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JCI online early table of contents: Oct. 10, 2011

EDITOR'S PICK: SIRT(ain) benefit of reducing calories

The number of individuals with type 2 diabetes is reaching epidemic proportions. One of the main risk factors for developing type 2 diabetes is resistance of cells in the body (particularly liver, fat, and skeletal muscle cells) to the effects of the hormone insulin. Substantially reducing caloric intake enhances the sensitivity of skeletal muscle to insulin. Defining the molecular signals within skeletal muscle linking caloric restriction to improved insulin action could provide new targets for therapeutics to reduce insulin resistance and thereby lower an individual's risk of developing type 2 diabetes. In this context, a team of researchers led by Jerrold Olefsky, at the University of California at San Diego, La Jolla, has now found that the mouse protein Sirt1 has an integral role within skeletal muscle in linking caloric restriction to improved insulin action. Furthermore, they have identified the downstream molecular mechanism by which Sirt1 translates decreases in nutrient intake into enhanced skeletal muscle insulin sensitivity.

TITLE: Sirt1 enhances skeletal muscle insulin sensitivity in calorie-restricted mice

Jerrold M. Olefsky
University of California at San Diego, La Jolla, California, USA.
Phone: 858.534.6651; Fax: 858.534.6653; E-mail:

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EDITOR'S PICK: Combination therapies for drug-resistant cancers

Some cancers can be effectively treated with drugs inhibiting proteins known as receptor tyrosine kinases, but not those cancers caused by mutations in the KRAS gene. A team of researchers led by Jeffrey Engelman, at Massachusetts General Hospital Cancer Center, Boston, has now identified a potential way to effectively use receptor tyrosine kinases inhibitors to treat individuals with KRAS mutant colorectal cancers combine them with inhibitors of the MEK/ERK signaling pathway.

In cases in which tyrosine kinase inhibitors are effective they reduce signaling via both the PI3K/AKT and MEK/ERK signaling pathways. It is thought that KRAS mutant cancers are resistant to tyrosine kinase inhibitors because the mutant KRAS protein can directly activate ERK and PI3K signaling. However, Engelman and colleagues discovered that although mutant KRAS activates ERK signaling in human KRAS mutant colorectal cancers, receptor tyrosine kinases control PI3K signaling. Of potential clinical significance, treating mice xenografted to bear a human KRAS mutant colorectal cancer cell line with a combination of a receptor tyrosine kinase inhibitor and a MEK inhibitor induced tumor regression. These data suggest a way in which receptor tyrosine kinase inhibitors could be used to treat individuals with KRAS mutant colorectal cancers. However, the authors caution that heterogeneity among KRAS mutant cancers means that the approach would not work in all patients with such cancers.

TITLE: Receptor tyrosine kinases exert dominant control over PI3K signaling in human KRAS mutant colorectal cancers

Jeffrey A. Engelman
Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617.724.7298; Fax: 617.724.9648; E-mail:

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EDITOR'S PICK: New insight into the cellular defects in Huntington disease

Huntington disease is a devastating neurogenerative disorder that causes a progressive loss of functional capacity and reduced life span. It is an inherited condition caused by a mutant HTT gene. Although this has been known for many years, the functions of the normal Htt protein and the mechanisms by which the mutant protein generated from the mutant HTT gene causes disease are not well understood. A team of researchers led by Frdric Saudou, at the Institut Curie, France, has now uncovered a new function for normal Htt protein and determined that this function is disrupted in a mouse model of Huntington disease and in patients with the disorder.

Detailed analysis by Saudou and colleagues determined that normal Htt protein regulates the formation of cellular structures known as cilia and that cilia were longer and disorganized in the mouse model of Huntington disease and patients. They therefore suggest that abnormal cilia could be a cause of some of the symptoms of Huntington disease. However, they also caution that further studies are needed to prove this. This point is also made in an accompanying commentary by Scott Zeitlin and Jeh-Ping Liu, at the University of Virginia, Charlottesville, who go on to note that determining this is critical to discerning whether therapeutic strategies designed to normalize ciliary function could ameliorate the symptoms of Huntington disease.

TITLE: Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease

Frdric Saudou
Institut Curie, CNRS UMR 3306, INSERM U1005, Orsay, France.
Phone:; Fax:; E-mail:

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TITLE: The long and the short of aberrant ciliogenesis in Huntington disease

Scott O. Zeitlin
University of Virginia, Charlottesville, Virginia, USA.
Phone: 434.924.5011; Fax: 434.982.4380; E-mail:

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ONCOLOGY: Can we predict tumor spread to the liver?

A common cause of cancer-related death in individuals with colorectal cancer the second leading cause of death from cancer in the United States is spreading of the cancer to the liver. Better understanding of the mechanisms underlying colorectal cancer spread to the liver (a process known as liver metastasis) are needed if this event is to be detected early and if we are to develop therapies to prevent it occurring.

Using a mouse model of colorectal cancer, a team of researchers led by Mien-Chie Hung, at The University of Texas MD Anderson Cancer Center, Houston, has now identified a potential role for the protein APOBEC3G in promoting liver metastasis. Of clinical significance, the APOBEC3G gene was found to be expressed at elevated levels in liver metastatic tumors from individuals with colorectal cancer. Furthermore, the colorectal tumors in these individuals expressed higher levels of the APOBEC3G gene than did colorectal tumors from individuals without liver metastases. Hung and colleagues therefore suggest that analyzing the level of expression of the APOBEC3G gene in an individual's colorectal tumor might help predict the likelihood of their tumor spreading to the liver.

TITLE: APOBEC3G promotes liver metastasis in an orthotopic mouse model of colorectal cancer and predicts human hepatic metastasis

Mien-Chie Hung
The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Phone: 713.792.3668; Fax: 713.794.3270; E-mail:

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NEPHROLOGY: Mechanistic link to increased risk of death in chronic kidney disease

It is estimated that approximately 26 million people in the United States have chronic kidney disease (CKD). These people are at increased risk of death from cardiovascular disease (a group of diseases of the heart or blood vessels that includes those that cause heart attack and stroke). Enlargement of the muscle wall of the main chamber of the heart (a condition known as left ventricular hypertrophy [LVH]) is a key factor in the development of cardiovascular disease in individuals with CKD. A team of researchers led by Myles Wolf and Christian Faul, at the University of Miami Miller School of Medicine, Miami, has now identified a potential approach to slowing the progression of LVH in individuals with CKD.

The initial analysis of Wolf, Faul, and colleagues determined that in a large, racially diverse group of individuals with CKD, elevated levels of the protein FGF23 are associated with LVH. These data confirm previous studies. However, Wolf, Faul, and colleagues went on to show that FGF23 has a causal role in LVH in rodents and that in a mouse model of CKD, LVH can be attenuated by administration of a molecule that blocks the protein to which FGF23 binds to mediate its effects. They therefore suggest that blocking the actions of FGF23 could perhaps reduce LVH and cardiovascular events in patients with CKD and thereby improve their survival.

TITLE: FGF23 induces left ventricular hypertrophy

Myles Wolf
University of Miami Miller School of Medicine, Miami, Florida, USA.
Phone: 305.243.7760; Fax: 305.243.8914; E-mail:

Christian Faul
University of Miami Miller School of Medicine, Miami, Florida, USA.
Phone: 305.243.3206; Fax: 305.243.3209; E-mail:

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PULMONARY BIOLOGY: FGF10 helps repair the damaged lung

The cells that line the airways are constantly exposed to potentially toxic agents and microbes. If damaged by any of these potential dangers, the airway lining is rapidly and effectively repaired. Understanding the molecular mechanisms by which the airway lining is repaired could identify new therapeutic approaches to treat individuals with lung diseases. A team of researchers led by Stijn De Langhe, at National Jewish Health, Denver, has now uncovered a key role for the protein FGF10 in repair of the mouse airway lining following naphthalene-induced injury. De Langhe and colleagues suggest that overactivation of the FGF10-dependent cellular and molecular pathways they uncovered might be involved in airway remodeling in response to chronic injury in individuals with asthma, although further studies are required to determine if this is the case.

TITLE: Parabronchial smooth muscle constitutes an airway epithelial stem cell niche in the mouse lung after injury

Stijn P. De Langhe
National Jewish Health, Denver, Colorado, USA.
Phone: 303.398.1763; Fax: 303.398.1225; E-mail:

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Contact: Karen Honey
Journal of Clinical Investigation

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