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JCI online early table of contents: Dec. 19, 2011

EDITOR'S PICK: Potential concern about drugs in clinical trial

Drugs that enhance levels of small molecules derived naturally in the body from a major component of animal fats (small molecules known as epoxyeicosatrienoic acids [EETs]) are currently in clinical trials for the treatment of high blood pressure and diabetes. A team of researchers led by Dipak Panigrahy and Mark Kieran, at the Dana-Farber Cancer Institute, Boston; Sui Huang, at the Institute for Systems Biology, Seattle; and Darryl Zeldin, at the National Institute of Environmental Health Science, Research Triangle Park has now generated data in mice that raise concern about the use of these drugs in humans.

The key observation of the team was that EETs promote primary tumor growth and spread to distant sites (metastasis) in a variety of mouse models of cancer. As noted by the authors and, in an accompanying commentary, Raymond DuBois and Dingzhi Wang, at The University of Texas MD Anderson Cancer Center, Houston, the data generated suggest not only that raising levels of EETs in humans could have severe adverse effects but also that EET antagonists could provide a new approach to preventing and treating metastasis.

TITLE: Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice

Dipak Panigrahy
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617-919-2198; Fax: 617-730-0231; E-mail:

Sui Huang
Institute for Systems Biology, Seattle, Washington, USA.
Phone: 206-354-3569; Fax: 206-732-1299; E-mail:

Mark W. Kieran
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617-632-4907; Fax: 617-632-4897; E-mail:

Darryl C. Zeldin
National Institute of Environmental Health Science, NIH, Research Triangle Park, North Carolina, USA.
Phone: 919-541-1169; Fax: 919-541-4214; E-mail:

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TITLE: Epoxyeicosatrienoic acids: a double-edged sword in cardiovascular diseases and cancer

Raymond N. DuBois
The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Phone: 713-745-4495; Fax: 713-792-6375; E-mail:

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EDITOR'S PICK: Blood pressure drug limits cigarette smokeinduced lung injury in mice

Chronic obstructive pulmonary disease (COPD) is among the most common causes of death in the US. It is a smoking-related disease for which there are currently no disease-altering therapies. However, hope that one could be developed is now provided by the work of Enid Neptune and colleagues, at Johns Hopkins University, Baltimore, in a mouse model of lung disease caused by exposure to cigarette smoke.

Neptune and colleagues found that lostartan, a drug used widely in the clinic (e.g., to treat high blood pressure), reduced lung disease in mice caused by exposure to cigarette smoke. Losartan blocks the protein angiotensin receptor type 1, and its effects on cigarette smokeinduced lung injury were a result of the fact that blocking angiotensin receptor type 1 leads to a decrease in levels of the soluble molecule TGF-beta. The authors therefore suggest that other TGF-betatargeted therapeutics might also be viable candidates for the treatment of COPD.

TITLE: Angiotensin receptor blockade attenuates cigarette smokeinduced lung injury and rescues lung architecture in mice

Enid Neptune
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Phone: 410-955-4176; Fax: 410-955-0036; E-mail:

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ONCOLOGY: A full TANC(1) needed to drive rhabdomyosarcoma

Rhabdomyosarcoma (RMS) accounts for 5% of all new pediatric cancers. In some patients, RMS is caused by a genetic event that gives rise to a fusion protein (PAX-FOXO1) that drives the development of the cancer. Rene Galindo and colleagues, at the University of Texas Southwestern Medical Center, Dallas, have now generated data in Drosophila and mammalian models that provide new insight into the molecular mechanisms by which PAX-FOXO1 drives the development of cancer. These data, which indicate a key role for the protein TANC1 in RMS driven by PAX-FOXO1, have identified new avenues of research for those seeking to develop candidates for targeted RMS therapy.

TITLE: Drosophila and mammalian models uncover a role for the myoblast fusion gene TANC1 in rhabdomyosarcoma

Rene L. Galindo
University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.
Phone: 214-648-4116; Fax: 214-648-4070; E-mail:

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ONCOLOGY: Growth factor link to breast cancer

The growth factor IGF-1 has been implicated in the development of breast cancer. A team of researchers led by Robin Fuchs-Young, at The University of Texas M.D. Anderson Cancer Center, Smithville, has now demonstrated in mice that the level of expression of the protein estrogen receptor alpha (ER-alpha) on mammary gland cells influences whether IGF-1 can promote breast cancer. Fuchs-Young and colleagues therefore suggest that prepubertal and postmenopausal women are likely to be most susceptible to the potential breast cancerpromoting effects of increased levels of IGF-1, since these are the times in a woman's life when ER-alpha levels are highest.

TITLE: Developmental stage determines estrogen receptor alpha expression and nongenomic mechanisms that control IGF-1 signaling and mammary proliferation

Robin Fuchs-Young
The University of Texas M.D. Anderson Cancer Center, Smithville, Texas, USA.
Phone: 512-237-9547; Fax: 512-237-6440; E-mail:

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METABOLIC DISEASE: Heparan sulfate: protecting the cells destroyed in type 1 diabetes

Type 1 diabetes is a lifelong disease characterized by high levels of sugar (glucose) in the blood. It is caused by the patient's immune system attacking and destroying the cells in their pancreas that produce the hormone insulin, which regulates blood glucose levels. Surprisingly, little is known about the mechanisms regulating the sensitivity and resistance of these cells, which are known as beta-cells, to immune system attack. Now, Charmaine Simeonovic and colleagues, at The Australian National University, Australia, have determined that the molecule heparan sulfate is essential for mouse beta-cell survival. Importantly, in a mouse model of type 1 diabetes, production of an active heparan sulfatedegrading protein (heparanase) was associated with beta-cell destruction, while treatment with an inhibitor of heparanase protected the mice from disease. Simeonovic and colleagues therefore suggest that maintaining expression of heparan sulfate on beta-cells could provide a new approach to preventing the development of type 1 diabetes.

TITLE: Heparan sulfate and heparanase play key roles in mouse beta-cell survival and autoimmune diabetes

Charmaine J. Simeonovic
The John Curtin School of Medical Research, The Australian National University, Canberra, Australia.
Phone: 61-2-6125-4709; Fax: 61-2-6125-2595; E-mail:

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GENETICS: Linking genetic variation to changes in protein function

Many common human diseases, including type 2 diabetes, are thought to arise as a result of both genetic and environmental factors. It is hoped that defining the genetic component of such diseases could provide not only insight into cause but also candidate therapeutic approaches. In this context, variants of the GCKR gene have been suggested to be clinically important, with some linked to type 2 diabetes. However, how these variants affect protein function and influence disease has not been determined. Now, a team of researchers led by Francis Collins, at the National Human Genome Research Institute, Bethesda, has characterized the function of a large number of variants of the GCKR gene. The data generated indicate that the majority of the GCKR variants tested do affect protein function and are likely to provide an important genetic component of several clinical conditions.

TITLE: Correlation of rare coding variants in the gene encoding human glucokinase regulatory protein with phenotypic, cellular, and kinetic outcomes

Francis S. Collins
National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Phone: 301-496-2433; Fax: 301-402-2700; E-mail:

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ENDOCRINOLOGY: Sugar overload: refining the role of the hormone GLP-1

How does the body deal with the sudden influx of sugar that it receives after we have eaten a meal? The answers to this question not only provide insight into how the body works but can yield information that could be useful in the development of new therapeutic approaches to treating type 2 diabetes, a chronic disease characterized by high levels of sugar (glucose) in the blood. In relation to this question, Daniel Drucker and colleagues, at the University of Toronto, Toronto, have investigated in detail the function of the hormone GLP-1, which is produced by cells in the gut after food ingestion. They find that GLP-1 acts directly on cells in the pancreas to control the production of insulin, the hormone that controls blood glucose levels. These data refine our understanding of the complexity of the response to sudden sugar influx.

TITLE: Pancreatic GLP-1 receptor activation is critical for incretin control of glucose metabolism in mice

Daniel J. Drucker
Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
Phone: 416-361-2661; Fax: 416-361-2669; E-mail:

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Contact: Karen Honey
Journal of Clinical Investigation

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