Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact

Concise Communications

  • 148 Articles
  • 0 Posts
  • ← Previous
  • 1
  • 2
  • …
  • 13
  • 14
  • 15
  • Next →
The nonsense-mediated RNA decay pathway is disrupted in inflammatory myofibroblastic tumors
JingWei Lu, … , Miles F. Wilkinson, YanJun Lu
JingWei Lu, … , Miles F. Wilkinson, YanJun Lu
Published June 27, 2016
Citation Information: J Clin Invest. 2016;126(8):3058-3062. https://doi.org/10.1172/JCI86508.
View: Text | PDF
Article has an altmetric score of 69

The nonsense-mediated RNA decay pathway is disrupted in inflammatory myofibroblastic tumors

  • Text
  • PDF
Abstract

Inflammatory myofibroblastic tumors (IMTs) are characterized by myofibroblast proliferation and an inflammatory cell infiltrate. Little is known about the molecular pathways that precipitate IMT formation. Here, we report the identification of somatic mutations in UPF1, a gene that encodes an essential component of the nonsense-mediated RNA decay (NMD) pathway, in 13 of 15 pulmonary IMT samples. The majority of mutations occurred in a specific region of UPF1 and triggered UPF1 alternative splicing. Several mRNA targets of the NMD pathway were upregulated in IMT samples, indicating that the UPF1 mutations led to reduced NMD magnitude. These upregulated NMD targets included NIK mRNA, which encodes a potent activator of NF-κB. In human lung cells, UPF1 depletion increased expression of chemokine-encoding genes in a NIK-dependent manner. Elevated chemokines and IgE class switching events were observed in IMT samples, consistent with NIK upregulation in these tumors. Together, these results support a model in which UPF1 mutations downregulate NMD, leading to NIK-dependent NF-κB induction, which contributes to the immune infiltration that is characteristic of IMTs. The molecular link between the NMD pathway and IMTs has implications for the diagnosis and treatment of these tumors.

Authors

JingWei Lu, Terra-Dawn Plank, Fang Su, XiuJuan Shi, Chen Liu, Yuan Ji, ShuaiJun Li, Andrew Huynh, Chao Shi, Bo Zhu, Guang Yang, YanMing Wu, Miles F. Wilkinson, YanJun Lu

×

The composition of the microbiota modulates allograft rejection
Yuk Man Lei, … , Caroline Bartman, Maria-Luisa Alegre
Yuk Man Lei, … , Caroline Bartman, Maria-Luisa Alegre
Published June 20, 2016
Citation Information: J Clin Invest. 2016;126(7):2736-2744. https://doi.org/10.1172/JCI85295.
View: Text | PDF
Article has an altmetric score of 143

The composition of the microbiota modulates allograft rejection

  • Text
  • PDF
Abstract

Transplantation is the only cure for end-stage organ failure, but without immunosuppression, T cells rapidly reject allografts. While genetic disparities between donor and recipient are major determinants of the kinetics of transplant rejection, little is known about the contribution of environmental factors. Because colonized organs have worse transplant outcome than sterile organs, we tested the influence of host and donor microbiota on skin transplant rejection. Compared with untreated conventional mice, pretreatment of donors and recipients with broad-spectrum antibiotics (Abx) or use of germ-free (GF) donors and recipients resulted in prolonged survival of minor antigen–mismatched skin grafts. Increased graft survival correlated with reduced type I IFN signaling in antigen-presenting cells (APCs) and decreased priming of alloreactive T cells. Colonization of GF mice with fecal material from untreated conventional mice, but not from Abx-pretreated mice, enhanced the ability of APCs to prime alloreactive T cells and accelerated graft rejection, suggesting that alloimmunity is modulated by the composition of microbiota rather than the quantity of bacteria. Abx pretreatment of conventional mice also delayed rejection of major antigen–mismatched skin and MHC class II–mismatched cardiac allografts. This study demonstrates that Abx pretreatment prolongs graft survival, suggesting that targeting microbial constituents is a potential therapeutic strategy for enhancing graft acceptance.

Authors

Yuk Man Lei, Luqiu Chen, Ying Wang, Andrew T. Stefka, Luciana L. Molinero, Betty Theriault, Keston Aquino-Michaels, Ayelet S. Sivan, Cathryn R. Nagler, Thomas F. Gajewski, Anita S. Chong, Caroline Bartman, Maria-Luisa Alegre

×

CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer
Kipp Weiskopf, … , Irving L. Weissman, Julien Sage
Kipp Weiskopf, … , Irving L. Weissman, Julien Sage
Published June 13, 2016
Citation Information: J Clin Invest. 2016;126(7):2610-2620. https://doi.org/10.1172/JCI81603.
View: Text | PDF
Article has an altmetric score of 167

CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer

  • Text
  • PDF
Abstract

Small-cell lung cancer (SCLC) is a highly aggressive subtype of lung cancer with limited treatment options. CD47 is a cell-surface molecule that promotes immune evasion by engaging signal-regulatory protein alpha (SIRPα), which serves as an inhibitory receptor on macrophages. Here, we found that CD47 is highly expressed on the surface of human SCLC cells; therefore, we investigated CD47-blocking immunotherapies as a potential approach for SCLC treatment. Disruption of the interaction of CD47 with SIRPα using anti-CD47 antibodies induced macrophage-mediated phagocytosis of human SCLC patient cells in culture. In a murine model, administration of CD47-blocking antibodies or targeted inactivation of the Cd47 gene markedly inhibited SCLC tumor growth. Furthermore, using comprehensive antibody arrays, we identified several possible therapeutic targets on the surface of SCLC cells. Antibodies to these targets, including CD56/neural cell adhesion molecule (NCAM), promoted phagocytosis in human SCLC cell lines that was enhanced when combined with CD47-blocking therapies. In light of recent clinical trials for CD47-blocking therapies in cancer treatment, these findings identify disruption of the CD47/SIRPα axis as a potential immunotherapeutic strategy for SCLC. This approach could enable personalized immunotherapeutic regimens in patients with SCLC and other cancers.

Authors

Kipp Weiskopf, Nadine S. Jahchan, Peter J. Schnorr, Sandra Cristea, Aaron M. Ring, Roy L. Maute, Anne K. Volkmer, Jens-Peter Volkmer, Jie Liu, Jing Shan Lim, Dian Yang, Garrett Seitz, Thuyen Nguyen, Di Wu, Kevin Jude, Heather Guerston, Amira Barkal, Francesca Trapani, Julie George, John T. Poirier, Eric E. Gardner, Linde A. Miles, Elisa de Stanchina, Shane M. Lofgren, Hannes Vogel, Monte M. Winslow, Caroline Dive, Roman K. Thomas, Charles M. Rudin, Matt van de Rijn, Ravindra Majeti, K. Christopher Garcia, Irving L. Weissman, Julien Sage

×

Soluble fms-like tyrosine kinase 1 promotes angiotensin II sensitivity in preeclampsia
Suzanne D. Burke, … , Iris Z. Jaffe, S. Ananth Karumanchi
Suzanne D. Burke, … , Iris Z. Jaffe, S. Ananth Karumanchi
Published June 6, 2016
Citation Information: J Clin Invest. 2016;126(7):2561-2574. https://doi.org/10.1172/JCI83918.
View: Text | PDF
Article has an altmetric score of 10

Soluble fms-like tyrosine kinase 1 promotes angiotensin II sensitivity in preeclampsia

  • Text
  • PDF
Abstract

Preeclampsia is a hypertensive disorder of pregnancy in which patients develop profound sensitivity to vasopressors, such as angiotensin II, and is associated with substantial morbidity for the mother and fetus. Enhanced vasoconstrictor sensitivity and elevations in soluble fms-like tyrosine kinase 1 (sFLT1), a circulating antiangiogenic protein, precede clinical signs and symptoms of preeclampsia. Here, we report that overexpression of sFlt1 in pregnant mice induced angiotensin II sensitivity and hypertension by impairing endothelial nitric oxide synthase (eNOS) phosphorylation and promoting oxidative stress in the vasculature. Administration of the NOS inhibitor l-NAME to pregnant mice recapitulated the angiotensin sensitivity and oxidative stress observed with sFlt1 overexpression. Sildenafil, an FDA-approved phosphodiesterase 5 inhibitor that enhances NO signaling, reversed sFlt1-induced hypertension and angiotensin II sensitivity in the preeclampsia mouse model. Sildenafil treatment also improved uterine blood flow, decreased uterine vascular resistance, and improved fetal weights in comparison with untreated sFlt1-expressing mice. Finally, sFLT1 protein expression inversely correlated with reductions in eNOS phosphorylation in placental tissue of human preeclampsia patients. These data support the concept that endothelial dysfunction due to high circulating sFLT1 may be the primary event leading to enhanced vasoconstrictor sensitivity that is characteristic of preeclampsia and suggest that targeting sFLT1-induced pathways may be an avenue for treating preeclampsia and improving fetal outcomes.

Authors

Suzanne D. Burke, Zsuzsanna K. Zsengellér, Eliyahu V. Khankin, Agnes S. Lo, Augustine Rajakumar, Jennifer J. DuPont, Amy McCurley, Mary E. Moss, Dongsheng Zhang, Christopher D. Clark, Alice Wang, Ellen W. Seely, Peter M. Kang, Isaac E. Stillman, Iris Z. Jaffe, S. Ananth Karumanchi

×

Two superoxide dismutase prion strains transmit amyotrophic lateral sclerosis–like disease
Elaheh Ekhtiari Bidhendi, … , Stefan L. Marklund, Thomas Brännström
Elaheh Ekhtiari Bidhendi, … , Stefan L. Marklund, Thomas Brännström
Published May 3, 2016
Citation Information: J Clin Invest. 2016;126(6):2249-2253. https://doi.org/10.1172/JCI84360.
View: Text | PDF
Article has an altmetric score of 157

Two superoxide dismutase prion strains transmit amyotrophic lateral sclerosis–like disease

  • Text
  • PDF
Abstract

Amyotrophic lateral sclerosis (ALS) is an adult-onset degeneration of motor neurons that is commonly caused by mutations in the gene encoding superoxide dismutase 1 (SOD1). Both patients and Tg mice expressing mutant human SOD1 (hSOD1) develop aggregates of unknown importance. In Tg mice, 2 different strains of hSOD1 aggregates (denoted A and B) can arise; however, the role of these aggregates in disease pathogenesis has not been fully characterized. Here, minute amounts of strain A and B hSOD1 aggregate seeds that were prepared by centrifugation through a density cushion were inoculated into lumbar spinal cords of 100-day-old mice carrying a human SOD1 Tg. Mice seeded with A or B aggregates developed premature signs of ALS and became terminally ill after approximately 100 days, which is 200 days earlier than for mice that had not been inoculated or were given a control preparation. Concomitantly, exponentially growing strain A and B hSOD1 aggregations propagated rostrally throughout the spinal cord and brainstem. The phenotypes provoked by the A and B strains differed regarding progression rates, distribution, end-stage aggregate levels, and histopathology. Together, our data indicate that the aggregate strains are prions that transmit a templated, spreading aggregation of hSOD1, resulting in a fatal ALS-like disease.

Authors

Elaheh Ekhtiari Bidhendi, Johan Bergh, Per Zetterström, Peter M. Andersen, Stefan L. Marklund, Thomas Brännström

×

Evaluation of direct-to-consumer low-volume lab tests in healthy adults
Brian A. Kidd, … , Eric E. Schadt, Joel T. Dudley
Brian A. Kidd, … , Eric E. Schadt, Joel T. Dudley
Published March 28, 2016
Citation Information: J Clin Invest. 2016;126(5):1734-1744. https://doi.org/10.1172/JCI86318.
View: Text | PDF | Corrigendum
Article has an altmetric score of 616

Evaluation of direct-to-consumer low-volume lab tests in healthy adults

  • Text
  • PDF
Abstract

BACKGROUND. Clinical laboratory tests are now being prescribed and made directly available to consumers through retail outlets in the USA. Concerns with these test have been raised regarding the uncertainty of testing methods used in these venues and a lack of open, scientific validation of the technical accuracy and clinical equivalency of results obtained through these services.

METHODS. We conducted a cohort study of 60 healthy adults to compare the uncertainty and accuracy in 22 common clinical lab tests between one company offering blood tests obtained from finger prick (Theranos) and 2 major clinical testing services that require standard venipuncture draws (Quest and LabCorp). Samples were collected in Phoenix, Arizona, at an ambulatory clinic and at retail outlets with point-of-care services.

RESULTS. Theranos flagged tests outside their normal range 1.6× more often than other testing services (P < 0.0001). Of the 22 lab measurements evaluated, 15 (68%) showed significant interservice variability (P < 0.002). We found nonequivalent lipid panel test results between Theranos and other clinical services. Variability in testing services, sample collection times, and subjects markedly influenced lab results.

CONCLUSION. While laboratory practice standards exist to control this variability, the disparities between testing services we observed could potentially alter clinical interpretation and health care utilization. Greater transparency and evaluation of testing technologies would increase their utility in personalized health management.

FUNDING. This work was supported by the Icahn Institute for Genomics and Multiscale Biology, a gift from the Harris Family Charitable Foundation (to J.T. Dudley), and grants from the NIH (R01 DK098242 and U54 CA189201, to J.T. Dudley, and R01 AG046170 and U01 AI111598, to E.E. Schadt).

Authors

Brian A. Kidd, Gabriel Hoffman, Noah Zimmerman, Li Li, Joseph W. Morgan, Patricia K. Glowe, Gregory J. Botwin, Samir Parekh, Nikolina Babic, Matthew W. Doust, Gregory B. Stock, Eric E. Schadt, Joel T. Dudley

×

Cross-species translation of the Morris maze for Alzheimer’s disease
Katherine L. Possin, … , Joel H. Kramer, Steven Finkbeiner
Katherine L. Possin, … , Joel H. Kramer, Steven Finkbeiner
Published January 19, 2016
Citation Information: J Clin Invest. 2016;126(2):779-783. https://doi.org/10.1172/JCI78464.
View: Text | PDF
Article has an altmetric score of 45

Cross-species translation of the Morris maze for Alzheimer’s disease

  • Text
  • PDF
Abstract

Analogous behavioral assays are needed across animal models and human patients to improve translational research. Here, we examined the extent to which performance in the Morris water maze — the most frequently used behavioral assay of spatial learning and memory in rodents — translates to humans. We designed a virtual version of the assay for human subjects that includes the visible-target training, hidden-target learning, and probe trials that are typically administered in the mouse version. We compared transgenic mice that express human amyloid precursor protein (hAPP) and patients with mild cognitive impairment due to Alzheimer’s disease (MCI-AD) to evaluate the sensitivity of performance measures in detecting deficits. Patients performed normally during visible-target training, while hAPP mice showed procedural learning deficits. In hidden-target learning and probe trials, hAPP mice and MCI-AD patients showed similar deficits in learning and remembering the target location. In addition, we have provided recommendations for selecting performance measures and sample sizes to make these assays sensitive to learning and memory deficits in humans with MCI-AD and in mouse models. Together, our results demonstrate that with careful study design and analysis, the Morris maze is a sensitive assay for detecting AD-relevant impairments across species.

Authors

Katherine 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, Steven Finkbeiner

×

Broadly neutralizing anti-influenza antibodies require Fc receptor engagement for in vivo protection
David J. DiLillo, … , Patrick C. Wilson, Jeffrey V. Ravetch
David J. DiLillo, … , Patrick C. Wilson, Jeffrey V. Ravetch
Published January 5, 2016
Citation Information: J Clin Invest. 2016;126(2):605-610. https://doi.org/10.1172/JCI84428.
View: Text | PDF
Article has an altmetric score of 8

Broadly neutralizing anti-influenza antibodies require Fc receptor engagement for in vivo protection

  • Text
  • PDF
Abstract

In vivo protection by antimicrobial neutralizing Abs can require the contribution of effector functions mediated by Fc-Fcγ receptor (Fc-FcγR) interactions for optimal efficacy. In influenza, broadly neutralizing anti-hemagglutinin (anti-HA) stalk mAbs require Fc-FcγR interactions to mediate in vivo protection, but strain-specific anti-HA head mAbs do not. Whether this rule applies only to anti-stalk Abs or is applicable to any broadly neutralizing Ab (bNAb) against influenza is unknown. Here, we characterized the contribution of Fc-FcγR interactions during in vivo protection for a panel of 13 anti-HA mAbs, including bNAbs and non-neutralizing Abs, against both the stalk and head domains. All classes of broadly binding anti-HA mAbs required Fc-FcγR interactions to provide protection in vivo, including those mAbs that bind the HA head and those that do not neutralize virus in vitro. Further, a broadly neutralizing anti-neuraminidase (anti-NA) mAb also required FcγRs to provide protection in vivo, but a strain-specific anti-NA mAb did not. Thus, these findings suggest that the breadth of reactivity of anti-influenza Abs, regardless of their epitope, necessitates interactions with FcγRs on effector cell populations to mediate in vivo protection. These findings will guide the design of antiviral Ab therapeutics and inform vaccine design to elicit Abs with optimal binding properties and effector functions.

Authors

David J. DiLillo, Peter Palese, Patrick C. Wilson, Jeffrey V. Ravetch

×
  • ← Previous
  • 1
  • 2
  • …
  • 13
  • 14
  • 15
  • Next →

No posts were found with this tag.

Advertisement

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Picked up by 10 news outlets
Posted by 5 X users
55 readers on Mendeley
See more details
Picked up by 20 news outlets
Blogged by 2
Posted by 8 X users
Referenced in 1 patents
On 1 Facebook pages
Highlighted by 1 platforms
98 readers on Mendeley
See more details
Picked up by 1 news outlets
Posted by 2 X users
On 1 Facebook pages
155 readers on Mendeley
See more details
Picked up by 17 news outlets
Blogged by 1
Posted by 24 X users
Referenced in 34 patents
381 readers on Mendeley
1 readers on CiteULike
See more details
Picked up by 4 news outlets
Blogged by 1
Posted by 18 X users
On 4 Facebook pages
Mentioned in 1 Google+ posts
132 readers on Mendeley
See more details
Picked up by 15 news outlets
Blogged by 4
Posted by 24 X users
On 3 Facebook pages
Mentioned in 1 Google+ posts
Reddited by 1
102 readers on Mendeley
See more details
Posted by 3 X users
Referenced in 18 patents
232 readers on Mendeley
See more details
Picked up by 65 news outlets
Blogged by 8
Posted by 106 X users
On 5 Facebook pages
Referenced in 2 Wikipedia pages
Reddited by 1
107 readers on Mendeley
See more details