Bergö, Markus F. Neurath, and Imke Atreya http://jci.me/80997
GeneticsMolecular etiology of arthrogryposis in multiple families of mostly Turkish originYavuz Bayram, Ender Karaca, Zeynep Coban Akdemir, Elif Ozdamar Yilmaz, Gulsen Akay Tayfun, Hatip Aydin, Deniz Torun, Sevcan Tug Bozdogan, Alper Gezdirici, Sedat Isikay, Mehmed M. Atik, Tomasz Gambin, Tamar Harel, Ayman W. El-Hattab, Wu-Lin Charng, Davut Pehlivan, Shalini N. Jhangiani, Donna M. Muzny, Ali Karaman, Tamer Celik, Ozge Ozalp Yuregir, Timur Yildirim, Ilhan A. Bayhan, Eric Boerwinkle, Richard A. Gibbs, Nursel Elcioglu, Beyhan Tuysuz, and James R. Lupski http://jci.me/84457
Osteoblast VEGF
Mucosal injury
Normal ileum
j c i . o r g / t h i s - m o n t h F e b r u a r y 2 0 1 6 3
Research articles in the current issue of the JCI
HematologyA chimeric platelet-targeted urokinase prodrug selectively blocks new thrombus formationRudy E. Fuentes, Sergei Zaitsev, Hyun Sook Ahn, Vincent Hayes, M. Anna Kowalska, Michele P. Lambert, Yuhuan Wang, Donald L. Siegel, Daniel W. Bougie, Richard H. Aster, Daniel D. Myers, Victoria Stepanova, Douglas B. Cines, Vladimir R. Muzykantov, and Mortimer Poncz http://jci.me/81470
ImmunologyTranscription factor ICBP90 regulates the MIF promoter and immune susceptibility locusJie Yao, Lin Leng, Maor Sauler, Weiling Fu, Junsong Zheng, Yi Zhang, Xin Du, Xiaoqing Yu, Patty Lee, and Richard Bucala http://jci.me/81937
Broadly neutralizing anti-influenza antibodies require Fc receptor engagement for in vivo protectionDavid J. DiLillo, Peter Palese, Patrick C. Wilson, and Jeffrey V. Ravetch http://jci.me/84428
Muscle biologyThe AMPK-related kinase SNARK regulates muscle mass and myocyte survivalSarah J. Lessard, Donato A. Rivas, Kawai So, Ho-Jin Koh, André Lima Queiroz, Michael F. Hirshman, Roger A. Fielding, and Laurie J. Goodyear http://jci.me/79197
NephrologyDNA methyltransferase inhibition restores erythropoietin production in fibrotic murine kidneysYu-Ting Chang, Ching-Chin Yang, Szu-Yu Pan, Yu-Hsiang Chou, Fan-Chi Chang, Chun-Fu Lai, Ming-Hsuan Tsai, Huan-Lun Hsu, Ching-Hung Lin, Wen-Chih Chiang, Ming-Shiou Wu, Tzong-Shinn Chu, Yung-Ming Chen, and Shuei-Liong Lin http://jci.me/82819
More, p. 7
NeuroscienceCross-species translation of the Morris maze for Alzheimer’s diseaseKatherine L. Possin, Pascal E. Sanchez, Cliff Anderson-Bergman, Roland Fernandez, Geoffrey A. Kerchner, Erica T. Johnson, Allyson Davis, Iris Lo, Nicholas T. Bott, Thomas Kiely, Michelle C. Fenesy, Bruce L. Miller, Joel H. Kramer, and Steven Finkbeiner http://jci.me/78464
With related Commentary by Kerin K. Higa, Jared W. Young, and Mark A. Geyer More, p. 9
CXCL13 drives spinal astrocyte activation and neuropathic pain via CXCR5Bao-Chun Jiang, De-Li Cao, Xin Zhang, Zhi-Jun Zhang, Li-Na He, Chun-Hua Li, Wen-Wen Zhang, Xiao-Bo Wu, Temugin Berta, Ru-Rong Ji, and Yong-Jing Gao http://jci.me/81950
More, p. 9
Muscle laminin
Fibrotic kidney
j c i . o r g / t h i s - m o n t h F e b r u a r y 2 0 1 64
Research articles in the current issue of the JCI
NeuroscienceActivating transcription factor 6 derepression mediates neuroprotection in Huntington diseaseJosé R. Naranjo, Hongyu Zhang, Diego Villar, Paz González, Xose M. Dopazo, Javier Morón-Oset, Elena Higueras, Juan C. Oliveros, María D. Arrabal, Angela Prieto, Pilar Cercós, Teresa González, Alicia De la Cruz, Juan Casado-Vela, Alberto Rábano, Carmen Valenzuela, Marta Gutierrez-Rodriguez, Jia-Yi Li, and Britt Mellström http://jci.me/82670
Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in miceMichael Fritz, Anna M. Klawonn, Anna Nilsson, Anand Kumar Singh, Joanna Zajdel, Daniel Björk Wilhelms, Michael Lazarus, Andreas Löfberg, Maarit Jaarola, Unn Örtegren Kugelberg, Timothy R. Billiar, David J. Hackam, Chhinder P. Sodhi, Matthew D. Breyer, Johan Jakobsson, Markus Schwaninger, Günther Schütz, Jan Rodriguez Parkitna, Clifford B. Saper, Anders Blomqvist, and David Engblom http://jci.me/83844
OncologyHistone demethylase JMJD2A drives prostate tumorigenesis through transcription factor ETV1Tae-Dong Kim, Fang Jin, Sook Shin, Sangphil Oh, Stan A. Lightfoot, Joseph P. Grande, Aaron J. Johnson, Jan M. van Deursen, Jonathan D. Wren, and Ralf Janknecht http://jci.me/78132
Nuclear pore protein NUP88 activates anaphase-promoting complex to promote aneuploidyRyan M. Naylor, Karthik B. Jeganathan, Xiuqi Cao, and Jan M. van Deursen http://jci.me/82277
Tetraspanin CD37 protects against the development of B cell lymphomaCharlotte M. de Winde, Sharon Veenbergen, Ken H. Young, Zijun Y. Xu-Monette, Xiao-xiao Wang, Yi Xia, Kausar J. Jabbar,
Michiel van den Brand, Alie van der Schaaf, Suraya Elfrink, Inge S. van Houdt, Marion J. Gijbels, Fons A.J. van de Loo, Miranda B. Bennink, Konnie M. Hebeda, Patricia J.T.A. Groenen, J. Han van Krieken, Carl G. Figdor, and Annemiek B. van Spriel http://jci.me/81041
The transcription factor BACH2 promotes tumor immunosuppressionRahul Roychoudhuri, Robert L. Eil, David Clever, Christopher A. Klebanoff, Madhusudhanan Sukumar, Francis M. Grant, Zhiya Yu, Gautam Mehta, Hui Liu, Ping Jin, Yun Ji, Douglas C. Palmer, Jenny H. Pan, Anna Chichura, Joseph G. Crompton, Shashank J. Patel, David Stroncek, Ena Wang, Francesco M. Marincola, Klaus Okkenhaug, Luca Gattinoni, and Nicholas P. Restifo http://jci.me/82884
More, p. 7
CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancerMark L. McCleland, Kathryn Mesh, Edward Lorenzana, Vivek S. Chopra, Ehud Segal, Colin Watanabe, Benjamin Haley, Oleg Mayba, Murat Yaylaoglu, Florian Gnad, and Ron Firestein http://jci.me/83265
Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation
Jian Yu, Liguang Chen, Bing Cui, George F. Widhopf II, Zhouxin Shen, Rongrong Wu, Ling Zhang, Suping Zhang, Steven P. Briggs, and Thomas J. Kipps http://jci.me/83535
PKLR promotes colorectal cancer liver colonization through induction of glutathione synthesisAlexander Nguyen, Jia Min Loo, Rohit Mital, Ethan M. Weinberg, Fung Ying Man, Zhaoshi Zeng, Philip B. Paty, Leonard Saltz, Yelena Y. Janjigian, Elisa de Stanchina, and Sohail F. Tavazoie http://jci.me/83587
More, p. 6
Chromatin bridge
Dopaminergic inhibition
Colon cancer BRD4
j c i . o r g / t h i s - m o n t h F e b r u a r y 2 0 1 6 5
Research articles in the current issue of the JCI
TAP-independent self-peptides enhance T cell recognition of immune-escaped tumorsElien M. Doorduijn, Marjolein Sluijter, Bianca J. Querido, Cláudia C. Oliveira, Adnane Achour, Ferry Ossendorp, Sjoerd H. van der Burg, and Thorbald van Hall http://jci.me/83671
With related Commentary by Rolf Kiessling More, p. 7
PulmonologyPlacenta growth factor augments airway hyperresponsiveness via leukotrienes and IL-13Marthe-Sandrine Eiymo Mwa Mpollo, Eric B. Brandt, Shiva Kumar Shanmukhappa, Paritha I. Arumugam, Swati Tiwari, Anastacia Loberg, Devin Pillis, Tilat Rizvi, Mark Lindsey, Bart Jonck, Peter Carmeliet, Vijay K. Kalra, Timothy D. Le Cras, Nancy Ratner, Marsha Wills-Karp, Gurjit K. Khurana Hershey, and Punam Malik http://jci.me/77250
More, p. 8
Stem cellsTGF-β/β2-spectrin/CTCF-regulated tumor suppression in human stem cell disorder Beckwith-Wiedemann syndromeJian Chen, Zhi-Xing Yao, Jiun-Sheng Chen, Young Jin Gi, Nina M. Muñoz, Suchin Kundra, H. Franklin Herlong, Yun Seong Jeong, Alexei Goltsov, Kazufumi Ohshiro, Nipun A. Mistry, Jianping Zhang, Xiaoping Su, Sanaa Choufani, Abhisek Mitra, Shulin Li, Bibhuti Mishra, Jon White, Asif Rashid, Alan Yaoqi Wang, Milind Javle, Marta Davila, Peter Michaely, Rosanna Weksberg, Wayne L. Hofstetter, Milton J. Finegold, Jerry W. Shay, Keigo Machida, Hidekazu Tsukamoto, and Lopa Mishra http://jci.me/80937
Airway allergen
j c i . o r g / t h i s - m o n t h F e b r u a r y 2 0 1 666
The liver is a frequent site of metastasis of colorectal cancers. Approximately 60 percent of patients with colorectal cancer will develop a liver metastasis, which is associated with poor prognosis, prompting Sohail Tavazoie and colleagues to investigate the mechanisms responsible for driving secondary liver tumors. Using a large-scale shRNA drop-out screen in three different colon cancer cell lines, they identified a requirement for liver and red blood cell pyruvate kinase (PKLR) for liver colonization after direct injection of cells into the liver. The researchers subsequently showed higher PKLR expression in patient metastases compared with that in primary colorectal tumors. Mass spectrometric identification of PKLR-binding partners revealed an association with the PKM2 isoform of pyruvate kinase, which has dual roles in cancer, both driving aerobic glycolysis and also limiting the reducing potential of cells to withstand ROS damage. Biochemically, PKLR was found to repress PKM2, and loss of PKLR led to decreased levels of the antioxidant glutathione. Further, small-molecule inhibition of glutathione synthesis also decreased the ability of colon cancer cells to colonize the liver in mice. Taken together, these findings indicate that PKLR promotes metastatic progression by inhibiting PKM2 enzymatic activity and suggest a common pathway that can be therapeutically targeted across a broad spectrum of colorectal cancers.
Colorectal cancer metastasis is driven by pyruvate kinase isozyme expression
Editor’s picksResearch
The accompanying image shows a tumor nodule from PKLR-depleted tumor cells (luciferase, green), with few cells in the nodule core and increased numbers of apoptotic cells (cleaved caspase-3, red). Nuclei are stained with DAPI.
PKLR promotes colorectal cancer liver colonization through induction of glutathione synthesisAlexander Nguyen, Jia Min Loo, Rohit Mital, Ethan M. Weinberg, Fung Ying Man, Zhaoshi Zeng, Philip B. Paty, Leonard Saltz, Yelena Y. Janjigian, Elisa de Stanchina, and Sohail F. Tavazoie http://jci.me/83587
j c i . o r g / t h i s - m o n t h F e b r u a r y 2 0 1 6 7
Research | Editor’s picks
Progression of cancer in immunocompetent individuals requires that antitumor immune responses are suppressed. Multiple immune cell lineages contribute to immunosuppression in cancer, but the molecular mechanisms underlying development of these lineages are unclear. In this issue, Rahul Roychoudhuri and colleagues demonstrate that the transcription factor BACH2, which regulates the differentiation of multiple cellular lineages of the innate and adaptive immune systems, is required to establish immunosuppression within tumors. Loss of Bach2 in mice activated innate and adaptive immunity within tumors, resulting in impaired tumor growth. Mechanistically, BACH2 promoted tumor immunosuppression through CD4+ Treg-mediated inhibition of intratumoral CD8+ T cells and the inflammatory cytokine IFN-γ. These results indicate that BACH2 is a potential therapeutic target to disrupt immunosuppression in cancer.
The transcription factor BACH2 promotes tumor immunosuppressionRahul Roychoudhuri, Robert L. Eil, David Clever, Christopher A. Klebanoff, Madhusudhanan Sukumar, Francis M. Grant, Zhiya Yu, Gautam Mehta, Hui Liu, Ping Jin, Yun Ji, Douglas C. Palmer, Jenny H. Pan, Anna Chichura, Joseph G. Crompton, Shashank J. Patel, David Stroncek, Ena Wang, Francesco M. Marincola, Klaus Okkenhaug, Luca Gattinoni, and Nicholas P. Restifo http://jci.me/82884
Transcription factor BACH2 suppresses antitumor immunityoncology
tumor cells frequently eliminate antigen-process-ing components such as transporter associated with antigen processing-1 (TAP1), thereby reducing MHC-I–mediated antigen presentation (MHC-Ilo) and avoiding recognition by CD8+ T cells. MHC-Ilo tumors produce a class of cell surface antigens known as T cell epitopes associated with impaired peptide processing (TEIPPs). Elien M. Doorduijn and colleagues analyzed T cells specific for a prototypical TEIPP antigen and found that these cells were efficiently selected in the thymus, were egressed with a naive phenotype, and could be exploited for
immunotherapy targeting TAP1-deficient MHC-Ilo tumors. Importantly, mice with global TAP1 deficiency expressed TEIPPs on all body cells, leading to thymic deletion and functionally impaired TEIPP-specific T cells. These data indicate that TEIPP antigens are derived from ubiquitously expressed, nonmutated proteins and constitute a class of neoantigens that arise during tumor immune evasion. In the accompanying Commentary, Rolf Kiessling discusses how TEIPP antigens could potentially be targeted by immunothera-peutic strategies.
TAP-independent self-peptides enhance T cell recognition of immune-escaped tumorsElien M. Doorduijn, Marjolein Sluijter, Bianca J. Querido, Cláudia C. Oliveira, Adnane Achour, Ferry Ossendorp, Sjoerd H. van der Burg, and Thorbald van Hall http://jci.me/83671
Related CommentaryTAP-ing into TIEPPs for cancer immunotherapyRolf Kiessling http://jci.me/86119
Patients with chronic kidney disease (CKD) frequently develop anemia due to poor production of erythropoietin (EPO). Renal EPO-producing cells are present in CKD kidneys, but, while these cells can make EPO, they do not respond appropriately to hypoxic stimuli. In this issue, Yu-Ting Chang and colleagues show that fibroblast-like kidney pericytes produce EPO through a HIF2α-mediated mechanism but EPO production is repressed when these cells differentiate into myofibroblasts, as occurs in CKD. Myofibroblasts upregulate DNA methyl-transferases (see the accompanying image), which hypermethylate DNA to suppress gene expression. Chang and colleagues found that the Epo
promoter was hypermethylated in kidney myofibroblasts. Importantly, treatment with the DNA methyltransferase inhibitor 5-azacytidine
restored EPO expression and ameliorated anemia in a murine CKD model.
DNA methyltransferase inhibition restores erythropoietin production in fibrotic murine kidneysYu-Ting Chang, Ching-Chin Yang, Szu-Yu Pan, Yu-Hsiang Chou, Fan-Chi Chang, Chun-Fu Lai, Ming-Hsuan Tsai, Huan-Lun Hsu, Ching-Hung
Lin, Wen-Chih Chiang, Ming-Shiou Wu, Tzong-Shinn Chu, Yung-Ming Chen, and Shuei-Liong Lin http://jci.me/82819
TAP-ing into neoantigens resulting from tumor immune evasion
Erythropoietin is epigenetically repressed in fibrotic murine kidneysnephrology
j c i . o r g / t h i s - m o n t h F e b r u a r y 2 0 1 68
Research | Editor’s picks
endocrinology
CYP24A1 inhibition ameliorates skeletal abnormalities associated with FGF23-mediated renal phosphate wastingthe mitochondrial enzyme CYP24A1 initiates the degradation of the physiologically active form of vitamin D3. Long-lasting and/or elevated expression of CYP24A1 is hypothesized to contribute to the pathology of diseases that could potentially be ameliorated by vitamin D administration. Xiuying Bai and colleagues demonstrate that FGF23-mediated renal phosphate wasting and hypophosphatemic osteomalacia are associated with increased CYP24 expression. Deletion of Cyp24 in two mouse strains with high circulating levels of FGF23 resulted in a near-complete reversal of rachitic/osteomalacic bone abnormalities in the absence of any improvement in the serum biochemical profile. Treatment of either mouse model with the CYP24 inhibitor CTA102 also attenuated skeletal abnormalities. In the accompanying Commentary, Valentin David and Myles Wolf discuss how these findings indicate that pharmacological inhibition of CYP24 could be used as a therapeutic adjuvant in the treatment of FGF23-mediated renal phosphate wasting disorders.
CYP24 inhibition as a therapeutic target in FGF23-mediated renal phosphate wasting disordersXiuying Bai, Dengshun Miao, Sophia Xiao, Dinghong Qiu, René St-Arnaud, Martin Petkovich, Ajay Gupta, David Goltzman, and Andrew C. Karaplis http://jci.me/81928
Related CommentaryPruning the ricket thicketValentin David and Myles Wolf http://jci.me/85005
Placental growth factor promotes airway hyperresponsiveness in sickle cell diseaseover half of children with sickle cell disease (sCD) exhibit airway hyperresponsiveness (AhR), even in the absence of asthma. Because placental growth factor (PlGF) is elevated in the plasma of patients with SCD and contributes to inflammation, Marthe- Sandrine Eiymo Mwa Mpollo and colleagues examined the role of PlGF in SCD-associated AHR. Loss of PlGF in mice blunted AHR and inflammation (see the accompanying image) in response to house dust mite (HDM) allergen and decreased goblet cell metaplasia and eosinophil recruitment compared with WT mice. Mechanistically, PlGF upregulates the Th2 cytokine IL-13 via STAT6 and activates a leukotriene-dependent pathway that drives AHR. Moreover, SCD mice exhibited increased AHR and elevated leukotriene levels that were attenuated by administration of an anti-PlGF antibody or zileuton, an inhibitor of the leukotriene generator 5-lipoxygenase.
Placenta growth factor augments airway hyperresponsiveness via leukotrienes and IL-13Marthe-Sandrine Eiymo Mwa Mpollo, Eric B. Brandt, Shiva Kumar Shanmukhappa, Paritha I. Arumugam, Swati Tiwari, Anastacia Loberg, Devin Pillis, Tilat Rizvi, Mark Lindsey, Bart Jonck, Peter Carmeliet, Vijay K. Kalra, Timothy D. Le Cras, Nancy Ratner, Marsha Wills-Karp, Gurjit K. Khurana Hershey, and Punam Malik http://jci.me/77250
pulmonology
j c i . o r g / t h i s - m o n t h F e b r u a r y 2 0 1 6 9
Research | Editor’s picks
neuroscience
CXCR5/CXCL13 signaling mediates neuropathic pain in miceRecent studies have implicated chemokine signaling in microglial activation and neuropathic pain. Bao-Chun Jiang and colleagues found that the chemokine CXCL13 was persistently upregulated in spinal cord neurons after spinal nerve ligation (SNL), a murine model of neuropathic pain. Intrathecal injection of CXCL13 induced astrocyte activation (see the accompanying image) and pain hypersensitivity via the chemokine receptor CXCR5, which is also upregulated after SNL, and the MAPK ERK. Conversely, shRNA-mediated inhibition of CXCL13 or deletion of Cxcr5 abrogated SNL-induced neuropathic pain. Additionally, CXCL13 colocalized with miR-186-5p, which was downregulated after SNL in the spinal cord. Overexpression of miR-186-5p decreased CXCL13 expression and attenuated neuropathic pain. These findings suggest that CXCL13, CXCR5, and miR-186-5p may be suitable therapeutic targets for neuropathic pain.
CXCL13 drives spinal astrocyte activation and neuropathic pain via CXCR5Bao-Chun Jiang, De-Li Cao, Xin Zhang, Zhi-Jun Zhang, Li-Na He, Chun-Hua Li, Wen-Wen Zhang, Xiao-Bo Wu, Temugin Berta, Ru-Rong Ji, and Yong-Jing Gao http://jci.me/81950
Translating a rodent behavioral assay for humansBehavioral assays for the assessment of neurological and cognitive phenotypes are a cornerstone of research using rodent models of Alzheimer’s disease (AD); however, clinical trials based on results from these models have been largely unsuccessful. Katherine Possin and col-leagues developed a virtual version of the most frequently used behavioral assay of spatial learning and memory in rodents, the Morris water maze (MWM), and tested it in humans. They compared the sensitivity of the traditional assay in mice expressing human amyloid precursor protein (hAPP) and patients with mild cognitive impairments due to AD. Possin and colleagues found that the patients and hAPP mice exhibited similar deficits in learning and remembering a target location, but only the hAPP mice showed deficits in procedural learning. In the accompanying Commentary, Kerin Higa, Jared Young, and Mark Geyer discuss how these findings suggest strategies to make the MWM more relevant to learning and memory deficits in humans.
Cross-species translation of the Morris maze for Alzheimer’s diseaseKatherine L. Possin, Pascal E. Sanchez, Clifford Anderson-Bergman, Roland Fernandez, Geoffrey A. Kerchner, Erica T. Johnson, Allyson Davis, Iris Lo, Nicholas T. Bott, Thomas Kiely, Michelle C. Fenesy, Bruce L. Miller, Joel H. Kramer, and Steven Finkbeiner http://jci.me/78464
Related CommentaryWet or dry: translatable “water mazes” for mice and humansKerin K. Higa, Jared W. Young, and Mark A. Geyer http://jci.me/86071
j c i . o r g / t h i s - m o n t h F e b r u a r y 2 0 1 610
Review Series
HIV
The development of combination antiretroviral therapy in the mid-1990s initially raised hopes that HIV was a curable disease; however, further studies revealed that the virus persists, even in patients with undetectable levels of HIV in their plasma. Resting CD4+ T cells harbor stably integrated viral genomes that can produce infectious virus following T cell activation. Importantly, treatment interruption leads to a rapid recrudescence of infection from this latent reservoir, usually within two to three weeks. Several distinct areas of HIV research are now focused on the development of strategies to prevent the latent reservoir from replicating or to eliminate it entirely. Reviews in this series detail progress in our understanding of the molecular and cellular mechanisms of viral latency, efforts to accurately assess the size and composition of the latent viral reservoir, the characterization and development of HIV-targeted broadly neutralizing antibodies and cytolytic T lymphocytes, and animal models for the study of HIV latency and therapeutic strategies.
Recent developments in the effort to cure HIV infection: going beyond N = 1Janet D. Siliciano and Robert F. Siliciano http://jci.me/86047
Dr. Robert Siliciano is a Howard Hughes Medical Institute investigator and Professor of Medicine at the Johns Hopkins University School of Medicine, with a joint appointment in the Department of Molecular Biology and Genetics. In 1995, Dr. Siliciano’s group provided the first demonstration that latently infected CD4+ T cells were present in patients with HIV-1 infection. His laboratory has gone on to characterize the different forms of HIV that persist in patients on antiretroviral therapy (ART) and to explore potential strategies for eliminating the virus, including the evaluation of drugs that target the latent reservoir and the development of assays that can be used to monitor the elimination of this reservoir.
Paving the way for an HIV cureSeries Editor: Robert F. siliciano
Towards HIV-1 remission: potential roles for broadly neutralizing antibodiesAriel Halper-Stromberg and Michel C. Nussenzweig
In vivo platforms for analysis of HIV persistence and eradicationJ. Victor Garcia
Hematopoietic stem cell transplantation for HIV cureDaniel R. Kuritzkes
The role of HIV integration in viral persistence: no more whistling past the proviral graveyardFrank Maldarelli
Molecular mechanisms of HIV latencyDaniele C. Cary, Koh Fujinaga, and B. Matija Peterlin
HIV-specific CD8+ T cells and HIV eradicationR. Brad Jones and Bruce D. Walker
Measuring the latent reservoir in vivoMarta Massanella and Douglas D. Richman
j c i . o r g / t h i s - m o n t h F e b r u a r y 2 0 1 6 11
Review Series | HIV
HIV persistence, integration, and clonal expansion
Applications of broadly neutralizing antibodies in HIV treatment
Murine models of HIV infectionDespite the ability of modern antiretroviral therapy (ARt) to suppress virus in the peripheral blood, HIV persists in patients indefinitely, and treatment interruption results in a rapid rebound of plasma viremia. The viral reservoir is likely to reside in cells and tissues such as the brain that are not easily accessible for analysis; therefore, animal models of HIV infection are required for the investigation of HIV persistence as well as the testing of strategies to eradicate the virus. J. Victor Garcia examines the utility of animal models for the investigation of HIV persistence and eradication strategies, focusing on recent humanized mouse models (see the accompanying image). Humanized mouse models can be used for the study of different types of viral infection, the analysis of latency and persistence in HIV-targeted human cell types in the periphery and within tissues, and the in vivo evaluation of new and established ART combinations, as well as novel shock-and-kill strategies.
In vivo platforms for analysis of HIV persistence and eradicationJ. Victor Garcia http://jci.me/80562
hiV cure will necessitate the use of strategies that eliminate all copies of the virus from host cells; however, for such strategies to be successful, it will be necessary to understand exactly how HIV persists in the host before and during antiretroviral therapy (ART). Integration of proviruses into the genome of host cells is a common feature of retroviruses, including HIV. Recent technological advances have allowed the characterization of proviruses and the host genes into which they integrate. Frank Maldarelli describes HIV populations prior to
and following the introduction of ART, the central role of HIV integration in long-term persistence, the evidence for clonal expansion of HIV-infected cells, and current concepts regarding the role of clonal expansion in the persistence of replication-competent HIV.
The role of HIV integration in viral persistence: no more whistling past the proviral graveyardFrank Maldarelli http://jci.me/80564
Methods to measure the HIV latent reservoirthe hiV latent reservoir is composed of infected cells that contain a viral genome in a dormant state from which virus replication can be induced. The ability to accurately measure the number of latently infected cells will be critical to assessing the effects of therapeutic strategies for eliminating the latent viral reservoir. Marta Massanella and Douglas Richman review the attributes and limitations of the methods that are currently being employed to measure the latent reservoir, including PCR-based assays and quantitative viral outgrowth assays (QVOA). Characterization of these assays will require standardization of the procedures used in different laboratories and rigorous evaluation of sensitivity, specificity, and reproducibility, as well as comparisons to clinical results.
Measuring the latent reservoir in vivoMarta Massanella and Douglas D. Richman http://jci.me/80567
the benefits of therapeutic cancer vaccines Broadly neutralizing antibodies (bNabs) are naturally arising antibodies that are capable of neutralizing multiple HIV-1 viral strains. Ariel Halper-Stromberg and Michel Nussenzweig discuss the potential roles that bNabs might play in HIV-1 treatment regimens, including prevention, therapy, and cure. Unlike current drug therapies, bNabs bind to virions directly and can engage other immune effector mechanisms through Fc receptors (see the accompanying image). Modifications that enhance potency or
targeting, such as increasing antibody half-lives, potency, and engagement of Fc receptors or the addition of immunotoxins, could enhance the antiviral functions of bNabs. Additionally, bNabs are currently being tested in “shock and kill” strategies to eradicate HIV.
Towards HIV-1 remission: potential roles for broadly neutralizing antibodiesAriel Halper-Stromberg and Michel C. Nussenzweig http://jci.me/80561
j c i . o r g / t h i s - m o n t h F e b r u a r y 2 0 1 612
Hematopoietic stem cell transplantation for HIV cure: challenges and perspectivesBecause antiretroviral therapy cannot completely eliminate HIV, patients can never be fully cured and must remain on therapy for the rest of their lives. A single HIV-infected patient with refractory lymphoma achieved apparent cure following hematopoietic stem cell transplantation (HSCT) from an allogeneic donor homozygous for the ccr5Δ32 mutation, which prevents infection with CCR5-tropic HIV strains. Daniel Kuritzkes reviews the experience with HSCT in HIV-infected patients to date and surveys the ongoing work in this field. Attempts to replicate the apparent cure of HIV-1 infection by HSCT have failed thus far, indicating that transplantation with CCR5-deficient cells is necessary but possibly not sufficient for eradication of the virus. Kuritzkes also discusses the potential of using genetically modified hematopoietic stem cells to cure HIV. Importantly, there are concerns regarding the safety of subjecting otherwise healthy HIV-infected individuals to HSCT.
Hematopoietic stem cell transplantation for HIV cureDaniel R. Kuritzkes http://jci.me/80563
Review Series | HIV
Search and destroy: helping CD8+ T cells eliminate HIV
Understanding HIV gene expression and latency
hiV infection elicits a vigorous hiV-specific response; however, the immune system is unable to eliminate infected cells. Studies using pharmacological strategies to drive the expression of virus in latently infected cells have indicated that infected cells do not die by viral cytopathic effects and will need to be eliminated by HIV-specific cytotoxic T lymphocytes (CTLs). Importantly, this anti-HIV response will need to be more potent than the response elicited by a naturally occurring infection. R. Brad Jones and Bruce Walker discuss the factors that determine the ability of CTLs to recognize infected cells and the barriers to CTL-mediated clearance of HIV-infected cells, including viral immune escape, T cell exhaustion and dysfunction, compartmentalization of CTLs and viral reservoirs, and HIV latency, as well as therapeutic strategies to overcome these barriers (see the accompanying image).
HIV-specific CD8+ T cells and HIV eradicationR. Brad Jones and Bruce D. Walker http://jci.me/80566
Resting CD4+ t cells as well as potentially other cells and tissues within the body harbor latent proviruses that are stably integrated into the genome. The goal of shock-and-kill strategies is to force latently infected cells to express virus so that they can be cleared by the immune system. Understanding the basic mechanisms that govern HIV gene expression will aid in the development of methods to induce viral expression. Daniele Cary, Koh Fujinaga, and Matija Peterlin describe the pathways that mediate HIV gene expression (see the accompanying image), including the mechanisms that prevent expression in latent cells. Additionally, they identify critical cellular and viral factors that may be suitable therapeutic targets for inducing viral expression while preventing T cell activation.
Molecular mechanisms of HIV latencyDaniele C. Cary, Koh Fujinaga, and B. Matija Peterlin http://jci.me/80565
j c i . o r g / t h i s - m o n t h F e b r u a r y 2 0 1 6 13
JCI Insight
Tubular Dickkopf-3 promotes the development of renal atrophy and fibrosisLoss of the Wnt pathway modulator Dickkopf-3 (DKK3) protects mice from kidney fibrosis, and elevated DKK3 correlates with interstitial fibrosis in patients.
Giuseppina Federico, Michael Meister, Daniel Mathow, Gunnar H. Heine, Gerhard Moldenhauer, Zoran V. Popovic, Viola Nordström, Annette Kopp-Schneider, Thomas Hielscher, Peter J. Nelson, Franz Schaefer, Stefan Porubsky, Danilo Fliser, Bernd Arnold, and Hermann-Josef Gröne http://jci.me/84916
Interaction of β1-adrenoceptor with RAGE mediates cardiomyopathy via CaMKII signalingThe β1-adrenergic receptor and danger signal pattern recognition receptor RAGE mediate myocardial cell death in a functionally dependent manner.
Weizhong Zhu, Sharon Tsang, David M. Browe, Anthony Y.H. Woo, Ying Huang, Chanjuan Xu, Jian-Feng Liu, Fengxiang Lv, Yan Zhang, and Rui-ping Xiao http://jci.me/84969
Relationships among injury, fibrosis, and time in human kidney transplantsTranscriptome analysis of human kidney transplant biopsies suggests that fibrosis reflects an adaptive response to injury.
Jeffery M. Venner, Konrad S. Famulski, Jeff Reeve, Jessica Chang, and Philip F. Halloran http://jci.me/85323
Blocking MHC class II on human endothelium mitigates acute rejectionIn a humanized mouse model, endothelial cell MHC class II activates CD4+ T effector memory cells and promotes vascular allograft rejection.
Parwiz Abrahimi, Lingfeng Qin, William G. Chang, Alfred L.M. Bothwell, George Tellides, W. Mark Saltzman, and Jordan S. Pober http://jci.me/85293
Dickkopf-3 mRNA
Myocardial fibrosis
Endothelial cell lining
Fibrosis over time
Research articles in the inaugural issue of JCI Insight, a new peer-reviewed journal dedicated to translational biomedical research, ranging from preclinical to clinical studies:
More information: http://jci.me/insinf or [email protected]
Alejandro Aballay
Abul K. Abbas
Domenico Accili
Rexford S. Ahima
Qais Al-Awqati
Kari Alitalo
James Allison
Dario C. Altieri
Masayuki Amagai
Mark E. Anderson
Brian H. Annex
Alan Attie
Jane E. Aubin
Steven P. Balk
Michael F. Beers
John A. Belperio
Nina Bhardwaj
Morris J. Birnbaum
Joyce Bischoff
Mina J. Bissell
Craig Blackstone
Bruce R. Blazar
Nancy Bonini
Brendan Boyce
Jonathan Bromberg
Frank C. Brosius
Hal E. Broxmeyer
Andrew Butler
Michael J. Caplan
Ruben D. Carrasco
Diego H. Castrillon
Harold Chapman
Ajay Chawla
Benjamin K. Chen
Benny J. Chen
Ju Chen
Marie-Françoise Chesselet
Vivian G. Cheung
Yongwon Choi
Thomas Clemens
Ronald G. Collman
Marco Colonna
George Cotsarelis
Shaun R. Coughlin
Christopher M. Counter
Peter D. Crompton
Tyler J. Curiel
David D’Alessio
Richard T. D’Aquila
Riccardo Dalla-Favera
Alan Daugherty
Ted Dawson
Sudhansu Dey
Harry C. Dietz III
Gianpietro Dotti
Michael Dustin
Connie J. Eaves
Dominique Eladari
Jack A. Elias
Joel K. Elmquist
Stephen G. Emerson
Jeffrey A. Engelman
Jonathan A. Epstein
Adrian Erlebacher
Joel D. Ernst
James M. Ervasti
Robert V. Farese Jr.
Eric R. Fearon
Edward A. Fisher
Susan Fisher
Richard A. Flavell
Tatiana Foroud
Velia M. Fowler
Martin Friedlander
Stephen J. Galli
J. Victor Garcia-Martinez
Alfred L. George Jr.
Stanton L. Gerson
Robert E. Gerszten
Todd Golde
Stanley Goldfarb
Larry B. Goldstein
Fred Sanford Gorelick
Kathleen J. Green
J. Timothy Greenamyre
Theresa A. Guise
David Hafler
Jonathan J. Hansen
Raymond C. Harris
Stanley L. Hazen
Peter Heeringa
Brian A. Hemmings
Meenhard Herlyn
Joachim Herz
Katherine A. High
Helen H. Hobbs
Ronald Hoffman
V. Michael Holers
Steven M. Holland
Michael J. Holtzman
Lawrence B. Holzman
Tamas L. Horvath
Gokhan S. Hotamisligil
Steven R. Houser
Scott J. Hultgren
Christopher A. Hunter
Ciro Indolfi
David E. James
William G. Kaelin Jr.
Klaus Kaestner
Mark L. Kahn
Raghu Kalluri
S. Ananth Karumanchi
Robert S. Kass
Masato Kasuga
Dontscho Kerjaschki
Sundeep Khosla
Richard N. Kitsis
Peter S. Klein
Steven Kliewer
Björn C. Knollmann
Walter J. Koch
Jay K. Kolls
Issei Komuro
Christopher D. Kontos
Murray Korc
Gary Koretzky
Calvin Kuo
Antonio La Cava
Fadi G. Lakkis
Terri Laufer
Mitchell A. Lazar
Brendan Lee
William M.F. Lee
Rudolph L. Leibel
Stanley M. Lemon
Jon D. Levine
Ross L. Levine
Klaus Ley
Richard M. Locksley
Gary Lopaschuk
Richard B. Mailman
Andrew R. Marks
Jack Martin
Steven O. Marx
Rodger P. McEver
Elizabeth McNally
Cornelius J. Melief
Shlomo Melmed
George Michalopoulos
Jeffrey H. Miner
Beverly Mitchell
Peter J. Mohler
Kelle Harbert Moley
Jeffery Molkentin
David D. Moore
Edward E. Morrisey
James H. Morrissey
Anthony J. Muslin
Martin G. Myers Jr.
Benjamin G. Neel
Eric N. Olson
Harry T. Orr
William C. Parks
Warren S. Pear
Sallie R. Permar
David J. Pinsky
Edward Plow
Jeffrey Pollard
Kornelia Polyak
Catherine Postic
Josef Prchal
Alice S. Prince
Louis J. Ptáček
Luigi Puglielli
Pere Puigserver
Bali Pulendran
Ellen Puré
Susan E. Quaggin
Marlene Rabinovitch
Daniel J. Rader
Shahin Rafii
Gwendalyn J. Randolph
Barbara Rehermann
Steven L. Reiner
Sarah A. Robertson
Paul B. Rosenberg
Theodora S. Ross
Marc E. Rothenberg
Anil Rustgi
J. Evan Sadler
Junichi Sadoshima
Jose-Alain Sahel
Jean E. Schaffer
Philipp E. Scherer
Michael D. Schneider
Detlef Schuppan
Michael W. Schwartz
William K. Scott
Randy Seeley
Amita Sehgal
Clay Semenkovich
Gregg L. Semenza
John Seykora
Steven D. Shapiro
Mari Shinohara
Steven E. Shoelson
Gerald I. Shulman
Roy L. Silverstein
M. Celeste Simon
Journal of Clinical Investigation Consulting Editors
Mihaela Skobe
Lois Smith
Steven R. Smith
Susan S. Smyth
Weihong Song
Ashley L. St. John
Herman F. Staats
Jonathan S. Stamler
John R. Stanley
Colin L. Stewart
Doris Stoffers
Warren Strober
Maureen A. Su
Katalin Susztak
Catharina Svanborg
Ira Tabas
Alan R. Tall
Sakae Tanaka
Victor J. Thannickal
Andrei Thomas-Tikhonenko
Georgia D. Tomaras
Peter Tontonoz
Laurence A. Turka
Raphael H. Valdivia
Marcel R.M. van den Brink
Luc Van Kaer
Matthias von Herrath
Yisong Y. Wan
Hong Wang
David Weinstock
Jeffrey Weiser
Stephen J. Weiss
Bart O. Williams
Joseph C. Wu
Thomas A. Wynn
Rudolf Zechner
Kang Zhang
Len Zon
Ming-Hui Zou
Weiping Zou
