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JCI online early table of contents: Nov. 21, 2011

EDITOR'S PICK: Boosting the aged immune response to flu virus

As people age, their immune system becomes less robust. This makes them more susceptible to serious and frequently life-threatening infections with viruses that affect the respiratory tract such as influenza A virus (IAV). Stanley Perlman and colleagues, at the University of Iowa, Iowa City, have now identified a new immune system defect in aged mice that makes them more susceptible than young mice to developing severe clinical disease upon infection with respiratory viruses such as IAV. Importantly, they were able to reverse the defect by inhibiting the immune molecule PGD2. Perlman and colleagues therefore suggest that inhibition of PGD2 could provide a way to improve clinical outcomes in older patients with severe respiratory viral infections and perhaps more importantly enhance the efficacy of flu vaccines in the elderly.

In an accompanying commentary, Thomas Braciale and Taeg Kim, at the University of Virginia, Charlottesville, discuss in more detail the clinical significance of the work of Perlman and colleagues.

TITLE: Age-related increases in PGD2 expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice

Stanley Perlman
University of Iowa, Iowa City, Iowa, USA.
Phone: 319-335-8549; Fax: 319-335-9006; E-mail:

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TITLE: Slowing down with age: lung DCs do it too

Thomas J. Braciale
University of Virginia, Charlottesville, Virginia, USA.
Phone: 434-924-1219; Fax: 434-924-1221; E-mail:

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EDITOR'S PICK: BRAF addiction of thyroid cancers makes them therapeutically vulnerable

Papillary carcinoma is the most common form of thyroid cancer. Approximately one quarter of these carcinomas have mutations in the BRAF gene. The prevalence of such mutations is even greater in high-grade carcinomas, particularly those that are refractory to standard treatment, which is radioactive iodine (RAI). A team of researchers led by James Fagin, at Memorial Sloan-Kettering Cancer Center, New York, has now identified a way to potentially exploit the expression of BRAF by such cancers for therapeutic purposes.

Despite the prevalence of BRAF mutations in papillary carcinoma it has remained unclear how dependent thyroid cancers are on BRAF expression. Fagin and colleagues first showed that thyroid tumors in mice expressing one of the most commonly detected BRAF mutations in human papillary thyroid carcinomas were exquisitely dependent on BRAF for viability. Of therapeutic significance, treating thyroid tumorbearing mice with drugs that inhibited the BRAF signaling pathway rendered the tumor cells susceptible to a therapeutic dose of RAI. Fagin and colleagues therefore suggest that their data provide rationale for clinical trials testing whether such drugs can restore the efficacy of RAI therapy in patients with papillary thyroid carcinomas expressing BRAF mutations.

TITLE: Small-molecule MAPK inhibitors restore radioiodine incorporation in mouse thyroid cancers with conditional BRAF activation

James A. Fagin
Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Phone: 646-888-2136; Fax: 646-422-0890; E-mail:

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EDITOR'S PICK: Expanding treatment options for Cushing disease

Cushing disease is a hormone disorder that causes a diverse array of symptoms, including fat accumulation, high blood pressure, osteoporosis, muscle wasting, and ultimately death. It is caused by a tumor in the anterior pituitary gland that results in the secretion of excess amounts of adrenocorticotropic hormone (ACTH). Treatment options are essentially limited to surgical resection. However, tumors commonly recur, meaning that new treatment options are needed. A team of researchers, led by Shlomo Melmed, at Cedars-Sinai Medical Center, Los Angeles, has now identified a potential new therapeutic target the protein EGFR, which is the target of a drug used to treat some patients with nonsmall cell lung cancer (gefitinib). As discussed by Melmed and colleagues in their paper, as well as Frederic Wondisford, at Johns Hopkins University School of Medicine, Baltimore, in an accompanying commentary, the data generated in human, canine, and mouse models provide strong support to investigate the clinical effects of gefitinib in patients with Cushing disease.

TITLE: EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting pituitary adenomas

Shlomo Melmed
Cedars-Sinai Medical Center, Los Angeles, California, USA.
Phone: 310-423-4691; Fax: 310-423-0119; E-mail:

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TITLE: A new medical therapy for Cushing disease?

Fredric E. Wondisford
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Phone: 410-502-5761; Fax 410-502-5779; E-mail:

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OTOLOGY: The proteins TMC1 and 2 key to sensing sound and gravity

Central to our ability to hear and to sense gravity is a cellular process known as mechanotransduction. Essential for this process is the opening of special channels in the surface membrane of inner ear hair cells. The molecular identity of these channels has eluded researchers despite intensive investigations over the years. But now, a team of researchers led by Andrew Griffith, at the National Institutes of Health, Rockville; and Jeffrey R. Holt, at Children's Hospital Boston, Boston has determined that in mice, the channel proteins TMC1 and TMC2 are necessary for inner ear hair cell mechanotransduction. These data are consistent with the fact that mutations in the TMC1 gene cause hearing loss in both humans and mice and provide new insight into the molecular mechanisms underlying the condition.

In an accompanying commentary, Xi Lin, at Emory University School of Medicine, Atlanta, discusses the importance of the findings of Griffith, Holt, and colleagues, and highlights the future utility of the mice they generated during their studies.

TITLE: Mechanotransduction in mouse inner ear hair cells requires transmembrane channellike genes

Andrew J. Griffith
National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland, USA.
Phone: 301-402-2829; Fax: 301-402-7580; E-mail:

Jeffrey R. Holt
Children's Hospital Boston, Boston, Massachusetts, USA.
Phone: 617-919-3574; Fax: 617-919-2771; E-mail:

Robin Latham
National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland, USA.
Phone: 301-496-7243; E-mail:

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TITLE: Perception of sound and gravity by TMC1 and TMC2

Xi Lin
Emory University School of Medicine, Atlanta, Georgia, USA.
Phone: 404-727-3723; Fax: 404-727-6356; E-mail address:

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CARDIOVASCULAR DISEASE: Visualizing the effectiveness of candidate anti-atherosclerotic approaches

Atherosclerosis is a disease of the major arterial blood vessels. It is one of the major causes of heart attack and stroke. An early event in the development of atherosclerosis is modification of the molecule LDL by oxidation. A team of researchers led by Yury Miller, at the University of California San Diego, La Jolla, has developed an approach to visualize the accumulation of oxidized LDL in zebrafish fed a diet high in cholesterol. Using their approach they were able to visualize the effects of treatment with an antioxidant it reversed the accumulation of oxidized LDL, as did switching the zebrafish to a diet low in cholesterol. Miller and colleagues therefore suggest that they have developed an efficient method of testing the potential effectiveness of dietary and/or other therapeutic antioxidant strategies under development as anti-atherosclerotic agents in humans.

TITLE: In vivo visualization and attenuation of oxidized lipid accumulation in hypercholesterolemic zebrafish

Yury I. Miller
University of California, San Diego, La Jolla, California, USA.
Phone: 858-822-5771; Fax: 858-534-2005; E-mail:

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NEUROLOGICAL DISEASE: Linking distinct genetic disorders together

Inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD) is a multisystem degenerative disorder characterized by progressive muscle weakness that is often accompanied by bone weakening and/or frontotemporal dementia. A team of researchers led by Yi-Ping Hsueh, at Academia Sinica, Taiwan; and Ming-Jen Lee, at National Taiwan University Hospital, Taiwan has now identified a potential link between the mechanisms underlying the dementia seen in patients with IBMPFD and those causing the cognitive deficits observed in patients with neurofibromatosis type 1.

IBMPFD is an inherited disease caused by mutations in the VCP gene. Neurofibromatosis type 1 is caused by mutations in the NF1 gene. Hsueh, Lee, and colleagues found that the proteins templated by the VCP and NF1 genes (VCP and NF1) interact to control the formation of nerve cell structures critical for nerve cell communication (dendritic spines). IBMPFD- and neurofibromatosis type 1associated mutations that disrupted the VCP/NF1 interaction resulted in reduced dendritic spine density. Hsueh, Lee, and colleagues therefore suggest that the dementia seen in individuals with IBMPFD might be a result of defects in VCP regulated dendritic spine formation.

In an accompanying commentary, Conrad Weihl, at Washington University School of Medicine, Saint Louis, highlights the importance of the work of Hsueh, Lee, and colleagues to understanding the complex genetic interactions that can lead to different patients experiencing different symptoms even if they have the same underlying VCP or NF1 mutation.

TITLE: Valosin-containing protein and neurofibromin interact to regulate dendritic spine density

Yi-Ping Hsueh
Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
Phone: 886-2-27899311; Fax: 886-2-27826085; E-mail:

Ming-Jen Lee,
National Taiwan University Hospital, Taipei, Taiwan.
Phone: 886-2-23123456 ext. 65342; Fax: 886-2-23418395; E-mail:

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TITLE: Another VCP interactor: NF is enough

Conrad C. Weihl
Washington University School of Medicine, Saint Louis, Missouri, USA.
Phone: 314-362-6981; Fax 314-362-4391; E-mail:

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IMMUNOLOGY: Identification of new genetic defects underlying Herpes simplex encephalitis

Herpes simplex encephalitis (HSE) is a rare but severe condition caused primarily by infection of the brain and spinal cord with herpes simplex virus-1 (HSV-1), the same virus that causes cold sores. Even with treatment, the condition is often fatal, and survivors, affected children in particular, usually suffer long-term brain damage. In some children, genetic mutations that affect the immune system underlie their susceptibility to HSE. A team of researchers led by Vanessa Sancho-Shimizu, at Necker Hospital, France; and Jean-Laurent Casanova, at The Rockefeller University, New York has now identified two new mutations, this time in the gene TRIF, as the reason for two unrelated children being susceptible to HSE. Further analysis defined the molecular mechanism by which these mutations, both of which resulted in TRIF deficiency, impaired the immune system and made the children susceptible to the condition.

TITLE: Herpes simplex encephalitis in children with autosomal recessive and dominant TRIF deficiency

Vanessa Sancho-Shimizu
Necker Hospital, Paris, France.
Phone: 33-1-40-61-55-39; Fax: 33-1-40-61-56-88; E-mail:

Jean-Laurent Casanova
The Rockefeller University, New York, New York, USA.
Phone: 212-327-7331; Fax: 212-327-7330; E-mail:

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HEPATOLOGY: The source of the liver cell uncovered

The liver has the remarkable ability to rapidly regenerate after tissue injury or partial resection. Many researchers are seeking to harness this ability to treat individuals with a wide range of liver diseases. However, in order to do this it is vital to know from what cell new liver cells (hepatocytes) arise in the adult. A team of researchers led by Holger Willenbring, at the University of California, San Francisco, has now generated a hepatocyte fate-tracing model that enabled them to demonstrate definitively in mice that hepatocytes themselves, and not specialized progenitor cells, are the source of new hepatocytes in the healthy liver and the predominant source of new liver cells in the acutely injured liver. As noted by Willenbring and colleagues, harnessing these cells for therapy will require knowing the signals that trigger their activation.

In an accompanying commentary, Klaus Kaetsner and Joshua Friedman, at the University of Pennsylvania, Philadelphia, discuss how the work of Willenbring and colleagues helps settle recent controversy regarding the origins of hepatocytes in adults.

TITLE: Fate tracing of mature hepatocytes in mouse liver homeostasis and regeneration

Holger Willenbring
University of California at San Francisco, San Francisco, California, USA.
Phone: 415-476-2417; Fax: 415-514-2346; E-mail:

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TITLE: On the origin of the liver

Klaus Kaestner
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: 215-898-8759; Fax: 215-573-5892; E-mail:

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Contact: Karen Honey
Journal of Clinical Investigation

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