Journal of Clinical Investigation (J CLIN INVEST )

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

Description

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.

  • Impact factor
    12.81
    Show impact factor history
     
    Impact factor
  • 5-year impact
    14.69
  • Cited half-life
    9.70
  • Immediacy index
    2.59
  • Eigenfactor
    0.20
  • Article influence
    6.43
  • Website
    Journal of Clinical Investigation website
  • ISSN
    0021-9738
  • OCLC
    55055897
  • Material type
    Document, Periodical, Internet resource
  • Document type
    Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details

American Society for Clinical Investigation

  • Pre-print
    • Author cannot archive a pre-print version
  • Post-print
    • Author can archive a post-print version
  • Conditions
    • Personal websites, institutional and funding-body repositories
    • Published source must be acknowledged
    • Please use publisher PDF
    • Cannot appear before publication
  • Classification
    ​ blue

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: Patient responses to placebo and sham effects are a major obstacle to the development of therapies for brain disorders, including Parkinson's disease (PD). Here, we used functional brain imaging and network analysis to study the circuitry underlying placebo effects in PD subjects randomized to sham surgery as part of a double-blind gene therapy trial. Metabolic imaging was performed prior to randomization, then again at 6 and 12 months after sham surgery. In this cohort, the sham response was associated with the expression of a distinct cerebello-limbic circuit. The expression of this network increased consistently in patients blinded to treatment and correlated with independent clinical ratings. Once patients were unblinded, network expression declined toward baseline levels. Analogous network alterations were not seen with open-label levodopa treatment or during disease progression. Furthermore, sham outcomes in blinded patients correlated with baseline network expression, suggesting the potential use of this quantitative measure to identify "sham-susceptible" subjects before randomization. Indeed, Monte Carlo simulations revealed that a priori exclusion of such individuals substantially lowers the number of randomized participants needed to demonstrate treatment efficacy. Individualized subject selection based on a predetermined network criterion may therefore limit the need for sham interventions in future clinical trials.
    Journal of Clinical Investigation 07/2014; 124(8):3656-3666.
  • [Show abstract] [Hide abstract]
    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;