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JCI online early table of contents: May 1, 2009
Date:5/1/2009

EDITOR'S PICK: Now we know what blocks the effects of a newly developed anticancer therapy

A new approach being developed to treat individuals with cancer that is resistant to standard therapy is the use of adenovirus-based therapies. Although promising clinical results have been obtained in some settings, in many cases the therapies have had little impact. One reason for this lack of efficacy has now been uncovered by a team of researchers, led by Nick Lemoine and Yahoe Wang, at Barts and The London School of Medicine and Dentistry, London.

In the study, they found that human pancreatic cancer cell lines expressing the protein CEACAM6 were not sensitive to being killed by adenoviruses. Further analysis revealed the molecular mechanism by which CEACAM6 mediates its effects and indicated that knocking down expression of CEACAM6 markedly increased the anticancer effects of an adenovirus in mice harboring human tumor cells. The authors therefore suggest that identifying whether or not a tumor expresses CEACAM6 and the downstream proteins required to block tumor cell killing by adenoviruses might provide a way to predict the response of patients to adenovirus-based therapies, and that these proteins might provide targets for the development of more effective adenovirus-based therapies.

TITLE: CEACAM6 attenuates adenovirus infection by antagonizing viral trafficking in cancer cells

AUTHOR CONTACT:
Nick Lemoine
Institute of Cancer, Barts and The London School of Medicine and Dentistry, London, United Kingdom.
Phone: 44-20-70140420; Fax: 44-20-70140431. E-mail: nick.lemoine@cancer.org.uk.

Yaohe Wang
Institute of Cancer, Barts and The London School of Medicine and Dentistry, London, United Kingdom.
Phone: 44-20-70140445; Fax: 44-20-70140431. E-mail: yaohe.wang@cancer.org.uk.

View the PDF of this article at: https://www.the-jci.org/article.php?id=37905


ONCOLOGY: How some immune cells improve cancer outcome

For a number of cancers, including neuroblastoma (the second most common tumor in children), tumor infiltration by a subset of immune cells known as V-alpha-24-invariant NKT cells is associated with a favorable outcome. But how these cells have an anticancer effect is unclear, as many tumors do not express the protein that V-alpha-24-invariant NKT cells target. However, Leonid Metelitsa and colleagues, at the University of Southern California Keck School of Medicine, and The Saban Research Institute of Childrens Hospital Los Angeles, Los Angeles, have now shown, in vitro and in mice, that human V-alpha-24-invariant NKT cells indirectly affect neuroblastoma growth by killing tumor-associated cells that promote the growth of neuroblastoma cells.

In the study, human tumor-associated cells known as monocytes/macrophages were found to produce the soluble factor IL-6, which further analysis revealed stimulates the growth of neuroblastoma cells in vitro and after they have been transplanted into mice. As expected, human V-alpha-24-invariant NKT cells did not kill neuroblastoma cells in vitro, but they did kill monocytes pulsed with tumor antigens. Consistent with this, the growth of neuroblastoma cells was substantially impaired in mice infused with monocytes and V-alpha-24-invariant NKT cells, when compared to mice only receiving monocytes. These data therefore provide insight into a mechanism by which V-alpha-24-invariant NKT cells can impact cancer outcome.

TITLE: V-alpha-24-invariant NKT cells mediate antitumor activity via killing of tumor-associated macrophages in mice and humans

AUTHOR CONTACT:
Leonid S. Metelitsa
Baylor College of Medicine, Houston, Texas, USA.
Phone: (832) 824-4395; Fax: (832) 825-4846; E-mail: metelits@bcm.tmc.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=37869


METABOLISM: The sweet smell of success: new understanding of the pathway affected in Maple Syrup Urine Disease

Yibin Wang and colleagues, at UCLA David Geffen School of Medicine, Los Angeles, have identified, in cultured cells and mice, a protein responsible for regulating the protein complex that breaks down branched-chain amino acids (three protein building blocks that cannot be made by humans but have to be obtained from the food we eat). Mice lacking this protein (PP2Cm) exhibited similar symptoms to some forms of human Maple Syrup Urine Disease (MSUD), an inherited disorder characterized by sweet-smelling urine that leads to severe brain damage and death if untreated. The authors therefore suggest that defects in PP2Cm may be responsible for some cases of MSUD.

TITLE: Protein phosphatase 2Cm is a critical regulator of branched chain-amino acid catabolism in mice and cultured cells

AUTHOR CONTACT:
Yibin Wang
David Geffen School of Medicine, University of California, at Los Angeles, Los Angeles, California, USA.
Phone: (310) 206-5197; Fax: (310) 206-5907; E-mail: yibinwang@mednet.ucla.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=38151


CARDIOLOGY: The fog lifts on the role for the protein Fog2 in the adult heart

The protein Fog2, which is a regulator of gene expression, is essential for embryonic development of both the heart and the blood vessels that supply the heart (coronary blood vessels), but its role in the adult heart has not been determined. However, William Pu and colleagues, at Children's Hospital Boston, have now determined that Fog2 regulates adult mouse heart function and the growth of new coronary vessels.

The authors generated mice lacking Fog2 in heart muscle cells either early or late in embryonic heart development. As has been observed for mice lacking Fog2 in all cells from the point of conception, mice in which Fog2 was deleted early in heart development died before birth, with the same heart and coronary vessel defects. By contrast, mice in which Fog2 was deleted later in heart development survived until 8󈝺 weeks after birth. However, these mice had decreased heart function and insufficient coronary vessels, which led to a lack of oxygen passing to the heart muscle cells and thereby death of the cells and scarring of the heart muscle. These data indicate that Fog2 is required for maintaining heart and coronary vessel function in the adult mouse heart.

TITLE: Fog2 is critical for cardiac function and maintenance of coronary vasculature in the adult mouse heart

AUTHOR CONTACT:
William T. Pu
Children's Hospital Boston, Boston, Massachusetts, USA.
Phone: (617) 919-2091; Fax: (617) 730-0140; E-mail: wpu@enders.tch.harvard.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=38723


AUTOIMMUNITY: Two opposing roles for the protein Bim: control of T cell activation and death

The protein Bim has previously been shown to have a role in the cellular process that kills developing T cells (a subset of immune cells) that are 'born' with the ability to attack the body's own tissues and cause autoimmune diseases. Surprisingly, Youhai Chen and colleagues, at University of Pennsylvania School of Medicine, Philadelphia, have now found that Bim also has a role in controlling the activation of mouse T cells.

In the study, in mouse models of two autoimmune diseases, multiple sclerosis and type 1 diabetes, mice with T cells that lacked Bim were observed to be protected from disease. In vitro analysis indicated that following stimulation, T cells lacking Bim were impaired in their ability to produce soluble factors known as cytokines (molecules that execute T cell effects). At the molecular level, Bim was shown to control T cell activation via an IP3R/calcium/NFAT pathway. As the authors point out, this study reveals that Bim joins a growing list of proteins with dual roles in T cell activation and death.

TITLE: Critical roles of Bim in T cell activation and T cellmediated autoimmune inflammation in mice

AUTHOR CONTACT:
Youhai H. Chen
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: (215) 898-4671; Fax: (215) 573-3434; E-mail: yhc@mail.med.upenn.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=37619


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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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