jci.org/impactfebruary 2015

Also in this issue:

Grehlin shapes feeding circuits 7

Alterations in lung cancer metabolism 9

Designer antibiotics avoid side effects 11

A summary of this month’s Journal of Clinical investigation

Mitochondrial dysfunction in lung fibrosisp. 6

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Alejandro Aballay

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Harold Chapman

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Journal of Clinical Investigation Consulting Editors

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t h e j o u r n a l o f c l i n i c a l i n v e s t i g a t i o n j c i . o r g / i m p a c t f e b r u a r y 2 0 1 5 1

editorHoward A. Rockman

Deputy 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, Cam Patterson, 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

senior science editorSarah C. Jackson

science editorJillian Hurst

Assistant science editorCorinne Williams

editor at largeUshma S. Neill

issn 2324-7703 (print)issn 2325-4556 (online)The American Society for Clinical Investigation holds the rights to and publishes the Journal of Clinical Investigation. The opinions expressed herein are solely those of the authors and are not necessarily endorsed by the ASCI.

Impactfebruary 2015

Contact the JCiThe Journal of Clinical Investigation2015 Manchester RoadAnn Arbor, Michigan 48104, USAPhone: 734.222.6050E-mail: staff@the-jci.org

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In recent years, questions have been raised regarding the failure of some pre-clinical work to translate to clinical benefit and the inability to reproduce some high-profile studies. While myriad factors contribute to these problems, an important step in improving the integrity of published work is for journals to enforce rigorous reporting of methods and results.

The Editorial Board of the JCI is committed to ensuring that all articles adhere to the highest standard of data rigor and transparency. In keeping with this, the JCI has revised its instructions to authors for manuscripts and data reporting requirements.

We now require both the number of samples and the statistical test used to be reported in the figure legends of all manuscripts. We continue to recommend that authors avoid the use of bar graphs and instead plot each individual data point to allow readers to better appreciate the sample size and distribution.

We are also asking authors to provide access to more types of high-throughput data sets in public repositories and to include more information in Methods sections regarding antibodies, cell lines, and newly synthesized chemical compounds. The JCI continues to require authors to include uncropped and unedited versions of all immunoblots and gels for review by the Editors and reviewers. We encourage authors to include these images with their publica-tion on our website as well.

The Editors believe that reporting of all of the information related to materials, samples, and statistics is paramount for researchers in the field to accurately assess the data and conduct follow-up experiments in their own labs. Our latest reporting requirements are an important step to ensure the highest quality and integrity of data in the JCI.

Sarah Jackson,Senior Science Editor

For the full version of Dr. Jackson’s editorial, see http://jci.me/80370.

The importance of being transparent

from the editor

2 t h e j o u r n a l o f c l i n i c a l i n v e s t i g a t i o n j c i . o r g / i m p a c t f e b r u a r y 2 0 1 5

Bone biologyIncreased glutamine catabolism mediates bone anabolism in response to WNT signalingCourtney M. Karner, Emel Esen, Adewole L. Okunade, Bruce W. Patterson, and Fanxin Long http://jci.me/78470

Retinoid X receptors orchestrate osteoclast differentiation and postnatal bone remodelingMaría P. Menéndez-Gutiérrez, Tamás Rőszer, Lucía Fuentes, Vanessa Núñez, Amelia Escolano, Juan Miguel Redondo, Nora De Clerck, Daniel Metzger, Annabel F. Valledor, and Mercedes Ricote http://jci.me/77186

More, p. 12

Clinical trialsMetabolically normal obese people are protected from adverse effects following weight gainElisa Fabbrini, Jun Yoshino, Mihoko Yoshino, Faidon Magkos, Courtney Tiemann Luecking, Dmitri Samovski, Gemma Fraterrigo, Adewole L. Okunade, Bruce W. Patterson, and Samuel Klein http://jci.me/78425

More, p. 9

EndocrinologyNeonatal ghrelin programs development of hypothalamic feeding circuitsSophie M. Steculorum, Gustav Collden, Berengere Coupe, Sophie Croizier, Sarah Lockie, Zane B. Andrews, Florian Jarosch, Sven Klussmann, and Sebastien G. Bouret http://jci.me/73688

With related Commentary by Jenny Tong and David D’Alessio More, p. 7

Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxineJoao Pedro Werneck de Castro, Tatiana L. Fonseca, Cintia B. Ueta, Elizabeth A. McAninch, Sherine Abdalla, Gabor Wittmann, Ronald M. Lechan, Balazs Gereben, and Antonio C. Bianco http://jci.me/77588

More, p. 7

GastroenterologyNeuroepithelial circuit formed by innervation of sensory enteroendocrine cellsDiego V. Bohórquez, Rafiq A. Shahid, Alan Erdmann, Alex M. Kreger, Yu Wang, Nicole Calakos, Fan Wang, and Rodger A. Liddle http://jci.me/78361

More, p. 12

Research articles in the current issue of the JCI

WNT-induced bone anabolism

Enteroendocrine neuropod

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GeneticsGlobal transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypesBo Yuan, Davut Pehlivan, Ender Karaca, Nisha Patel, Wu-Lin Charng, Tomasz Gambin, Claudia Gonzaga-Jauregui, V. Reid Sutton, Gozde Yesil, Sevcan Tug Bozdogan, Tulay Tos, Asuman Koparir, Erkan Koparir, Christine R. Beck, Shen Gu, Huseyin Aslan, Ozge Ozalp Yuregir, Khalid Al Rubeaan, Dhekra Alnaqeb, Muneera J. Alshammari, Yavuz Bayram, Mehmed M. Atik, Hatip Aydin, Bilge Geckinli, Mehmet Seven, Hakan Ulucan, Elif Fenercioglu, Mustafa Ozen, Shalini Jhangiani, Donna M. Muzny, Eric Boerwinkle, Beyhan Tuysuz, Fowzan S. Alkuraya, Richard A. Gibbs, and James R. Lupski http://jci.me/77435

HepatologyVascular adhesion protein-1 promotes liver inflammation and drives hepatic fibrosisChris J. Weston, Emma L. Shepherd, Lee C. Claridge, Pia Rantakari, Stuart M. Curbishley, Jeremy W. Tomlinson, Stefan G. Hubscher, Gary M. Reynolds, Kristiina Aalto, Quentin M. Anstee, Sirpa Jalkanen, Marko Salmi, David J. Smith, Christopher P. Day, and David H. Adams http://jci.me/73722

ImmunologyThe HMGB1/RAGE axis triggers neutrophil-mediated injury amplification following necrosisPeter Huebener, Jean-Philippe Pradere, Celine Hernandez, Geum-Youn Gwak, Jorge Matias Caviglia, Xueru Mu, John D. Loike, Rosalind E. Jenkins, Daniel J. Antoine, and Robert F. Schwabe http://jci.me/76887

GP96 is a GARP chaperone and controls regulatory T cell functionsYongliang Zhang, Bill X. Wu, Alessandra Metelli, Jessica Thaxon, Feng Hong, Saleh Rachidi, Ephraim Ansa-Addo, Shaoli Sun, Chenthamarakshan Vasu, Yi Yang, Bei Liu, and Zihai Li http://jci.me/79014

UCP2-induced fatty acid synthase promotes NLRP3 inflammasome activation during sepsisJong-Seok Moon, Seonmin Lee, Mi-Ae Park, Ilias I. Siempos, Maria Haslip, Patty J. Lee, Mijin Yun, Chun K. Kim, Judi Howrylak, Stefan W. Ryter, Kiichi Nakahira, and Augustine M.K. Choi http://jci.me/78253

Infectious diseaseTLR4 genotype and environmental LPS mediate RSV bronchiolitis through Th2 polarizationMauricio T. Caballero, M. Elina Serra, Patricio L. Acosta, Jacqui Marzec, Luz Gibbons, Maximiliano Salim, Andrea Rodriguez, Andrea Reynaldi, Alejandro Garcia, Daniela Bado, Ursula J. Buchholz, Diego R. Hijano, Silvina Coviello, Dawn Newcomb, Miguel Bellabarba, Fausto M. Ferolla, Romina Libster, Ada Berenstein, Susana Siniawaski, Valeria Blumetti, Marcela Echavarria, Leonardo Pinto, Andrea Lawrence, M. Fabiana Ossorio, Arnoldo Grosman, Cecilia G. Mateu, Carola Bayle, Alejandra Dericco, Mariana Pellegrini, Ignacio Igarza, Horacio A. Repetto, Luciano Alva Grimaldi, Prathyusha Gudapati, Norberto R. Polack, Fernando Althabe, Min Shi, Fernando Ferrero, Eduardo Bergel, Renato T. Stein, R. Stokes Peebles, Mark Boothby, Steven R. Kleeberger, and Fernando P. Polack http://jci.me/75183

Annexin1 regulates DC efferocytosis and cross-presentation during Mycobacterium tuberculosis infectionFanny Tzelepis, Mark Verway, Jamal Daoud, Joshua Gillard, Kimya Hassani-Ardakani, Jonathan Dunn, Jeffrey Downey, Marilena Elena Gentile, Joanna Jaworska, Anthony Michel Jean Sanchez, Yohann Nédélec, Hojatollah Vali, Maryam Tabrizian, Arnold Scott Kristof, Irah Luther King, Luis Bruno Barreiro, and Maziar Divangahi http://jci.me/77014

More, p. 11

Research articles in the current issue of the JCI

VAP-1 in fibrotic liver

Treg-deficient small bowel

Efferocytosis in spleen

4 t h e j o u r n a l o f c l i n i c a l i n v e s t i g a t i o n j c i . o r g / i m p a c t f e b r u a r y 2 0 1 5

NephrologySirtuin 3–dependent mitochondrial dynamic improvements protect against acute kidney injuryMarina Morigi, Luca Perico, Cinzia Rota, Lorena Longaretti, Sara Conti, Daniela Rottoli, Rubina Novelli, Giuseppe Remuzzi, and Ariela Benigni http://jci.me/77632

Polycystin-1 maturation requires polycystin-2 in a dose-dependent mannerVladimir G. Gainullin, Katharina Hopp, Christopher J. Ward, Cynthia J. Hommerding, and Peter C. Harris http://jci.me/76972

NeuroscienceDisrupting SUMOylation enhances transcriptional function and ameliorates polyglutamine androgen receptor–mediated diseaseJason P. Chua, Satya L. Reddy, Zhigang Yu, Elisa Giorgetti, Heather L. Montie, Sarmistha Mukherjee, Jake Higgins, Richard C. McEachin, Diane M. Robins, Diane E. Merry, Jorge A. Iñiguez-Lluhí, and Andrew P. Lieberman http://jci.me/73214

With related Commentary by Tim J. Craig and Jeremy M. Henley More, p. 10

Dysregulation of microRNA-219 promotes neurodegeneration through post-transcriptional regulation of tauIsmael Santa-Maria, Maria E. Alaniz, Neil Renwick, Carolina Cela, Tudor A. Fulga, David Van Vactor, Thomas Tuschl, Lorraine N. Clark, Michael L. Shelanski, Brian D. McCabe, and John F. Crary http://jci.me/78421

More, p. 11

MHCII-independent CD4+ T cells protect injured CNS neurons via IL-4James T. Walsh, Sven Hendrix, Francesco Boato, Igor Smirnov, Jingjing Zheng, John R. Lukens, Sachin Gadani, Daniel Hechler, Greta Gölz, Karen Rosenberger, Thomas Kammertöns, Johannes Vogt, Christine Vogelaar, Volker Siffrin, Ali Radjavi, Anthony Fernandez-Castaneda, Alban Gaultier, Ralf Gold, Thirumala-Devi Kanneganti, Robert Nitsch, Frauke Zipp, and Jonathan Kipnis http://jci.me/76210

With related Commentary by Lawrence Steinman More, p. 10

OncologyPyruvate carboxylase is critical for non–small-cell lung cancer proliferationKatherine Sellers, Matthew P. Fox, Michael Bousamra II, Stephen P. Slone, Richard M. Higashi, Donald M. Miller, Yali Wang, Jun Yan, Mariia O. Yuneva, Rahul Deshpande, Andrew N. Lane, and Teresa W.-M. Fan http://jci.me/72873

With related Commentary by Christopher T. Hensley and Ralph J. DeBerardinis More, p. 9

Tumor-specific cytotoxic T lymphocyte activity determines colorectal cancer patient prognosisChristopher Reissfelder, Slava Stamova, Christina Gossmann, Marion Braun, Andreas Bonertz, Ute Walliczek, Mario Grimm, Nuh N. Rahbari, Moritz Koch, Maral Saadati, Axel Benner, Markus W. Büchler, Dirk Jäger, Niels Halama, Khashayarsha Khazaie, Jürgen Weitz, and Philipp Beckhove http://jci.me/74894

More, p. 8

F-box protein FBXW7 inhibits cancer metastasis in a non-cell-autonomous mannerKanae Yumimoto, Sayuri Akiyoshi, Hiroki Ueo, Yasuaki Sagara, Ichiro Onoyama, Hiroaki Ueo, Shinji Ohno, Masaki Mori, Koshi Mimori, and Keiichi I. Nakayama http://jci.me/78782

More, p. 8

Research articles in the current issue of the JCI

SIRT3 in proximal tubules

Muscle fiber atrophy

Lung macrophages

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Proximity ligation assay evaluates IDH1R132H presentation in gliomasLukas Bunse, Theresa Schumacher, Felix Sahm, Stefan Pusch, Iris Oezen, Katharina Rauschenbach, Marina Gonzalez, Gergely Solecki, Matthias Osswald, David Capper, Benedikt Wiestler, Frank Winkler, Christel Herold-Mende, Andreas von Deimling, Wolfgang Wick, and Michael Platten http://jci.me/77780

NOTCH pathway inactivation promotes bladder cancer progressionAntonio Maraver, Pablo J. Fernandez-Marcos, Timothy P. Cash, Marinela Mendez-Pertuz, Marta Dueñas, Paolo Maietta, Paola Martinelli, Maribel Muñoz-Martin, Mónica Martínez-Fernández, Marta Cañamero, Giovanna Roncador, Jorge L. Martinez-Torrecuadrada, Dimitrios Grivas, Jose Luis de la Pompa, Alfonso Valencia, Jesús M. Paramio, Francisco X. Real, and Manuel Serrano http://jci.me/78185

More, p. 8

OphthalmologyCRALBP supports the mammalian retina visual cycle and cone visionYunlu Xue, Susan Q. Shen, Jonathan Jui, Alan C. Rupp, Leah C. Byrne, Samer Hattar, John G. Flannery, Joseph C. Corbo, and Vladimir J. Kefalov http://jci.me/79651

OtologyDesigner aminoglycosides prevent cochlear hair cell loss and hearing lossMarkus E. Huth, Kyu-Hee Han, Kayvon Sotoudeh, Yi-Ju Hsieh, Thomas Effertz, Andrew A. Vu, Sarah Verhoeven, Michael H. Hsieh, Robert Greenhouse, Alan G. Cheng, and Anthony J. Ricci http://jci.me/77424

More, p. 11

PulmonologyPINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosisMarta Bueno, Yen-Chun Lai, Yair Romero, Judith Brands, Claudette M. St. Croix, Christelle Kamga, Catherine Corey, Jose D. Herazo-Maya, John Sembrat, Janet S. Lee, Steve R. Duncan, Mauricio Rojas, Sruti Shiva, Charleen T. Chu, and Ana L. Mora http://jci.me/74942

More, p. 6

HIF2α signaling inhibits adherens junctional disruption in acute lung injuryHaixia Gong, Jalees Rehman, Haiyang Tang, Kishore Wary, Manish Mittal, Pallavi Chatturvedi, Youyang Zhao, Yulia A. Komorova, Stephen M. Vogel, and Asrar B. Malik http://jci.me/77701

Telomerase mutations in smokers with severe emphysemaSusan E. Stanley, Julian J.L. Chen, Joshua D. Poldlevsky, Jonathan K. Adler, Nadia N. Hansel, Rasika A. Mathias, Xiaodong Qi, Nicholas M. Rafaels, Robert A. Wise, Edwin K. Silverman, Kathleen C. Barnes, and Mary Armanios http://jci.me/78554

Stem cellsDifferentiation of hypothalamic-like neurons from human pluripotent stem cellsLiheng Wang, Kana Meece, Damian J. Williams, Kinyui Alice Lo, Matthew Zimmer, Garrett Heinrich, Jayne Martin Carli, Charles A. Leduc, Lei Sun, Lori M. Zeltser, Matthew Freeby, Robin Goland, Stephen H. Tsang, Sharon L. Wardlaw, Dieter Egli, and Rudolph L. Leibel http://jci.me/79220

TherapeuticsVector design influences hepatic genotoxicity after adeno-associated virus gene therapyRandy J. Chandler, Matthew C. LaFave, Gaurav K. Varshney, Niraj S. Trivedi, Nuria Carrillo-Carrasco, Julien S. Senac, Weiwei Wu, Victoria Hoffmann, Abdel G. Elkahloun, Shawn M. Burgess, and Charles P. Venditti http://jci.me/79213

Research articles in the current issue of the JCI

Disrupted adherens junctions

66

Idiopathic pulmonary fibrosis (IPf), a progres-sive disorder for which there is no cure, results in scarring of lung tissue. The risk of developing IPF profoundly increases with age; however, the molecular processes that drive IPF patho-genesis are poorly understood. In this month’s issue of the JCI, Marta Bueno and colleagues provide data suggesting that mitochondrial dysfunction in cells of the alveolus, the gas exchange region of the lung, promotes IPF. They found that IPF was associated with mito-chondrial abnormalities and ER stress in alveo-lar type II cells (AECIIs) in patients. In a mouse model, the researchers showed that impair-ments in mitochondrial function increase in AECIIs with age. Further, treatment of young mice with tunicamycin, a compound that trig-gers ER stress, led to increased mitochrondrial mass in AECIIs and greater susceptibility to fibrosis. Impaired mitochondria in tunicamy-cin-treated mice, aging mice, and IPF patients were correlated with reduced expression of PTEN-induced putative kinase 1 (PINK1). The research team showed that mice lacking PINK1 had impaired mitochondrial function in AECIIs and a greater propensity to develop lung fibro-sis. Their work suggests that ER stress–induced PINK1 downregulation leads to mitochondrial dysfunction in AECIIs that contributes to IPF development. The accompanying image is a transmission electron micrograph of an alveo-lar type II cell from the lung of an IPF patient. Dysmorphic, swollen mitochondria are false-colored in pink.

Mitochondrial dysfunction in alveolar type II cells promotes lung fibrosis

Editor’s picksresearch

t h e j o u r n a l o f c l i n i c a l i n v e s t i g a t i o n j c i . o r g / i m p a c t f e b r u a r y 2 0 1 5

PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosisMarta Bueno, Yen-Chun Lai, Yair Romero, Judith Brands, Claudette M. St. Croix, Christelle Kamga, Catherine Corey, Jose D. Herazo-Maya, John Sembrat, Janet S. Lee, Steve R. Duncan, Mauricio Rojas, Sruti Shiva, Charleen T. Chu, and Ana L. Mora http://jci.me/74942

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Research | Editor’s picks

Tissue-specific differences in deiodinase ubiquitination affect thyroid hormone homeostasishypothyroidism is commonly treated by the administration of levothyroxine (l-t4), a synthetic thyroid prohormone (T4) that is converted to triiodothyronine (T3) primarily by the type 2 iodothyronine deiodinase (D2). Patients treated with L-T4 exhibit a relatively higher T4/T3 ratio and lower serum T3 levels compared with those of individuals with normal thyroid function. This relatively low serum T3 could explain why a fraction of patients treated with L-T4 report persistent symptoms, despite normal thyroid-stimulating

hormone (TSH) levels. In this issue, Antonio Bianco and colleagues discover that the reason behind the low serum T3 is a decrease in T4-induced D2 ubiquitination in the hypo-thalamus compared with the rest of the body, allowing the hypothalamus to continue T3 production in the face of elevated serum T4. Thus, the increased level of D2-generated T3 in the hypothalamus decreases TSH secretion, even before serum T3 has been normalized. Treatment of thyroidectomized rats with a combination of L-T4 and L-T3 normalized

serum T3 levels and normalized T3-dependent gene expression and metabolic markers.

Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxineJoao Pedro Werneck de Castro, Tatiana L. Fonseca, Cintia B. Ueta, Elizabeth A. McAninch, Sherine Abdalla, Gabor Wittmann, Ronald M. Lechan, Balazs Gereben, and Antonio C. Bianco http://jci.me/77588

Ghrelin regulates development of the neonatal hypothalamus

the arcuate nucleus of the hypothalamus (ARh) is a central regulator of body weight and energy balance. It has been suggested that impaired hypothalamic development, which is influenced by endocrine signals early in life, could contribute to lifelong metabolic dysfunction. Ghrelin is a peptide hormone that is produced in the gastrointes-tinal tract and acts on the ARH to promote appetite. Sophie Steculorum and colleagues investigated the role of ghrelin in hypothalamic development by administering an anti-ghrelin aptamer in neonatal mice. Blockade of ghrelin activity increased the density of ARH neural projections. In contrast, excess ghrelin blunted ARH axonal growth, counteracting the progrowth effects of leptin (see the accompanying image), and caused lifelong metabolic disturbances. In the accompanying Commentary, Jenny Tong and David D’Alessio discuss how alterations in neonatal ghrelin levels could have profound effects on adult metabolism.

endocrinology

Neonatal ghrelin programs development of hypothalamic feeding circuitsSophie M. Steculorum, Gustav Collden, Berengere Coupe, Sophie Croizier, Sarah Lockie, Zane B. Andrews, Florian Jarosch, Sven Klussmann, and Sebastien G. Bouret http://jci.me/73688

Related CommentaryGhrelin and hypothalamic development: too little and too much of a good thingJenny Tong and David D’Alessio http://jci.me/79187

8 t h e j o u r n a l o f c l i n i c a l i n v e s t i g a t i o n j c i . o r g / i m p a c t f e b r u a r y 2 0 1 5

Research | Editor’s picks

Recent studies have demonstrated that greater effector and memory T cell infiltration of tumors is associated with improved overall and relapse-free survival in patients with colorectal cancer (CRC), suggesting that these lymphocytes play a protective role. To investigate the role of tumor-infiltrating lymphocytes in CRC, Christoph Reissfelder, Slava Stamova, and colleagues assessed the presence, antigen specificity, and functional

The ubiquitin ligase–associated F-box FBXW7 counteracts stromal metastatic signals

tumor stroma has a profound affect on the ability of tumors to metastasize. Kanae Yumimoto, Sayuri Akiyoshi, and colleagues investi-gated the role of the ubiquitin ligase–

associated F-box protein and tumor suppressor FBXW7. Bone marrow–specific deletion of Fbwx7 in mice promoted lung metastasis of breast cancer cells in tumor transplant models (see the accompanying image). Mechanistically, loss of Fbwx7 resulted in the accumulation of Notch, thereby enhancing the production of the chemokine CCL2 by bone marrow–derived stromal cells. Increased CCL2 resulted in the recruitment of monocytic myeloid-derived suppressor cells (MDSCs) and macrophages, creating metastatic niches. Inhibition of CCL2 signaling reduced metastasis in Fbwx7-deficient animals. Finally, low levels of FBXW7 expression in stroma were associated with poor patient prognosis.

F-box protein FBXW7 inhibits cancer metastasis in a non-cell-autonomous mannerKanae Yumimoto, Sayuri Akiyoshi, Hiroki Ueo, Yasuaki Sagara, Ichiro Onoyama, Hiroaki Ueo, Shinji Ohno, Masaki Mori, Koshi Mimori, and Keiichi I. Nakayama http://jci.me/78782

Intratumoral cytotoxic T cell activity predicts colorectal cancer survival

oncology

NOTCH signaling suppresses bladder tumorigenesisComponents of the notCh signaling pathway are frequently mutated in human cancers. Notably, NOTCH serves as a tumor suppressor in cancers with squamous histology. In this issue, Antonio Maraver, Pablo Fernandez-Marcos, and colleagues demonstrate that human bladder cancers harbor loss-of-function mutations in NOTCH1 and NOTCH2. Loss of NOTCH signaling accelerated bladder cancer tumorigenesis in mice and promoted the formation of squamous cell carcinomas with mesenchymal features, a particularly aggressive form of bladder cancer. NOTCH signaling promoted expression of the transcription factor HES1, which prevents epithelial-mesenchymal transition (EMT). Maraver and colleagues found that human bladder cancers with low levels of HES1 exhibited greater EMT and invasive features.

NOTCH pathway inactivation promotes bladder cancer progressionAntonio Maraver, Pablo J. Fernandez-Marcos, Timothy P. Cash, Marinela Mendez-Pertuz, Marta Dueñas, Paolo Maietta, Paola Martinelli, Maribel Muñoz-Martin, Mónica Martínez-Fernández, Marta Cañamero, Giovanna Roncador, Jorge L. Martinez-Torrecuadrada, Dimitrios Grivas, Jose Luis de la Pompa, Alfonso Valencia, Jesús M. Paramio, Francisco X. Real, and Manuel Serrano http://jci.me/78185

Tumor-specific cytotoxic T lymphocyte activity determines colorectal cancer patient prognosisChristoph Reissfelder, Slava Stamova, Christina Gossmann, Marion Braun, Andreas Bonertz, Ute Walliczek, Mario Grimm, Nuh N. Rahbari, Moritz Koch, Maral Saadati, Axel Benner, Markus W. Büchler, Dirk Jäger, Niels Halama, Khashayarsha Khazaie, Jürgen Weitz, and Philipp Beckhove http://jci.me/74894

activity of systemic and intratumoral effector T cells in 88 patients with CRC. They found that activated, tumor-specific T cells were character-ized by increased TNF-α expression. Further, intratumoral TNF-α levels were positively correlated with improved patient survival. This correlation was replicated in an additional 102 patients with CRC, indicating that intratumoral TNF-α levels could serve as a prognostic factor for long-term survival in CRC.

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Research | Editor’s picks

Pyruvate carboxylase upregulation drives non–small-cell lung cancer Hepatomancy:

identifying obese individuals prone to adverse metabolic outcomesobesity is associated with metabolic abnormalities, including insulin resistance and increased intrahepatic triglycerides (IHTGs), which can lead to insulin resistance, liver disease, and cardiometabolic complica-tions; however, not all obese individuals develop these complications. Previous studies have demonstrated that IHTG is directly correlated with obesity-associated metabolic dysfunction. Based on IHTG levels and insulin sensitivity, obese adults can be classified as metabolically normal (MNO) or abnormal (MAO). Samuel Klein and colleagues tested the hypothesis that MNO individuals are resistant, while MAO individuals are prone to the development of obesity-associated adverse metabolic effects. Twelve MNO and eight MAO individuals were fed a high-calorie diet to induce a 6% increase in body weight. Klein and colleagues found that while the increase in body weight and fat mass was the same in both groups, MAO but not MNO individuals exhibited deteriorations in insulin sensitivity and increased VLDL-ApoB100 concentration and secretion. Moreover, global transcriptional analysis of adipose tissue showed that MAO individuals had increased lipogenesis-associated gene transcription. These data suggest that increased lipogenic capacity in adipose tissue protects against the adverse metabolic effects of weight gain.

Metabolically normal obese people are protected from adverse effects following weight gainElisa Fabbrini, Jun Yoshino, Mihoko Yoshino, Faidon Magkos, Courtney Tiemann Luecking, Dmitri Samovski, Gemma Fraterrigo, Adewole L. Okunade, Bruce W. Patterson, and Samuel Klein http://jci.me/78425

Cancer cells undergo metabolic alterations in order to meet increased energy demands that support excess growth and survival under adverse conditions. Pyruvate carboxylase (PC) and glutaminase 1 (GLS1) mediate anaplerotic reactions that supply intermediates for the Krebs cycle. Katherine Sellers and colleagues measured the activity of these two enzymes in patients with early-stage non–small-cell lung cancer (NSCLC). By infusing the patients with 13C-labeled glucose immediately prior to tumor resection, they demonstrated that PC is selectively activated in NSCLC. Moreover, PC expression was increased in cancerous tissues compared with that in paired noncancerous tissues (see the accompa-nying image). Knockdown of PC in human NSCLC cells decreased proliferation and colony formation and reduced tumor growth in murine xenografts. Loss of PC also induced Krebs cycle perturbations, inhibited lipid and nucleotide biosynthesis, and altered glutathione homeostasis. In the accompanying Commentary, Christopher Hensley and Ralph DeBerardinis discuss how these findings support a role for PC in early-stage NSCLC metabolic adaptations.

oncologyclinical trials

Pyruvate carboxylase is critical for non–small-cell lung cancer proliferationKatherine Sellers, Matthew P. Fox, Michael Bousamra II, Stephen P. Slone, Richard M. Higashi, Donald M. Miller, Yali Wang, Jun Yan, Mariia O. Yuneva, Rahul Deshpande, Andrew N. Lane, and Teresa W.-M. Fan http://jci.me/72873

Related CommentaryIn vivo analysis of lung cancer metabolism: nothing like the real thingChristopher T. Hensley and Ralph J. DeBerardinis http://jci.me/79188

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Research | Editor’s picks

SUMO wrestling the androgen receptor in spinobulbar muscular atrophy

T cells produce IL-4 to promote recovery after neuronal injuryCns injuries trigger a series of molecular events that induce cell death and neurodegeneration. T cells accumulate at sites of injury and have been shown previously to serve a neuroprotective function; however, it is unclear how these protective T cells are activated. To examine how CD4+ T cells mediate neuroprotec-tion in response to injury, the laboratories of Jonathan Kipnis and Frauke Zipp used two in vivo murine CNS injury models, optic nerve crush injury and spinal cord contusion injury. They found that T cells are activated in an antigen-, MHC class II–, and T cell receptor–independent manner. IL-4–producing T cells were induced by damage-associated molecular mediators originating from the injured CNS tissue. In turn, IL-4 potentiated neuronal neurotrophin signaling to promote neural survival and regrowth. These results indicate that IL-4 plays a critical role in neuroprotection and repair. In the accompanying Commentary, Lawrence Steinman discusses how these pathways could potentially serve as therapeutic targets in diseases associated with neuronal injury.

MHCII-independent CD4+ T cells protect injured CNS neurons via IL-4James T. Walsh, Sven Hendrix, Francesco Boato, Igor Smirnov, Jingjing Zheng, John R. Lukens, Sachin Gadani, Daniel Hechler, Greta Gölz, Karen Rosenberger, Thomas Kammertöns, Johannes Vogt, Christine Vogelaar, Volker Siffrin, Ali Radjavi, Anthony Fernandez-Castaneda, Alban Gaultier, Ralf Gold, Thirumala-Devi Kanneganti, Robert Nitsch, Frauke Zipp, and Jonathan Kipnis http://jci.me/76210

Related CommentaryRole reversal: infiltrating T cells protect the brainLawrence Steinman http://jci.me/80279

neuroscience

a D V e r T I S e M e N T

spinobulbar muscular atrophy (sBMA) is a progressive neuromuscular disorder caused by polyglutamine (polyQ) tract expansion in the androgen receptor (AR). The expanded polyQ tract promotes hormone-dependent unfolding and oligomerization of the receptor, leading to proteotoxicity. AR-mediated transcription is also disrupted, but it is unclear to what extent loss of AR-mediated transcription contributes to neuromuscular impairment. To determine how AR transcriptional deficits contribute to SBMA, Jason Chua and colleagues enhanced AR-mediated transcription by disrupting inhibitory SUMOylation of polyQ-expanded AR. In mice, loss of AR SUMOylation rescued type I muscle fiber atrophy

(see the accompanying image) and increased exercise endurance and survival. Notably, there was no change in expression or aggregation of the

polyQ-expanded AR. In the accompanying Commentary, Tim Craig and Jeremy Henley discuss how these findings provide insight into the role of AR-mediated transcription in SBMA.

Disrupting SUMOylation enhances transcriptional function and ameliorates polyglutamine androgen receptor–mediated diseaseJason P. Chua, Satya L. Reddy, Zhigang Yu, Elisa Giorgetti, Heather L. Montie, Sarmistha Mukherjee, Jake Higgins, Richard C. McEachin, Diane M. Robins, Diane E. Merry, Jorge A. Iñiguez-Lluhí, and Andrew P. Lieberman http://jci.me/73214

Related CommentaryFighting polyglutamine disease by wrestling with SUMOTim J. Craig and Jeremy M. Henley http://jci.me/80278

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Research | Editor’s picks

Alzheimer’s disease (AD) and several other neurodegenerative disorders are characterized by the accumulation of tau. In this issue, Ismael Santa-Maria and colleagues report that expression of the brain-specific microRNA miR-219 is downregulated in autopsy brain tissue from patients with AD and severe, primary age-related tauopathy. Santa-Maria and colleagues found that tau toxicity is

exacerbated by loss of miR-219, while overexpression of the microRNA reduces toxicity in a transgenic Drosophila melanogaster model expressing human tau. Expression of human tau induced a rough eye phenotype, which could be partially reversed by coexpression of miR-219 (see the accompanying image). Using mammalian PC12 cells, they showed that miR-219 silences tau expression through direct interaction with the 3′-untranslated region of the tau mRNA.

Dysregulation of microRNA-219 promotes neurodegeneration through post-transcriptional regulation of tauIsmael Santa-Maria, Maria E. Alaniz, Neil Renwick, Carolina Cela, Tudor A. Fulga, David Van Vactor, Thomas Tuschl, Lorraine N. Clark, Michael L. Shelanski, Brian D. McCabe, and John F. Crary http://jci.me/78421

Aminoglycosides are potent, broad-spectrum antibiotics that are used to treat a number of different bacterial infections; however, aminogly-cosides cause hair cell death and hearing impairment in as many as 50% of patients. Previous studies demon-strated that hair cell mechanotransducer channels mediate hair cell uptake of aminoglycosides. Based on these observations, Markus Huth and colleagues designed nine new aminoglycosides with modifications to impair their uptake via these channels. Compared with the parent compound, sisomicin, each of the new compounds displayed substantially reduced ototoxicity in vitro, with the lead compound N1MS exhibiting a 17-fold decrease in ototoxicity in vivo and preserving hearing in mice. Importantly, N1MS successfully eliminated E. coli from urinary tract tissues, without compromising auditory function.

Designer aminoglycosides prevent cochlear hair cell loss and hearing lossMarkus E. Huth, Kyu-Hee Han, Kayvon Sotoudeh, Yi-Ju Hsieh, Thomas Effertz, Andrew A. Vu, Sarah Verhoeven, Michael H. Hsieh, Robert Greenhouse, Alan G. Cheng, and Anthony J. Ricci http://jci.me/77424

Modified aminoglycoside antibiotics reduce ototoxicity

Tau expression is post-translationally regulated by miR-219

neuroscience

Annexin1 regulates dendritic cell responses in Mycobacterium tuberculosis infectionefferocytosis is a host-defense mechanism in which macrophages and dendritic cells (DCs) phagocytose apoptotic cells and vesicles. DCs are then able to cross-present antigens derived from infected, apoptotic cells to cytotoxic CD8+ T cells, which specifically eliminate pathogen-infected cells. In this issue, Fanny Tzelepis and colleagues demonstrate that the phospholipid-binding protein annexin 1 (ANXA1) is required for DC efferocytosis and cross-presentation of Mycobacterium tuberculosis (Mtb) antigens. Anxa1-deficient mice were more susceptible to Mtb infection than their WT counterparts and exhibited an impaired CD8+ T cell response to infection. In apoptotic cells, ANXA1 serves as a ligand for DC recognition and efferocytosis, while in DCs, ANXA1 is required for efficient cross-presentation. Intriguingly, Tzelepis and colleagues found that Mtb infection blocks expression of ANXA1 in human blood monocyte–derived DCs, suggesting that this is a mechanism by which the pathogen escapes elimination.

Annexin1 regulates DC efferocytosis and cross-presentation during Mycobacterium tuberculosis infectionFanny Tzelepis, Mark Verway, Jamal Daoud, Joshua Gillard, Kimya Hassani-Ardakani, Jonathan Dunn, Jeffrey Downey, Marilena Elena Gentile, Joanna Jaworska, Anthony Michel Jean Sanchez, Yohann Nédélec, Hojatollah Vali, Maryam Tabrizian, Arnold Scott Kristof, Irah Luther King, Luis Bruno Barreiro, and Maziar Divangahi http://jci.me/77014

otology

infectious disease

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Closing the loop between enteroendocrine cells and nerves

Research | Editor’s picks

a D V e r T I S e M e N T

Bone remodeling is regulated by retinoid X receptor–mediated osteoclast differentiationosteoporosis is associated with increased osteoclast differentiation and activity, and therapeutics targeting the activity of these cells could potentially be used to prevent and treat bone loss. Mercedes Ricote and colleagues demonstrate that osteoclast differentiation is governed by the nuclear retinoid X receptors (RXRs), which form homodimers that induce transcription of the transcription factor v-maf musculoaponeurotic fibrosarcoma oncogene family, protein B (MAFB) in osteoclast progenitors. Loss of functional RXRs in hematopoietic cells resulted in the formation of giant nonresorbing osteoclasts and protected female mice from ovariectomy-induced osteoporosis. These effects are mediated through RXR-induced MAFB expression, which controls osteoclast differentiation, proliferation, and activation. Strikingly, pharmaco-logical activation of RXRs induces an RXR/liver X receptor dimer that inhibits osteoclast differentiation.

Retinoid X receptors orchestrate osteoclast differentiation and postnatal bone remodelingMaría P. Menéndez-Gutiérrez, Tamás Rőszer, Lucía Fuentes, Vanessa Núñez, Amelia Escolano, Juan Miguel Redondo, Nora De Clerck, Daniel Metzger, Annabel F. Valledor, and Mercedes Ricote http://jci.me/77186

enteroendocrine cells allow the gut to sense nutrients, bacterial products, and other environmental cues and respond by releasing hormones that modulate satiety, food preferences, and even mood. These cells are thought to primarily communicate with nerve cells indirectly via hormone secretion; however, Diego Bohórquez and colleagues identified an enteroendocrine cellular structure, known as a neuropod, that directly interacts with nerve cells. By fluorescently labeling specific enteroendocrine cell populations in mice, they demonstrated that nerves in the gut mucosa directly contact the enteroendocrine neuropod. The accompanying image shows a colonic peptide YY–containing enteroendocrine cell neuropod (green) in contact with a calcitonin gene–related peptide nerve (cyan). Moreover, enteroendo-crine cells express pre- and postsynaptic proteins, indicating that they can form synapses with nerve cells. Finally, enteroendocrine cells were able to transmit a fluorescently labeled form of the rabies virus to adjacent nerve cells, indicating the presence of a functional neural circuit.

gastroenterology

bone biology

Neuroepithelial circuit formed by innervation of sensory enteroendocrine cellsDiego V. Bohórquez, Rafiq A. Shahid, Alan Erdmann, Alex M. Kreger, Yu Wang, Nicole Calakos, Fan Wang, and Rodger A. Liddle http://jci.me/78361

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James RothmanJames Rothman shared the 2013 nobel Prize in Physiology or Medicine for his discoveries of the cellular machinery that regulates vesicle trafficking. These processes are important for nearly every aspect of cell biology, and defects in vesicle trafficking have been linked to a variety of disease states. In an interview with JCI Editor at Large Ushma Neill, Rothman discusses his career trajectory, including his initial interest in physics, which was eventually replaced by biology during a brief stint in medical school. After falling in love with vesicle transport, Rothman earned his doctorate in Eugene Kennedy’s lab, followed by postdoctoral work with Harvey Lodish. Rothman also discusses his use of a cell-free approach to studying protein function, which at the time was a highly unusual technique; however, he was ultimately able to reconstitute vesicle transport.

http://jci.me/80641

Features

conversations with giants in medicine

Chewing the fat: thermogenic adipocytes in adult humans

Brown adipose tissue (BAt) is a specialized form of fat that dissipates energy to produce heat, helping to protect human newborns from hypother-mia. Small quantities of BAT are also present in adult humans and become metabolically active upon cold exposure (see the accompanying image). Beige adipocytes are thermogenic cells that reside within white fat deposits and can be converted to BAT by a variety of external cues, including cold exposure,

exercise, and specific hormones. Importantly, BAT mass is inversely correlated with BMI and adiposity, suggesting that increasing BAT deposits is a potential strategy to combat obesity and obesity-related diseases. In this issue, Labros Sidossis and Shingo Kajimura describe recent advances in our understanding of the developmental, anatomical, and functional characteristics of brown and beige adipocytes and their role in whole-body energy and glucose homeostasis.

Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasisLabros Sidossis and Shingo Kajimura http://jci.me/78362

Next-gen sequencing in cancer carethe emergence of high-throughput sequencing technolo-gies has led to an exponential increase in the number of characterized human cancer genomes. A subset of genomic alterations is clinically actionable; however, the vast majority are variants of unknown significance. In this Review, Neil Hayes and William Kim discuss how this new library of new mutations will require careful characteriza-tion, particularly with respect to responses to a given therapeutic intervention. Such characterization will allow for the creation of a genomic cancer taxonomy stratified by tumor type and key oncogenic pathways. Integration of such information into clinical trials will aid in the identification of biomarkers that predict therapeutic responses and define pathways that mediate resistance to targeted therapies.

The next steps in next-gen sequencing of cancer genomesD. Neil Hayes and William Y. Kim http://jci.me/68339

reviews

hindsight

Targeting the extrinsic apoptotic pathway for cancer therapyDysfunctional apoptosis enables cancer cells to proliferate uncontrollably, and strategies to reinstate apoptosis in these cells have been extensively explored. In 1999, Avi Ashkenazi and colleagues demonstrated that recombinant Apo2L/TRAIL, which triggers the extrinsic apoptotic pathway, promotes tumor cell death, but is not toxic in nonhuman primates. Despite demonstrated efficacy in preclinical models, Apo2L/TRAIL and other proapoptotic receptor agonists (PARAs) have had little success in clinical trials. In this issue, Ashkenazi discusses possible reasons for the discrepancies seen between preclinical cancer models and patients and highlights potential strategies to improve PARA efficacy.

Targeting the extrinsic apoptotic pathway in cancer: lessons learned and future directionsAvi Ashkenazi http://jci.me/80420

The JCI welcomes submissions in the following categories:

Regular: Substantial new mechanistic insights into biology and disease.

Technical advance: New and important research tools and techniques with the potential for broad impact.

Brief report: Discrete, highly significant findings in a short format.

Sample article: brown adipose tissue regulates glucose homeostasis and insulin sensitivityKristin I. Stanford, Roeland J.W. Middelbeek, Kristy L. Townsend, Ding An, Eva B. Nygaard, Kristen M. Hitchcox, Kathleen R. Markan, Kazuhiro Nakano, Michael F. Hirshman, Yu-Hua Tseng, and Laurie J. Goodyear

Published January 2013 http://jci.me/62308 Times cited: 71

Sample article: Parthenogenetic stem cells for tissue-engineered heart repairMichael Didié, Peter Christalla, Michael Rubart, Vijayakumar Muppala, Stephan Döker, Bernhard Unsöld, Ali El-Armouche, Thomas Rau, Thomas Eschenhagen, Alexander P. Schwoerer, Heimo Ehmke, Udo Schumacher, Sigrid Fuchs, Claudia Lange, Alexander Becker, Wen Tao, John A. Scherschel, Mark H. Soonpaa, Tao Yang, Qiong Lin, Martin Zenke, Dong-Wook Han, Hans R. Schöler, Cornelia Rudolph, Doris Steinemann, Brigitte Schlegelberger, Steve Kattman, Alec Witty, Gordon Keller, Loren J. Field, and Wolfram-Hubertus Zimmermann

Published March 2013 http://jci.me/66854 Times cited: 29

Sample article: recruited brown adipose tissue as an antiobesity agent in humansTakeshi Yoneshiro, Sayuri Aita, Mami Matsushita, Takashi Kayahara, Toshimitsu Kameya, Yuko Kawai, Toshihiko Iwanaga, and Masayuki Saito

Published August 2013 http://jci.me/67803 Times cited: 40

Clinical medicine:research that reports early-stage, effective new therapies that impact disease outcomes in patients.

Sample article: exenatide and the treatment of patients with Parkinson’s diseaseIciar Aviles-Olmos, John Dickson, Zinovia Kefalopoulou, Atbin Djamshidian, Peter Ell, Therese Soderlund, Peter Whitton, Richard Wyse, Tom Isaacs, Andrew Lees, Patricia Limousin, and Thomas Foltynie

Published June 2013 http://jci.me/68295 Times cited: 36

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