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JCI online early table of contents: Nov. 6, 2008
Date:11/6/2008

EDITOR'S PICK: Visualizing asthma-causing immune cells at work

Immune cells known as eosinophils have a central role in causing asthma. Now, a team of researchers at Massachusetts General Hospital, Boston, has developed approaches to noninvasively visualize in real-time eosinophil responses in the lungs and airways of mice with a disease that mimics asthma (experimental allergic airway inflammation); they hope that these approaches might be developed to help assess the efficacy of treatments (both old and new) for the disease.

The team, led by Mikael Pittet and Ralph Weissleder, visualized eosinophils at single-cell resolution using various noninvasive real-time molecular imaging technologies (specifically, near-infrared fluorescence fiber optic bronchoscopy, intravital microscopy, and fluorescence-mediated tomography) following injection of an optical sensor that targets proteins produced by eosinophils known as MMPs. Using a combination of the sensitive optical sensor and fluorescence-mediated tomography, it was observed that dexamethasone (a drug used to treat severe asthma) decreased the number of eosinophils in the lungs of mice with allergic airway inflammation. As some of the imaging techniques have the potential to be developed for the clinic, the authors suggest that in combination with an appropriate optical sensor they might improve our ability to diagnose asthma and assess treatment efficacy.

TITLE: Real-time assessment of inflammation and treatment response in a mouse model of allergic airway inflammation

AUTHOR CONTACT:
Mikael J. Pittet
Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 726-6481; Fax: (617) 726-5708; E-mail: mpittet@mgh.harvard.edu.

Ralph Weissleder
Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 726-6481; Fax: (617) 726-5708;
E-mail: rweissleder@mgh.harvard.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36335


GENETICS: Unraveling the genetic defects underlying two kidney conditions

John Rasko and colleagues, at the Centenary Institute, Australia, have provided new insight into the genes that are mutated in individuals with two related kidney defects: iminoglycinuria (IG), which occurs when individuals cannot efficiently reabsorp the protein building blocks glycine, proline, and hydroxyproline, so they are excreted at high levels in the urine; and hyperglycinuria without iminoaciduria (HG), which occurs when individuals cannot efficiently reabsorp glycine, so it is excreted at high levels in the urine.

By screening many candidate genes in 7 families first identified through newborn IG screening programs, the authors found that most individuals with IG had two nonfunctional copies of the gene SLC36A2, which is normally responsible for making a transporter protein that helps kidney cells reabsorp protein building blocks. Furthermore, inheritance of one nonfunctional copy of SLC36A2 was the cause of HG. However, the genetic cause of these disorders was not quite that simple, as some individuals with IG had an SLC36A2 gene that could make protein, but it was not as functional as the normal protein. In these people, mutations in other transporter proteins were detected, leading the authors to conclude that mutations in a major gene (SLC36A2) and accompanying modifier genes are the genetic cause of these related conditions.

TITLE: Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters

AUTHOR CONTACT:
John E.J. Rasko
Centenary Institute, Camperdown, New South Wales, Australia.
Phone: 61-2-95656156; Fax: 61-2-95656101; E-mail: j.rasko@centenary.usyd.edu.au.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36625


ONCOLOGY: Getting rid of J(u)NK impairs human liver cancer growth in mice

A type of liver cancer known as hepatocellular carcinoma (HCC) is the third most common cause of death from cancer in the world. Erwin Wagner and colleagues, at the Research Institute of Molecular Pathology, Austria, have now provided insight into the signaling molecules that control the proliferation of HCC cells, and suggest that targeting one of these molecules (JNK1) should be considered as a potential therapeutic approach for the treatment of individuals with HCC.

In the study, activation of the protein JNK1 but not JNK2 was increased in human primary HCC samples. Furthermore, JNK1 was required for human HCC cells to proliferate in vitro and form tumors when they were transplanted into mice. Mechanistically, decreased proliferation and tumor development were associated with increased expression of the protein p21 and reduced expression of the protein c-Myc. Crucial support for the authors suggestion that targeting JNK1 might be beneficial to individuals with HCC came from the observation that treatment with a inhibitor of JNK1/2 markedly decreased the growth of human HCC cells transplanted into mice.

TITLE: Proliferation of human HCC cells and chemically induced mouse liver cancers requires JNK1-dependent p21 downregulation

AUTHOR CONTACT:
Erwin F. Wagner
Spanish National Cancer Research Center, Madrid, Spain.
Phone: 34-917-328-000 ext. 3800; Fax: 34-912-246-980; E-mail: ewagner@cnio.es.

View the PDF of this article at: https://www.the-jci.org/article.php?id=37156


TUMOR IMMUNOLOGY: Harnessing a bacterium to help boost antitumor immune therapy

Nina Bhardwaj, Mojca Skoberne, and colleagues, at New York University School of Medicine, New York, have developed a new approach to using human immune cells known as dendritic cells (DCs) to enhance antitumor immune responses, and have shown that it works efficiently in a mouse model of melanoma (an aggressive type of skin cancer).

The bacterium Listeria monocytogenes can cause listeriosis. However, in the study, a noninfectious form of the bacterium, known as KBMA Listeria monocytogenes, was used to activate DCs and load them with tumor proteins that stimulate immune cells known as T cells to mount a strong antitumor immune response. For example, KBMA Listeria monocytogenes engineered to express part of the human tumor protein MelanA was used in vitro to induce human DCs to stimulate a strong human CD8+ T cell immune responses that killed MelanA-expressing, patient-derived melanoma cells. Furthermore when mice with a tumor (composed of mouse CT-26 colon carcinoma cells) were injected with KBMA Listeria monocytogenes engineered to express a protein known to be found in the tumor they mounted a powerful protective antitumor immune response. The authors therefore suggest that the use of appropriately engineered KBMA Listeria monocytogenes might improve the clinical antitumor potential of DCs.

TITLE: KBMA Listeria monocytogenes is an effective vector for DC-mediated induction of antitumor immunity

AUTHOR CONTACT:
Mojca Skoberne
New York University School of Medicine, New York, New York, USA.
Fax: (212) 263-6729; E-mail: Mojcaskoberne@yahoo.de.

Nina Bhardwaj
New York University School of Medicine, New York, New York, USA.
Phone: (212) 263-5814; Fax: (212) 263-6729; E-mail: Nina.Bhardwaj@nyumc.org.

View the PDF of this article at: https://www.the-jci.org/article.php?id=31350


PHYSIOLOGY: Identifying stem cells in the esophagus

The cells in our body are constantly being replaced with new ones, which are often derived from local populations of stem cells. In many parts of the body these stem cell populations are not well characterized. Now, Anil Rustgi and colleagues, at the University of Pennsylvania, Philadelphia, have identified a potential population of stem cells responsible for maintaining the epithelial cells lining the mouse esophagus (the part of the intestine that links the throat to the stomach). Importantly, administration of the cells, identified as CD34+, to mice with a damaged esophageal epithelium reconstituted the lining of the esophagus. As the esophagus is often exposed to noxious agents, e.g., acid, bile, and infection, the authors hope that these data will provide new insight into the response of the esophageal epithelium following injury and initiate studies to determine whether dysregulation in this process contributes to the development of esophageal cancer.

TITLE: A subpopulation of mouse esophageal basal cells has properties of stem cells with the capacity for self-renewal and lineage specification

AUTHOR CONTACT:
Anil K. Rustgi
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: (215) 898-0154; Fax: (215) 573-2024; E-mail: anil2@mail.med.upenn.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35012


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Contact: Karen Honey
press_releases@the-jci.org
215-573-1850
Journal of Clinical Investigation
Source:Eurekalert

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