Journal of Clinical Investigation (J CLIN INVEST )

Publisher: American Society for Clinical Investigation, American Society for Clinical Investigation


The Journal of Clinical Investigation has a respected history as a vital publication for the physician and scientist alike. Since 1924, the JCI has published research that examines the basic science behind clinical presentation. The JCI continues to offer expanded commentary on published articles and series focused on critical topics in emerging areas of biomedicine.

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    Journal of Clinical Investigation website
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  • Material type
    Document, Periodical, Internet resource
  • Document type
    Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details

American Society for Clinical Investigation

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    • Authors personal websites, institutional repositories and funding-body repositories
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Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: The most severe form of autosomal dominant polycystic kidney disease occurs in patients with mutations in PKD1. PKD1 encodes polycystin-1 (PC1), a complex polytopic membrane protein that is expressed in cilia and undergoes autoproteolytic cleavage at a G-protein coupled receptor proteolytic site (GPS). A quarter of PC1 mutations are missense variants for which the mechanisms of loss-of-function have not been determined. We established a cell-based system with which we showed that cleavage at the GPS is required for trafficking of PC1 to cilia. More generally, we found that a subset of pathogenic missense mutations share failure of PC1 to traffic to cilia as a common feature regardless of effects on GPS cleavage. A missense mutant in polycystin-2 (PC2) showed similar cilia trafficking defects. We used Pkd1-BAC recombineering to establish an in vivo model that validated the in vitro studies showing that only cleaved polycystin-1 (Pc1) exited the endoplasmic reticulum. Unexpectedly, the steady state expression level of the intramembranous COOH-terminal fragment of cleaved PC1 is critically dependent on intact interaction with PC2. This study demonstrates a novel relationship of PC1 protein expression with PC2 interaction and provides a framework for functional assays to categorize the effects of missense mutations in polycystins.
    Journal of Clinical Investigation 11/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Glioblastoma (GBM) is the most common and lethal brain tumor in adults. Glioma-initiating cells (GICs) are stem-like cells that have been implicated in glioblastoma progression and recurrence; however, the distinct properties of GICs and non-GICs within GBM tumors are largely uncharacterized. Here, we evaluated stem cell-associated microRNA (miR) expression in GICs from GBM patients and GICs derived from xenografted human glioma cell lines and determined that miR-33a promotes GIC growth and self-renewal. Moreover, evaluation of a GBM tissue array revealed that higher miR-33a expression was associated with poor prognosis of GBM patients. Antagonizing miR-33a function in GICs reduced self-renewal and tumor progression in immune-compromised mice, whereas overexpression of miR-33a in non-GICs promoted the display of features associated with GICs. We identified the mRNAs encoding phosphodiesterase 8A (PDE8A) and UV radiation resistance-associated gene (UVRAG) as direct miR-33a targets. PDE8A and UVRAG negatively regulated the cAMP/PKA and NOTCH pathways, respectively; therefore, miR-33a-dependent reduction of these proteins promoted growth and self-renewal of GICs by enhancing PKA and NOTCH activity. Furthermore, in GBM specimens, there was an inverse correlation between the expression levels of miR-33a and PDE8A and UVRAG expression. These findings reveal a miR-33a-centered signaling network that promotes GIC maintenance and has potential as a therapeutic target for GBM treatment.
    Journal of Clinical Investigation 09/2014;
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    ABSTRACT: Colitis-associated colon cancer (CAC) develops as a result of inflammation-induced epithelial transformation, which occurs in response to inflammatory cytokine-dependent downregulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and subsequent suppression of prostaglandin metabolism. Agents that both enhance 15-PGDH expression and suppress cyclooxygenase-2 (COX-2) production may more effectively prevent CAC. Synthetic triterpenoids are a class of small molecules that suppress COX-2 as well as inflammatory cytokine signaling. Here, we found that administration of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-C28-methyl ester (CDDO-Me) suppresses CAC in mice. In a spontaneous, inflammation-driven intestinal neoplasia model, deletion of Smad4 specifically in T cells led to progressive production of inflammatory cytokines, including TNF-α, IFN-γ, iNOS, IL-6, IL-1β; as well as activation of STAT1 and STAT3; along with suppression of 15-PGDH expression. Oral administration of CDDO-Me to mice with SMAD4-deficient T cells increased survival and suppressed intestinal epithelial neoplasia by decreasing production of inflammatory mediators and increasing expression of 15-PGDH. Induction of 15-PGDH by CDDO-Me was dose dependent in epithelial cells and was abrogated following treatment with TGF-β signaling inhibitors in vitro. Furthermore, CDDO-Me-dependent 15-PGDH induction was not observed in Smad3-/- mice. Similarly, CDDO-Me suppressed azoxymethane plus dextran sodium sulfate-induced carcinogenesis in wild-type animals, highlighting the potential of small molecules of the triterpenoid family as effective agents for the chemoprevention of CAC in humans.
    Journal of Clinical Investigation 05/2014;