1. No category

A summary of
this month’s
Journal of Clinical
Investigation
Also in this issue:
Hormone independence
in breast cancer 7
Biomarkers of active
tuberculosis 8
Lipid oxidation in dendritic
cell maturation 11
Engineering targeted
epigenetic suppression 12
jci.org/impact
may 2015
Scan with your mobile device
for the digital version of JCI Impact.
Visualizing tumor-infiltrating T cells
p. 6
Impact
May 2015
Featured Editor
The JCI’s Editorial Board is composed of peer scientists at Duke University Medical Center, the University of
North Carolina, Duke-NUS, and the Sanford-Burnham Medical Research Institute. Editorial Board members
review and oversee peer review of each manuscript that is submitted to the JCI, and the board meets weekly
to discuss the manuscripts undergoing review.
Clinical Medicine Associate Editors
Michael A. Morse, Andrew J. Muir,
Scott M. Palmer, Mark A. Stacy
Scott Palmer, MD, MHS, Associate Editor, is an Associate
Professor and Vice Chair for Research in the Department
of Medicine, Duke University Medical Center; Director
of Pulmonary Research at the Duke Clinical Research
Institute; and a member of the ASCI. His primary research
interests are centered on bronchiolitis obliterans, lung
transplantation, and advanced lung disease. He made the
important obser­vation that variations in innate pattern
recognition receptors regulate lung rejection, thereby
estab­lishing the clinical importance of innate immune mechanisms in solid organ
transplant rejection. His work also highlighted the adverse effects of cytomegalo­
virus infection after lung transplantation. As a result, he led a multicenter random­
ized clinical trial that established a new and more effective clinical standard of
care to prevent cytomegalovirus infection from developing. Dr. Palmer’s current
research leverages translational human studies and rodent models to better under­
stand the mechanisms that lead to lung rejection and develop clinically relevant
approaches to modulate these processes and improve transplant outcomes. He
also leads clinical and translational studies in the treatment of fibrotic lung diseases,
including idiopathic pulmonary fibrosis and occupational airway diseases.
Asia Editor
David M. Virshup
Publication highlights
Editor
Howard A. Rockman
Deputy Editors
Garnett Kelsoe, Bryan L. Roth
Associate Editors
Soman 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
Chair, Executive Council
Robert J. Lefkowitz
Biostatisticians
Cynthia Coffman, Barry Moser,
Maren Olsen
Bioethicist
Arthur L. Caplan
Senior Science Editor
Sarah C. Jackson
Science Editor
Jillian Hurst
Assistant Science Editor
Corinne Williams
Todd JL, Jain R, Pavlisko EN, Finlen Copeland CA, Reynolds JM, Snyder LD,
Palmer SM. Impact of forced vital capacity loss on survival after the onset of
chronic lung allograft dysfunction. Am J Respir Crit Care Med. 2014;189(2):159–166.
Tsuang WM, Vock DM, Finlen Copeland CA, Lederer DJ, Palmer SM. An acute
change in lung allocation score and survival after lung transplantation: a cohort
study. Ann Intern Med. 2013;158(9):650–657.
Palmer SM, Limaye AP, Banks M, Gallup D, Chapman J, Lawrence EC, Dunitz J,
Milstone A, Reynolds J, Yung GL, Chan KM, Aris R, Garrity E, Valentine V,
McCall J, Chow SC, Davis RD, Avery R. Extended valganciclovir prophylaxis to
prevent cytomegalovirus after lung transplantation: a randomized, controlled
trial. Ann Intern Med. 2010;152(12):761–769.
Editor at Large
Ushma 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.
the journal of clinical investigation
For the full JCI
online, go to
jci.me/125/5
or scan the code
at left with your
mobile device.
jci.org/impact
Contact the JCI
The Journal of Clinical Investigation
2015 Manchester Road
Ann Arbor, Michigan 48104, USA
Phone: 734.222.6050
E-mail: [email protected]
may 2015
1
Research articles in the
current issue of the JCI
Aging
Lifespan of mice and primates correlates with immunoproteasome expression
Andrew M. Pickering, Marcus Lehr, and Richard A. Miller http://jci.me/80514
Poly(A)-specific ribonuclease deficiency impacts telomere biology
and causes dyskeratosis congenita
PARN in lymphoblastoid cells
Hemanth Tummala, Amanda Walne, Laura Collopy, Shirleny Cardoso, Josu de la Fuente, Sarah Lawson, James Powell,
Nicola Cooper, Alison Foster, Shehla Mohammed, Vincent Plagnol, Thomas Vulliamy, and Inderjeet Dokal
http://jci.me/78963
With related Commentary by Philip J. Mason and Monica Bessler
More, p. 11
AIDS/HIV
Ex vivo analysis identifies effective HIV-1 latency–reversing drug combinations
Gregory M. Laird, C. Korin Bullen, Daniel I.S. Rosenbloom, Alyssa R. Martin, Alison L. Hill, Christine M. Durand, Janet D. Siliciano,
and Robert F. Siliciano http://jci.me/80142
More, p. 10
Clinical trials
Biomarkers on patient T cells diagnose active tuberculosis and monitor treatment response
Toidi Adekambi, Chris C. Ibegbu, Stephanie Cagle, Ameeta S. Kalokhe, Yun F. Wang, Yijuan Hu, Cheryl L. Day, Susan M. Ray, and Jyothi Rengarajan
http://jci.me/77990
More, p. 8
Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington’s disease patients
Edward J. Wild, Roberto Boggio, Douglas Langbehn, Nicola Robertson, Salman Haider, James R.C. Miller, Henrik Zetterberg, Blair R. Leavitt, Rainer Kuhn,
Sarah J. Tabrizi, Douglas Macdonald, and Andreas Weiss
http://jci.me/80743
More, p. 8
Genomic imbalances in pediatric patients with chronic kidney disease
Miguel Verbitsky, Simone Sanna-Cherchi, David A. Fasel, Brynn Levy, Krzysztof Kiryluk, Matthias Wuttke, Alison G. Abraham,
Frederick Kaskel, Anna Köttgen, Bradley A. Warady, Susan L. Furth, Craig S. Wong, and Ali G. Gharavi
http://jci.me/80877
With related Commentary by Martin R. Pollak
More, p. 8
2
the journal of clinical investigation
jci.org/impact
may 2015
Research articles in the current issue of the JCI
Genetics
TALE-mediated epigenetic suppression of CDKN2A increases replication in human fibroblasts
Diana L. Bernstein, John E. Le Lay, Elena G. Ruano, and Klaus H. Kaestner http://jci.me/77321
More, p. 12
Ube3a reinstatement identifies distinct developmental windows in a murine
Angelman syndrome model
Sara Silva-Santos, Geeske M. van Woerden, Caroline F. Bruinsma, Edwin Mientjes, Mehrnoush Aghadavoud Jolfaei, Ben Distel,
Steven A. Kushner, and Ype Elgersma http://jci.me/80554
More, p. 12
Hematology
Endothelium and NOTCH specify and amplify
aorta-gonad-mesonephros–derived hematopoietic stem cells
AKT-expressing endothelial cells
Brandon K. Hadland, Barbara Varnum-Finney, Michael G. Poulos, Randall T. Moon, Jason M. Butler,
Shahin Rafii, and Irwin D. Bernstein http://jci.me/80137
Ash1l controls quiescence and self-renewal potential in hematopoietic stem cells
Morgan Jones, Jennifer Chase, Michelle Brinkmeier, Jing Xu, Daniel N. Weinberg, Julien Schira, Ann Friedman, Sami Malek, Jolanta Grembecka,
Tomasz Cierpicki, Yali Dou, Sally A. Camper, and Ivan Maillard http://jci.me/78124
Hepatology
CCN1 induces hepatic ductular reaction through integrin αvβ5–mediated
activation of NF-κB
NOTCH inhibition in liver
Ki-Hyun Kim, Chih-Chiun Chen, Gianfranco Alpini, and Lester F. Lau
http://jci.me/79327
Immunology
mTORC1 and mTORC2 selectively regulate CD8+ T cell differentiation
Kristen N. Pollizzi, Chirag H. Patel, Im-Hong Sun, Min-Hee Oh, Adam T. Waickman, Jiayu Wen, Greg M. Delgoffe, and Jonathan D. Powell http://jci.me/77746
12/15-lipoxygenase–mediated enzymatic lipid oxidation regulates DC maturation and function
Tobias Rothe, Florian Gruber, Stefan Uderhardt, Natacha Ipseiz, Susanne Rössner, Olga Oskolkova, Stephan Blüml, Norbert Leitinger, Wolfgang Bicker,
Valery N. Bochkov, Masayuki Yamamoto, Alexander Steinkasserer, Georg Schett, Elisabeth Zinser, and Gerhard Krönke http://jci.me/78490
More, p. 11
Metabolism
Calcium release channel RyR2 regulates insulin release and glucose
homeostasis
Abnormal mitochondria in β cells
Gaetano Santulli, Gennaro Pagano, Celestino Sardu, Wenjun Xie, Steven Reiken, Salvatore Luca D’Ascia,
Michele Cannone, Nicola Marziliano, Bruno Trimarco, Theresa A. Guise, Alain Lacampagne, and Andrew R. Marks
http://jci.me/79273
More, p. 10
the journal of clinical investigation
jci.org/impact
may 2015
3
Research articles in the current issue of the JCI
Nephrology
Gq signaling causes glomerular injury by activating TRPC6
Liming Wang, Grant Jirka, Paul B. Rosenberg, Anne F. Buckley, Jose A. Gomez, Timothy A. Fields, Michelle P. Winn,
and Robert F. Spurney http://jci.me/76767
Mesangial expansion
More, p. 9
Integrated compensatory network is activated in the absence of NCC phosphorylation
P. Richard Grimm, Yoskaly Lazo-Fernandez, Eric Delpire, Susan M. Wall, Susan G. Dorsey, Edward J. Weinman, Richard Coleman, James B. Wade,
and Paul A. Welling http://jci.me/78558
With related Commentary by Mark A. Knepper
More, p. 9
Sec63 and Xbp1 regulate IRE1α activity and polycystic disease severity
Sorin V. Fedeles, Jae-Seon So, Amol Shrikhande, Seung Hun Lee, Anna-Rachel Gallagher, Christina E. Barkauskas, Stefan Somlo, and Ann-Hwee Lee
http://jci.me/78863
Neuroscience
TREM2 sustains microglial expansion during aging and response
to demyelination
Microglia after demyelination
Pietro Luigi Poliani, Yaming Wang, Elena Fontana, Michelle L. Robinette, Yoshinori Yamanishi, Susan Gilfillan,
and Marco Colonna http://jci.me/77983
Parkin cooperates with GDNF/RET signaling to prevent dopaminergic neuron degeneration
Durga Praveen Meka, Anne Kathrin Müller-Rischart, Prakash Nidadavolu, Behnam Mohammadi, Elisa Motori, Srinivas Kumar Ponna, Helia Aboutalebi,
Mahmoud Basal, Anil Annamneedi, Barbara Finckh, Margit Miesbauer, Natalie Rotermund, Christian Lohr, Jörg Tatzelt, Konstanze F. Winklhofer,
and Edgar R. Kramer http://jci.me/79300
Oncology
TIGIT and PD-1 impair tumor antigen–specific CD8+ T cells in melanoma patients
Joe-Marc Chauvin, Ornella Pagliano, Julien Fourcade, Zhaojun Sun, Hong Wang, Cindy Sander, John M. Kirkwood, Tseng-hui Timothy Chen,
Mark Maurer, Alan J. Korman, and Hassane M. Zarour http://jci.me/80445
Immunosurveillance and therapy of multiple myeloma is CD226 dependent
Camille Guillerey, Lucas Ferrari de Andrade, Slavica Vuckovic, Kim Miles, Shin Foong Ngiow, Michelle C.R. Yong, Michele W.L. Teng, Marco Colonna,
David S. Ritchie, Martha Chesi, P. Leif Bergsagel, Geoffrey R. Hill, Mark J. S­myth, and Ludovic Martinet http://jci.me/77181
Noninvasive detection of tumor-infiltrating T cells by PET reporter imaging
Melissa N. McCracken, Dimitrios N. Vatakis, Dhaval Dixit, Jami McLaughlin, Jerome A. Zack, and Owen N. Witte http://jci.me/77326
More, p. 6
Pharmacological HIF2α inhibition improves VHL disease–associated
phenotypes in zebrafish model
Zebrafish blood vessel sprouting
4
Ana Martins Metelo, Haley R. Noonan, Xiang Li, Youngnam Jin, Rania Baker, Lee Kamentsky,
Yiyun Zhang, Ellen van Rooijen, Jordan Shin, Anne E. Carpenter, Jing-Ruey Yeh,
Randall T. Peterson, and Othon Iliopoulos
http://jci.me/73665
the journal of clinical investigation
jci.org/impact
may 2015
Research articles in the current issue of the JCI
Specific molecular signatures predict decitabine response
in chronic myelomonocytic leukemia
CXCL4 in bone marrow
Kristen Meldi, Tingting Qin, Francesca Buchi, Nathalie Droin, Jason Sotzen, Jean-Baptiste Micol,
Dorothée Selimoglu-Buet, Erico Masala, Bernardino Allione, Daniela Gioia, Antonella Poloni,
Monia Lunghi, Eric Solary, Omar Abdel-Wahab, Valeria Santini, and Maria E. Figueroa
http://jci.me/78752
Telomerase regulates MYC-driven oncogenesis independent of its reverse transcriptase activity
Cheryl M. Koh, Ekta Khattar, Shi Chi Leow, Chia Yi Liu, Julius Muller, Wei Xia Ang, Yinghui Li, Guido Franzoso, Shang Li,
Ernesto Guccione, and Vinay Tergaonkar
http://jci.me/79134
IRX1 hypomethylation promotes osteosarcoma metastasis
via induction of CXCL14/NF-κB signaling
Metastatic osteosarcoma
Jinchang Lu, Guohui Song, Qinglian Tang, Changye Zou, Feng Han, Zhiqiang Zhao, Bicheng Yong,
Junqiang Yin, Huaiyuan Xu, Xianbiao Xie, Tiebang Kang, YingLee Lam, Huiling Yang, Jingnan Shen,
and Jin Wang http://jci.me/78437
More, p. 7
MEL-18 loss mediates estrogen receptor–α downregulation and hormone independence
Jeong-Yeon Lee, Hee-Young Won, Ji-Hye Park, Hye-Yeon Kim, Hee-Joo Choi, Dong-Hui Shin, Ju-Hee Kang, Jong-Kyu Woo, Seung-Hyun Oh, Taekwon Son,
Jin-Woo Choi, Sehwan Kim, Hyung-Yong Kim, Kijong Yi, Ki-Seok Jang, Young-Ha Oh, and Gu Kong http://jci.me/73743
More, p. 7
Estrogen regulates Hippo signaling via GPER in breast cancer
Xin Zhou, Shuyang Wang, Zhen Wang, Xu Feng, Peng Liu, Xian-Bo Lv, Fulong Li, Fa-Xing Yu, Yiping Sun,
Haixin Yuan, Hongguang Zhu, Yue Xiong, Qun-Ying Lei, and Kun-Liang Guan http://jci.me/79573
GPER in invasive ductal carcinoma
An epigenetically distinct breast cancer cell subpopulation
promotes collective invasion
Jill M. Westcott, Amanda M. Prechtl, Erin A. Maine, Tuyen T. Dang, Matthew A. Esparza, Han Sun, Yunyun Zhou,
Yang Xie, and Gray W. Pearson http://jci.me/77767
Pulmonology
Airway epithelial SPDEF integrates goblet cell differentiation and pulmonary Th2 inflammation
Priya Rajavelu, Gang Chen, Yan Xu, Joseph A. Kitzmiller, Thomas R. Korfhagen, and Jeffrey A. Whitsett
http://jci.me/79422
the journal of clinical investigation
jci.org/impact
may 2015
5
Research
Editor’s picks
A window into adoptive cellular immunotherapy
Cancer immunotherapy holds great promise
as a therapeutic strategy to target malig­
nant cells. Adoptive cellular immuno­
therapy relies on infusion of engineered
T cells that recognize cancer cells or
tumor-­infiltrating lymphocytes that have
been expanded ex vivo. While manip­
ulating the immune system has shown
encour­aging results, serious complications
may develop, including graft-versus-host
disease or autoimmune reactions. Thus,
improved methods for detecting the local­
ization of transferred cells are needed to
improve preclinical studies and to monitor
for deleterious outcomes in clinical immu­
notherapy settings. In this month’s JCI, a
study led by Owen Witte describes a non­
invasive technique for tracking transferred
immune cells in multiple mouse models
of immunotherapy. This team introduced
a construct that expresses the PET re­
porter deoxycytidine kinase triple mutant
(hdCK3mut) and the anti-melanoma
T cell receptor F5 into hematopoietic stem
cells or peripheral blood mono­nuclear
cells. The resulting engineered T cells
showed normal activation, cytokine pro­
duction, and cytotoxicity and were able
to infiltrate tumors in vivo, as shown by
immunohistochemistry. Importantly, PET
reporter imaging allowed visualization
of the engraftment of transferred cells
as well as homing to tumor sites. These
studies indicate that the introduction of
hdCK3­mut is a powerful and sensitive
method to noninvasively detect the local­
ization of engineered cells in adoptive
cellular immuno­therapy studies.
6
The accompanying image shows a modified 3D reconstruction of a [18F]L-FMAU PET/CT scan to detect hdCK3mut-­labeled hematopoietic cells.
A strong signal indicates infiltration of labeled cells within a tumor on the
left flank; total hematopoietic engraftment is demonstrated by a signal
within the bone marrow.
Noninvasive detection of tumor-infiltrating T cells
by PET reporter imaging
Melissa N. McCracken, Dimitrios N. Vatakis, Dhaval Dixit, Jami McLaughlin,
Jerome A. Zack, and Owen N. Witte http://jci.me/77326
the journal of clinical investigation
jci.org/impact
may 2015
Research | Editor’s picks
oncology
IRX1 hypomethylation promotes osteosarcoma metastasis
Osteosarcoma is the most common primary malignant bone tumor. Epigenetic dysregulation has previously
been implicated in osteosarcoma development, but its role in metastasis is unknown. Jinchang Lu and
colleagues analyzed DNA methylation patterns in two syngeneic primary human osteosarcoma cell lines
with different metastatic potentials to identify putative metastatic drivers. They found that the promoter of
Iroquois homeobox 1 (IRX1) was hypomethylated in metastatic osteosarcoma, leading to overexpression of
the protein. Increased IRX1 expression enhanced migration, invasion, and anoikis resistance and increased
lung metastases in a murine xenograft model (see the accompanying image). IRX1 upregulated expression
of CXCL14, which acts in an autocrine manner to drive metastatic behavior via NF-κB activation.
Importantly, expression of IRX1 and CXCL14 was positively correlated with lung metastasis and poor
metastasis-free survival in osteosarcoma patients.
IRX1 hypomethylation promotes
osteosarcoma metastasis via
induction of CXCL14/NF-κB signaling
Jinchang Lu, Guohui Song, Qinglian Tang,
Changye Zou, Feng Han, Zhiqiang Zhao,
Bicheng Yong, Junqiang Yin, Huaiyuan Xu,
Xianbiao Xie, Tiebang Kang, YingLee Lam,
Huiling Yang, Jingnan Shen, and Jin Wang
http://jci.me/78437
Polycomb protein MEL-18 loss drives hormone independence
in breast cancer
Aggressive, hormone-independent
breast cancers are characterized by a
loss of estrogen receptor–α (ERα)
expression; however, the mechanisms
underlying this loss are poorly
understood. Jeong-Yeon Lee and
colleagues determined that loss of
MEL-18, a component of the polycomb
repressive complex–1 (PRC-1), contributes
to ERα loss in breast cancer. MEL-18
downregulation was associated with
hormone-independent triple-negative
breast cancers (TNBCs), resistance to
antihormone therapy, and poor
prognosis, as well as decreased
expression of the progesterone receptor
(PR). MEL-18 overexpression restored
both ERα and PR mRNA expression and
conferred antihormonal therapy
sensitivity in TNBC. In a murine xenograft
model, knockdown of MEL-18 induced
estrogen-independent tumor growth.
Mechanistically, MEL-18 blocked
SUMOylation of p53 and the transcription
factor SP1, which mediate transcription of
the gene encoding ERα. These data
identify MEL-18 as an important regulator
of ERα expression and a prognostic
marker for antihormonal therapy
response in breast cancer patients.
the journal of clinical investigation
jci.org/impact
MEL-18 loss mediates estrogen
receptor–α downregulation
and hormone independence
Jeong-Yeon Lee, Hee-Young Won,
Ji-Hye Park, Hye-Yeon Kim, Hee-Joo Choi,
Dong-Hui Shin, Ju-Hee Kang,
Jong-Kyu Woo, Seung-Hyun Oh,
Taekwon Son, Jin-Woo Choi, Sehwan Kim,
Hyung-Yong Kim, Kijong Yi, Ki-Seok Jang,
Young-Ha Oh, and Gu Kong
http://jci.me/73743
may 2015
7
Research | Editor’s picks
clinical trials
Tracking Huntington’s disease progression in human
cerebrospinal fluid
Huntington’s disease (HD) is caused by a
mutation in the huntingtin protein (mHTT).
Genetic testing can identify individuals with HD
before the development of symptoms; however,
the clinical course of the disease is unpredict­
able. Edward Wild, Roberto Boggio, and
colleagues used an immunoassay method to
quantify levels of mHTT in cerebrospinal fluid
(CSF) from two independent patient cohorts.
They were able to detect mHTT in mutation
carriers but not in control volunteers.
CSF mHTT concentrations were higher in
patients manifesting disease symptoms
compared with those in premanifest mutation
carriers, and CSF mHTT concentrations were
higher at later disease stages. Moreover,
mHTT levels could independently predict
patient performance on cognitive assessments.
These results demonstrate that mHTT levels
in CSF can serve as a biomarker to track HD
progression and may be useful in the
evaluation of new HD therapeutics.
Uncovering the etiology of pediatric
chronic kidney disease
Chronic kidney disease (CKD) has a profound impact on children, including increased
morbidity from hypertension and cardiovascular and neurodevelopmental complications.
In many cases, the etiology of the disease is unknown. Miguel Verbitsky and colleagues
performed chromosomal microarrays to detect genomic imbalances in 419 children enrolled
in the Chronic Kidney Disease in Children (CKiD) prospective cohort study and compared the
microarrays with those of 21,575 children and adults who did not have CKD. Genomic
disorders were detected in 4.5% of children enrolled in the CKiD study compared with 0.45%
of individuals in the control cohorts. Additionally, large, gene-disrupting copy number
variations (>500 kb) were detected nearly twice as often in CKD patients compared with
controls. These findings indicate that a significant proportion of children with CKD have an
unsuspected genomic imbalance that provides valuable diagnostic information and could
potentially lead to improved personalized clinical care. In the accompanying Commentary,
Martin Pollak discusses the role of genomic technologies in clinical care.
Genomic imbalances in pediatric patients with chronic
kidney disease
Miguel Verbitsky, Simone Sanna-Cherchi, David A. Fasel, Brynn Levy, Krzysztof Kiryluk,
Matthias Wuttke, Alison G. Abraham, Frederick Kaskel, Anna Köttgen, Bradley A. Warady,
Susan L. Furth, Craig S. Wong, and Ali G. Gharavi
http://jci.me/80877
Related Commentary
Idiopathic pediatric chronic kidney disease:
can genomic technology crack the case?
Martin R. Pollak
http://jci.me/81509
8
the journal of clinical investigation
Quantification of mutant huntingtin
protein in cerebrospinal fluid from
Huntington’s disease patients
Edward J. Wild, Roberto Boggio, Douglas Langbehn,
Nicola Robertson, Salman Haider, James R.C. Miller,
Henrik Zetterberg, Blair R. Leavitt, Rainer Kuhn,
Sarah J. Tabrizi, Douglas Macdonald,
and Andreas Weiss
http://jci.me/80743
Biomarkers of
active tuberculosis
infection
Diagnosis of active tuberculosis (TB) infection
currently relies on extensive medical evaluation
and direct detection of Mycobacterium
tuberculosis (Mtb) bacteria in a patient’s sputum,
and there is a need for more rapid testing that
can be used for diagnosis and to evaluate
treatment responses. Toidi Adekambi and
colleagues used polychromatic flow cytometry to
evaluate the expression of immune activation
(CD38 and HLA-DR) and intracellular proliferation
(Ki-67) markers on Mtb-specific IFN-γ+CD4+
T cells from patients with asymptomatic latent
Mtb infection and active disease as well as those
undergoing treatment. They found that these
markers accurately distinguished active TB
patients from those with latent infection.
Additionally, these markers correlated with
decreasing Mtb loads during treatment.
Biomarkers on patient T cells diagnose
active tuberculosis and monitor
treatment response
Toidi Adekambi, Chris C. Ibegbu, Stephanie Cagle,
Ameeta S. Kalokhe, Yun F. Wang,
Yijuan Hu, Cheryl L. Day, Susan M. Ray,
and Jyothi Rengarajan
http://jci.me/77990
jci.org/impact
may 2015
Research | Editor’s picks
nephrology
Targeting Gq-mediated signaling in kidney disease
Gain-of-function mutations in the transient receptor potential channel C6 (TRPC6) cause familial forms of
focal segmental glomerulosclerosis (FSGS). These TRPC6 mutations enhance intracellular calcium levels and
promote kidney injury. TRPC6 is activated by Gq-linked GPCR-stimulated cell signaling pathways. Liming Wang
and colleagues examined the role of Gq/TRPC6 signaling in puromycin aminonucleoside nephrosis, a murine
model of podocyte injury. Expression of a constitutively active form of Gq (GqQ>L) in podocytes stimulated
calcium influx, activating calcineurin. Calcineurin upregulated expression of TRPC6, leading to FSGS-like
features. Importantly, either deletion of TRPC6 or treatment with the calcineurin inhibitor FK506 reduced
GqQ>L-induced kidney injury (see the accompanying image). These data indicate that the Gq/TRPC6 signaling
pathway may be a therapeutic target in glomerular disease.
Gq signaling causes glomerular injury
by activating TRPC6
Liming Wang, Grant Jirka, Paul B. Rosenberg,
Anne F. Buckley, Jose A. Gomez, Timothy A. Fields,
Michelle P. Winn, and Robert F. Spurney
http://jci.me/76767
Maintaining balance in the kidney
Salt-sensitive hypertension is commonly treated
with thiazide diuretics that target the sodiumchloride cotransporter NCC; however, renal
compensatory processes can limit response to these
drugs. Paul Grimm and colleagues elucidated
compensatory processes in mice that lack SPAK, a
kinase that activates NCC. In the absence of SPAK,
salt reabsorption is mediated by the coordinate
upregulation of multiple genes. This genetic program
results in increased apical expression of the
sodium-independent chloride/bicarbonate
transporter pendrin in pendrin-positive intercalated
cells (PP-ICs; see the accompanying image),
remodeling of the distal nephron via induction of
jagged 1/NOTCH signaling, and induction of an
α-ketoglutarate paracrine signaling system in PP-ICs
that stimulates salt transport. These data identify an
integrated compensatory mechanism that preserves
the journal of clinical investigation
jci.org/impact
salt balance and blood pressure in the absence of
NCC activity. In the accompanying Commentary,
Mark Knepper discusses how these compensatory
mechanisms may contribute to the development
of diuretic resistance.
Integrated compensatory network
is activated in the absence of
NCC phosphorylation
P. Richard Grimm, Yoskaly Lazo-Fernandez,
Eric Delpire, Susan M. Wall, Susan G. Dorsey,
Edward J. Weinman, Richard Coleman,
James B. Wade, and Paul A. Welling
http://jci.me/78558
Related Commentary
Systems biology of diuretic resistance
Mark A. Knepper
http://jci.me/81505
may 2015
9
Research | Editor’s picks
metabolism
A leaky endoplasmic
reticulum calcium
channel impairs
insulin secretion
Calcium flux plays a pivotal role in insulin
secretion by pancreatic β cells. The type 2
ryanodine receptor (RyR2) is a calcium release
channel on the endoplasmic reticulum (ER) that is
expressed in pancreatic β cells; however, its role in
insulin secretion is unclear. Humans with rare RyR2
mutations that render the channel “leaky” are at
risk for a form of exercise-induced sudden cardiac
death known as catecholaminergic polymorphic
ventricular tachycardia (CPVT). Gaetano Santulli
and colleagues demonstrate that these individuals
also have glucose intolerance and impaired insulin
secretion. Mice expressing CPVT-associated RyR2
mutations (CPVT mice) exhibited intracellular
calcium leak, activated ER stress response, and
mitochondrial abnormalities (see the accompanying image) in pancreatic β cells, accompanied by
decreased fuel-stimulated insulin release and
impaired glucose homeostasis. Importantly,
pharmacological stabilization of RyR2 ameliorated
these defects in CPVT mice, in a murine model of
type II diabetes, and in pancreatic islets isolated
from diabetic patients. These results provide
evidence that intracellular calcium leak via RyR2
contributes to β cell dysfunction.
Calcium release channel RyR2
regulates insulin release and
glucose homeostasis
Gaetano Santulli, Gennaro Pagano, Celestino Sardu,
Wenjun Xie, Steven Reiken, Salvatore Luca D’Ascia,
Michele Cannone, Nicola Marziliano, Bruno Trimarco,
Theresa A. Guise, Alain Lacampagne,
and Andrew R. Marks http://jci.me/79273
aids/hiv
HIV-1 latency reversal: cracking the drug combination
Even though antiretroviral therapy (ART) can suppress HIV-1
viral loads to undetectable levels, resting CD4+ T cells (rCD4s)
can harbor latent HIV-1 proviruses that are not targeted by ART
and are invisible to the host immune system, necessitating
lifelong treatment. The virus could potentially be eradicated
through reactivation of the latent viral reservoir in infected rCD4s.
Gregory Laird, Korin Bullen, and colleagues compared the effects
of multiple two-drug combinations of candidate latency-reversing
agents (LRAs) on latent HIV-1 in rCD4s from infected individuals,
as measured by inductions of intracellular HIV-1 mRNA and virion
production. While a number of combinations effectively reversed
latency, PKC agonists in combination with the BRD4 inhibitor
JQ1 or histone deacetylase inhibitors induced marked HIV-1
transcrip­tion and virus production in the absence of proinflam-
10
matory cytokine release. Mathematical modeling showed that
these combinations had synergistic effects on latency reversal.
These studies establish an ex vivo quantitative approach for
evaluating the efficacy of therapeutic LRA combinations and
identifying multiple combinations that may be effective in vivo.
Ex vivo analysis identifies effective
HIV-1 latency–reversing drug combinations
Gregory M. Laird, C. Korin Bullen, Daniel I.S. Rosenbloom,
Alyssa R. Martin, Alison L. Hill, Christine M. Durand,
Janet D. Siliciano, and Robert F. Siliciano
http://jci.me/80142
the journal of clinical investigation
jci.org/impact
may 2015
Research | Editor’s picks
aging
Poly(A)-specific ribonuclease
mutations cause dyskeratosis congenita
Dyskeratosis congenita is an inherited disorder that is characterized by short telomeres,
mucocutaneous abnormalities, and BM failure; the genetic mutations underlying this disease are
unknown in about 40% of cases. Using whole exome sequencing, Hemanth Tummala, Amanda
Walne, and colleagues identified biallelic mutations in the gene encoding poly(A)-specific
ribonuclease (PARN) in three families with severe dyskeratosis congenita. All of the mutations
affect domains within PARN that are required for its deadenylation activity, which is involved in
mRNA decay. This lack of deadenylation induces an abnormal DNA damage response, resulting in
cell cycle arrest and increased cell death. Additionally, loss of PARN activity results in the
downregulation of four genes involved in telomere maintenance, resulting in shortened
telomeres. In the accompanying Commentary, Philip Mason and Monica Bessler discuss how
these results establish a causative role for PARN in a severe form of dyskeratosis congenita.
Poly(A)-specific ribonuclease deficiency impacts telomere biology
and causes dyskeratosis congenita
Hemanth Tummala, Amanda Walne, Laura Collopy, Shirleny Cardoso, Josu de la Fuente,
Sarah Lawson, James Powell, Nicola Cooper, Alison Foster, Shehla Mohammed,
Vincent Plagnol, Thomas Vulliamy, and Inderjeet Dokal http://jci.me/78963
Related Commentary
mRNA deadenylation and telomere disease
Philip J. Mason and Monica Bessler http://jci.me/81506
immunology
Lipid oxidation controls DC maturation
and immune specificity
Upon exposure to pathogen- or danger-associated molecular patterns, DCs undergo a maturation process
that initiates specific T cell responses. This maturation process must be tightly controlled to avoid
autoimmunity and nonspecific responses. In this issue, Tobias Rothe and colleagues demonstrate that
12/15-lipoxygenase–mediated lipid oxidation is required for the maturation and function of DCs. Loss of
12/15-lipoxygenase in murine or human DCs accelerated maturation and resulted in an altered cytokine profile
that favored the differentiation of Th17 T cells and exacerbated a model of autoimmune disease in mice. This
effect was replicated by exposing DCs to 12/15-lipoxygenase–derived oxidized phospholipids, which control the
maturation process by activating the transcription factor NRF2, thereby impeding Th17-directed differentiation.
12/15-lipoxygenase–mediated enzymatic lipid oxidation
regulates DC maturation and function
Tobias Rothe, Florian Gruber, Stefan Uderhardt, Natacha Ipseiz, Susanne Rössner, Olga Oskolkova,
Stephan Blüml, Norbert Leitinger, Wolfgang Bicker, Valery N. Bochkov, Masayuki Yamamoto,
Alexander Steinkasserer, Georg Schett, Elisabeth Zinser, and Gerhard Krönke http://jci.me/78490
the journal of clinical investigation
jci.org/impact
may 2015
11
Research | Editor’s picks
genetics
Smart bomb: TALE-DNMTs direct
DNA methylation at specific genetic loci
Inappropriate epigenetic modifications, such
as alterations in DNA methylation, can lead to a
variety of disease states, making epigenetic
regulators attractive therapeutic targets;
however, general inhibitors of globally
expressed epigenetic regulators may have
deleterious effects. Diana Bernstein and
colleagues developed a method to direct DNA
methylation to specific genetic loci by
conjugating the catalytic domains of DNA
methyl­transferases (DNMTs) to engineered
transcription activator–like effectors (TALEs).
Using primary human fibroblasts, Bernstein and
colleagues showed that they could induce
methylation of the genetic locus encoding the
cyclin-dependent kinase inhibitor p16, CDKN2A,
resulting in decreased p16 expression and
increased cellular proliferation. The
accompanying image shows increased DNA
replication (red) in control (bottom) versus
p16-targeted TALE-DNMT–treated cells.
TALE-mediated epigenetic
suppression of CDKN2A increases
replication in human fibroblasts
Diana L. Bernstein, John E. Le Lay,
Elena G. Ruano, and Klaus H. Kaestner
http://jci.me/77321
A therapeutic window
of opportunity in
Angelman syndrome
Angelman syndrome (AS) is a severe neurodevelopmental disorder caused
by a lack of maternal UBE3A expression. Children with AS exhibit motor
impairments, epilepsy, intellectual disability, anxiety, and autistic traits.
Activation of the paternal allele could potentially ameliorate the disorder, but
previous studies have indicated that activation in adulthood is insufficient to
rescue most neurocognitive phenotypes in a murine AS model. Sara
Silva-Santos and colleagues reinstated Ube3a expression at different time
points in AS mice to determine the window for therapeutic intervention for
AS-relevant phenotypes. They found that early embryonic expression of
Ube3a completely rescued the neurological and behavioral phenotype of AS
mice. Postnatal reactivation rescued motor deficits but did not rescue
autism- or anxiety-related phenotypes. In contrast, electrophysiological
alterations could be rescued at any age. These results indicate that early
UBE3A expression is necessary to rescue AS behavioral phenotypes.
Ube3a reinstatement identifies distinct developmental
windows in a murine Angelman syndrome model
Sara Silva-Santos, Geeske M. van Woerden, Caroline F. Bruinsma,
Edwin Mientjes, Mehrnoush Aghadavoud Jolfaei, Ben Distel,
Steven A. Kushner, and Ype Elgersma http://jci.me/80554
12
the journal of clinical investigation
jci.org/impact
may 2015
Features
reviews
Aberrant kinase signaling:
a hallmark of cancer
Kinase-mediated protein phosphorylation
underlies nearly every cellular function, and
many kinase-driven signaling pathways are
now known to underlie a number of
the “hallmark” phenotypes of cancer
biology (see the accompanying image).
There has been a substantial effort to
develop small molecule inhibitors of
key kinases for therapeutic intervention
as well as interrogation of signaling
pathways. In this issue, Klaus Hoeflich
and colleagues review the mechanisms
of kinase activation in cancer and
discuss the clinical impact of selective
kinase inhibitors. They also detail
ongoing work in the design of the new kinase
inhibitors, including new targets in the tumor
micro­environment and immune system, and discuss
potential combination strategies to improve efficacy
and circumvent on-target resistance mechanisms.
Targeting cancer with kinase inhibitors
Stefan Gross, Rami Rahal, Nicolas Stransky, Christoph Lengauer,
and Klaus P. Hoeflich http://jci.me/76094
Common themes
in ALS pathogenesis
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder that
is inherited in roughly 10% of cases. Both familial and sporadic forms of
ALS are frequently accompanied by frontotemporal lobar dementia
(FLTD-ALS), and even though these disorders involve different parts of the
nervous system, they are characterized by similar molecular pathologies.
In this issue, Robert Brown and colleagues detail the genetic underpinnings
of familial and sporadic ALS and mixed FTLD-ALS, and they identify
four major pathological characteristics common to these disorders:
(a) perturbations in protein stability and degradation, (b) altered
homeostasis of RNA/DNA-binding proteins, (c) impaired cytoskeleton
function, and (d) the involvement of non-neuronal cells as modifiers of
disease phenotype. Targeting of these dysfunctional processes could
potentially lead to the development of effective therapeutics.
Emerging mechanisms of molecular pathology in ALS
Owen M. Peters, Mehdi Ghasemi, and Robert H. Brown Jr.
http://jci.me/71601
the journal of clinical investigation
hindsight
Abdominal fat and metabolic
dysfunction
An abundance of abdominal adipose tissue correlates with an increased risk
of metabolic dysfunction, and a large waist circumference is a component of
the metabolic syndrome diagnosis. In 1983, Ulf Smith and colleagues
evaluated the metabolic profiles of 930 men and women and determined that
for a given BMI, an abdominal fat distribution is linked to insulin resistance
and increased risk of type 2 diabetes and cardiovascular disease. In this issue,
Smith reflects on how he became interested in the relationship between
adipose tissue and metabolism and the collaborative effort behind the 1983
JCI study. Moreover, Smith discusses possible drivers of the relationship
between abdominal adiposity and the metabolic complications of obesity.
Abdominal obesity: a marker of ectopic fat accumulation
Ulf Smith http://jci.me/81507
jci.org/impact
may 2015
13
Journal of Clinical Investigation
Consulting Editors
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
J. Timothy Greenamyre
Theresa A. Guise
David Hafler
Jonathan J. Hansen
Raymond C. Harris
Stanley L. Hazen
Peter Heeringa
Brian A. Hemmings
Gary Koretzky
Calvin Kuo
Antonio La Cava
Fadi G. Lakkis
Terri Laufer
Mitchell A. Lazar
Brendan Lee
William M.F. Lee
David J. Pinsky
Edward Plow
Jeffrey Pollard
Kornelia Polyak
Catherine Postic
Josef Prchal
Alice S. Prince
Louis J. Ptáček
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
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
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
Deborah M. Muoio
Anthony J. Muslin
Martin G. Myers Jr.
Benjamin G. Neel
Eric N. Olson
Harry T. Orr
William C. Parks
Warren S. Pear
Richard M. Peek Jr.
Sallie R. Permar
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
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