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JCI table of contents: Jan. 25, 2011

2011-01-26
(Press-News.org) EDITOR'S PICK: Possible new approach to treating a life-threatening blood disorder

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease of the blood system. The condition is caused by the presence of ultralarge multimers of the protein von Willebrand factor, which promote the formation of blood clots (thrombi) in small blood vessels throughout the body. Current treatments are protracted and associated with complications. However, a team of researchers, led by José López, at the Puget Sound Blood Center, Seattle, has generated data in mice that suggest that the drug N-acetylcysteine (NAC), which is FDA approved as a treatment for chronic obstructive lung disease and as an antidote for toxicity due to acetaminophen (paracetamol), might provide a rapid and effective treatment for patients with TTP through its ability to decrease the size of von Willebrand factor multimers.

In an accompanying commentary, Michael Berndt and Robert Andrews, concur with the conclusions of López and colleagues, although they caution that there are a number of caveats to the view that NAC could be used to treat patents with TTP.

TITLE: N-acetylcysteine reduces the size and activity of von Willebrand factor in human plasma and mice

AUTHOR CONTACT:
José A. López
Puget Sound Blood Center, Seattle, Washington, USA.
Phone: 206.398.5930; Fax: 206.587.6056; E-mail: josel@psbcresearch.org.

View this article at: http://www.jci.org/articles/view/41062?key=f24412516a0e75fcdeae

ACCOMPANYING COMMENTARY
TITLE: Thrombotic thrombocytopenic purpura: reducing the risk?

AUTHOR CONTACT:
Michael C. Berndt
Dublin City University, and Royal College of Surgeons in Ireland, Dublin, Ireland.
Phone: 353.1.7007658; Fax: 353.1.7006558; E-mail: michael.berndt@dcu.ie.

View this article at: http://www.jci.org/articles/view/46091?key=72ff692cf01de9590c43



ONCOLOGY: Not such a good anticancer approach: inhibiting the protein Notch1

Excessive signaling through the protein Notch1 has been linked to several types of cancer. Inhibiting the Notch1 signaling cascade is therefore being considered as an anti-cancer therapy. Previous preclinical studies have indicated that short-term blockade of Notch1 signaling has minimal side effects. However, Raphael Kopan and colleagues, at Washington University, St. Louis, have now determined in mice that loss of the Notch1 gene, in a context that mimics chronic Notch1 inhibition, leads to blood vessel tumors in the liver and decreased survival. These data raise concerns regarding the safety of chronic use of drugs targeting Notch1, leading the authors and, in an accompany commentary, Sandra Ryeom, at the University of Pennsylvania School of Medicine, Philadelphia, to suggest that the development of Notch1 therapies should be reevaluated.

TITLE: Notch1 loss of heterozygosity causes vascular tumors and lethal hemorrhage in mice

AUTHOR CONTACT:
Raphael Kopan
Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA.
Phone: 314.747.5520; Fax: 314.747.5503; E-mail: Kopan@wustl.edu.

View this article at: http://www.jci.org/articles/view/43114?key=0c69f3b0d223127cb0e6

ACCOMPANYING COMMENTARY
TITLE: The cautionary tale of side effects of chronic Notch1 inhibition

AUTHOR CONTACT:
Sandra W. Ryeom
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: 215.573.5857; Fax: 215.573.2014; E-mail: sryeom@upenn.edu.

View this article at: http://www.jci.org/articles/view/45976?key=0691d06bba3bde5fff57



CARDIOLOGY: Developmental misstep results in extremely fast heartbeat

Wolff-Parkinson-White syndrome is characterized by periods of an extremely fast heartbeat. These occur because of the presence of additional electrical pathways in the heart that cause the bottom chambers of the heart (the ventricles) to contract prematurely. The developmental reasons for premature ventricular contraction (also known as ventricular preexcitation) are not well understood. However, two independent research groups have now identified in mice a new mechanism by which additional electrical pathways in the heart can form, resulting in ventricular preexcitation. Specifically, the data from both groups — one led by Jonathan Epstein, at the University of Pennsylvania, Philadelphia; and the other by Vincent Christoffels, at the Academic Medical Center, The Netherlands — indicate that additional electrical pathways in the heart form as a result of inappropriate development of a structure in the embryonic heart known as the AV canal.

In an accompanying commentary, Hiroshi Akazawa and Issei Komuro, at the Osaka University Graduate School of Medicine, Japan, discuss the importance of these two papers for understanding the mechanisms of physiologic and pathologic heart development.

TITLE: Notch signaling regulates murine atrioventricular conduction and the formation of accessory pathways

AUTHOR CONTACT:
Jonathan A. Epstein
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: 215.898.8731; Fax: 215.573.2094; E-mail: epsteinj@mail.med.upenn.edu.

View this article at: http://www.jci.org/articles/view/44470?key=845c740fe207e4a7265b

ACCOMPANYING ARTICLE
TITLE: Defective Tbx2-dependent patterning of the atrioventricular canal myocardium causes accessory pathway formation in mice

AUTHOR CONTACT:
Vincent M. Christoffels
Academic Medical Center, Amsterdam, The Netherlands.
Phone: 0031.20.566.7821; Fax: 31.20.697.6177; E-mail: v.m.christoffels@amc.uva.nl.

View this article at: http://www.jci.org/articles/view/44350?key=c08a399d64c3aa01813d

ACCOMPANYING COMMENTARY
TITLE: Navigational error in the heart leads to premature ventricular excitation

AUTHOR CONTACT:
Issei Komuro
Osaka University Graduate School of Medicine, Osaka, Japan.
Phone: 81.6.6879.3631; Fax: 81.6.6879.3639; E-mail: komuro-tky@umin.ac.jp.

View this article at: http://www.jci.org/articles/view/46038?key=de37f31e59fa64978ae8



IMMUNOLOGY: To modify or not to modify proteins with inflammatory function

A team of researchers, led by Martin Bergo, at the University of Gothenburg, Sweden, has generated in mice surprising data with clinical implications that call into question current dogma that modification of proteins known as Rho proteins by the fat molecule geranylgeranyl are critical to the function of inflammatory cells.

Geranylgeranyl modification of Rho proteins by geranylgeranyltransferase type I (GGTase-I) is considered essential for their function and that of inflammatory cells. Bergo and colleagues therefore hypothesized that mice lacking GGTase-I in immune cells known as macrophages would be protected from inflammatory disease. However, these mice were found to develop severe joint inflammation resembling erosive rheumatoid arthritis. Importantly, the disease was initiated by the GGTase-I–deficient macrophages, which hypersecreted inflammatory molecules known as cytokines. As the authors note and Mark Philips, at New York University, New York points out, in an accompanying commentary, these data have important implications for drug development, where GGTase-I inhibitors have been proposed as a strategy to treat inflammatory disorders and are under development as anticancer drugs.

TITLE: Geranylgeranyltransferase type I (GGTase-I) deficiency hyperactivates macrophages and induces erosive arthritis in mice

AUTHOR CONTACT:
Martin O. Bergo
Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Phone: 46.31.342.78.58; Fax: 46.31.82.37.62; E-mail: martin.bergo@wlab.gu.se.

View this article at: http://www.jci.org/articles/view/43758?key=3a26ecf260de7bfbb5ca

ACCOMPANYING COMMENTARY
TITLE: The perplexing case of the geranylgeranyl transferase–deficient mouse

AUTHOR CONTACT:
Mark R. Philips
New York University Cancer Institute, New York, New York, USA.
Phone: 212.263.7404; Fax: 212.263.9210; E-mail: mark.philips@nyumc.org.

View this article at: http://www.jci.org/articles/view/45952?key=84050ca36dfb7be0c5e6



IMMUNOLOGY: More regulators of Th17 immune cell generation

A subset of immune cells known as Th17 cells have an important role in clearing certain bacterial and fungal infections. However, they are also thought to sometimes attack other cells and tissues of the body, causing autoimmune diseases such as multiple sclerosis. Understanding the regulatory pathways underlying the generation of these cells is therefore of immense clinical interest. In this context, a team of researchers, led by Ying Qin Zang, at the Chinese Academy of Sciences, Shanghai, has now determined that the protein LXR negatively regulates the generation of both mouse and human Th17 cells. Importantly, LXR activation in mice ameliorated disease in a model of multiple sclerosis, whereas LXR deficiency exacerbated disease. Further analysis defined the signaling pathway underlying LXR-mediated regulation of Th17 cell generation. Thus, as highlighted by Liang Zhou and colleagues, at Northwestern University, Chicago, in an accompanying commentary, these data have important implications for those seeking to develop treatments for Th17 cell–mediated autoimmune diseases.

TITLE: Liver X receptor (LXR) mediates negative regulation of mouse and human Th17 differentiation

AUTHOR CONTACT:
Ying Qin Zang
Institute for Nutritional Sciences, Chinese Academy of Sciences, Shanghai, China.
Phone: 86.21.54920913; Fax: 86.21.54920913; E-mail: yqin@sibs.ac.cn.

View this article at: http://www.jci.org/articles/view/42974?key=fb9e07860b073ae41198

ACCOMPANYING COMMENTARY
TITLE: Nuclear receptors take center stage in Th17 cell–mediated autoimmunity

AUTHOR CONTACT:
Liang Zhou
Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Phone: 312.503.3182; Fax: 312.503.8240; E-mail: L-Zhou@northwestern.edu.

View this article at: http://www.jci.org/articles/view/45939?key=37afc300bad910d99b5a



ONCOLOGY: Stromal instigation promotes tumor growth

Critical to the growth and progression of a tumor is the aberrant fibrous tissue, which is known as the tumor stroma, that surrounds the cancer cells. More complete understanding of how the tumor stroma forms might provide new targets for anticancer therapeutics. In this context, a team of researchers, led by Sandra McAllister, at Harvard Medical School, Boston, has now identified in mice a mechanism by which certain types of tumor at one site can stimulate the growth of indolent tumors at distant sites, providing potential new therapeutic targets.

Preclinical data have indicated that certain tumors, which have been termed instigators, stimulate cells in the bone marrow to enter the circulation and subsequently promote the growth of otherwise indolent cancer cells (responders) at distant sites. In this study, McAllister and colleagues have characterized the bone marrow cells involved in this process and found that they secrete the protein granulin, which promotes the formation of a tumor stroma around the responding cancer cells. The clinical relevance of these data are highlighted by the observation that high levels of granulin expression in human breast cancer correlated with an aggressive form of breast cancer and reduced patient survival. The authors therefore suggest that granulin and the cells that produce it might provide new targets for anticancer therapeutics, a point with which Andrew Bateman, at McGill University, Montreal, concurs in an accompanying commentary.

TITLE: Human tumors instigate granulin-expressing hematopoietic cells that promote malignancy by activating stromal fibroblasts in mice

AUTHOR CONTACT:
Sandra S. McAllister
Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617.355.9059; Fax: 617.355.9093; E-mail: smcallister1@partners.org.

View this article at: http://www.jci.org/articles/view/43757?key=35d0bca89ec3ee754eae

ACCOMPANYING COMMENTARY
TITLE: Growing a tumor stroma: a role for granulin and the bone marrow

AUTHOR CONTACT:
Andrew Bateman
Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
Phone: 514.934.1934; Fax: 514.843.2819; E-mail: Andrew.bateman@muhc.mcgill.ca.

View this article at: http://www.jci.org/articles/view/46088?key=d7dca6a27fa8539cece0

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[Press-News.org] JCI table of contents: Jan. 25, 2011