JCI online early table of contents: May 18, 2009

There appears to be a link between sleep and weight control, with some studies indicating that sleep disruption can increase weight gain and others that diet affects sleep. Victor Uebele and colleagues, at Merck Research Laboratories, West Point, have now provided further evidence to support this association by showing that T-type calcium channels regulate body weight maintenance and sleep in mice. These data suggest that sleep and circadian treatment approaches may be of benefit in the fight against obesity.

Previous studies have shown that mice lacking the CaV3.1 T-type calcium channel have disrupted sleep/wake activity. In this study, the researchers found that these mice were resistant to weight gain when fed a high-fat diet. Consistent with these data, when normal-weight rodents were administered a drug that specifically antagonized T-type calcium channels during their inactive phase they showed increased sleep and were protected from weight gain due to a high-fat diet. Further, when the same drug was given to obese rodents it reduced body weight and fat mass. The authors conclude that the benefits of the drug are likely to be a result of better alignment of feeding patterns and the circadian rhythm, and that targeting T-type calcium channels might provide a new avenue of research for those developing drugs to treat obesity.

TITLE: Antagonism of T-type calcium channels inhibits high-fat diet–induced weight gain in mice

AUTHOR CONTACT:
Victor N. Uebele
Merck Research Laboratories, West Point, Pennsylvania, USA.
Phone: (215) 652-9356; Fax: (215) 652-1658; E-mail: victor_uebele@merck.com.

MEDIA CONTACT:
Caroline Lappetito
Phone: (267) 218-1584; E-mail: Caroline_lappetito@merck.com.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36954

Glucocorticoids are steroid hormones that have numerous functions; for example, they regulate the response to stress and suppress inflammation. Synthetic glucocorticoids are used clinically in many situations, most famously to treat asthma, allergies, and autoimmunity. They have also been shown in animals and humans to help protect the heart from the damaging effects of heart attack, and this has been attributed to their anti-inflammatory effects. However, Motoaki Sano and colleagues, at Keio University School of Medicine, Japan, have now determined another mechanism by which glucocorticoids protect rodent hearts from the damaging effects of heart attack. Specifically, glucocorticoids, acting via the glucocorticoid receptor (GR), induced mouse and rat heart muscle cells to produce PGD2, and this was responsible for the ability of glucocorticoids to reduce damage to mouse hearts in both an ex vivo and an in vivo model of heart attack. The authors therefore suggest that GR-selective glucocorticoids might be more beneficial to humans following heart attack than glucocorticoids that activate both GR and the MR protein, activation of which occurs in response to stress and might have unwanted consequences.

TITLE: Glucocorticoid protects rodent hearts from ischemia/reperfusion injury by activating lipocalin-type prostaglandin D synthase–derived PGD2 biosynthesis

AUTHOR CONTACT:
Motoaki Sano
Keio University School of Medicine, Tokyo, Japan.
Phone: 81-3-5363-3874; Fax: 81-3-5363-3875; E-mail: msano@sc.itc.keio.ac.jp.

View the PDF of this article at: https://www.the-jci.org/article.php?id=37413

The muscle damage that occurs in individuals with Duchenne muscular dystrophy (DMD) is associated with inflammation that, in turn, can make the muscle damage worse. To identify potential drug targets that could break this cycle of progressive muscle degeneration, Melissa Spencer and colleagues, at the UCLA David Geffen School of Medicine, Los Angeles, analyzed the inflammatory and immune responses in damaged muscle in mdx mice, a model of DMD. Of particular interest, a molecule known as OPN, which promotes immune cell migration and survival, was found to be expressed at high levels in the serum of mdx mice and muscle biopsies after disease onset. Further, increased levels of OPN were also detected in muscle biopsies from individuals with DMD. As mdx mice lacking OPN exhibited increased muscle strength and reduced scarring of the diaphragm and heart, the authors suggest that targeting OPN might be of benefit to individuals with DMD.

TITLE: Osteopontin promotes fibrosis in dystrophic mouse muscle by modulating immune cell subsets and intramuscular TGF-beta

AUTHOR CONTACT:
Melissa J. Spencer
UCLA David Geffen School of Medicine, Los Angeles, California, USA.
Phone: (310) 794-5225; Fax: (310) 206-1998; E-mail: mspencer@mednet.ucla.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=37662

A team of researchers, at the Max Planck Institute for Neurological Research, Germany, and the Dana-Farber Cancer Institute, Harvard Medical School, Boston, has developed a new genomics approach that enabled them to predict whether non–small cell lung cancers (NSCLCs) will respond to specific therapeutics in vitro and in mouse models of lung cancer. They hope that this information can be translated into clinical practice.

The team, led by Roman Thomas, Kwok-Kin Wong, and Matthew Meyerson, determined that the genomes of a large panel of human NSCLC cell lines are highly representative of those of primary NSCLC tumors. Using this panel of cell lines they identified genomic and molecular indicators of a response to clinically relevant drugs. For example, cell lines with an increased number of copies of the ABL2 gene and/or an increased number of copies of the Ephrin receptor kinase and SRC kinase family genes were sensitive to treatment with a clinically used SRC/ABL inhibitor (dasatinib), both in vitro and when they were xenografted into mice. The authors suggest that the cell line collection characterized here will provide a tool for investigating the effect of potential new anticancer drugs in genomically defined cancer types and thereby help define the patients for which a drug will be most effective.

TITLE: Predicting drug susceptibility of non–small cell lung cancers based on genetic lesions

AUTHOR CONTACT:
Roman K. Thomas
Max Planck Institute for Neurological Research, Köln, Germany.
Phone: 49-221-4726-259; Fax: 49-221-4726-298; E-mail: nini@nf.mpg.de.

Kwok-Kin Wong,
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 632-6084; Fax: (617) 582-7839;E-mail: kwong1@partners.org.

Matthew Meyerson
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 632-4768; Fax: (617) 582-7880;E-mail: matthew_meyerson@dfci.harvard.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=37127

In human breast cancer, poor prognosis has been associated with loss of the cancer cell's response to signaling triggered by the molecule TGF-beta. To understand this association more clearly, Harold Moses and colleagues, at Vanderbilt University, Nashville, used mouse breast cancer cell lines to generate gene expression signatures of breast cancer cells not responsive to TGF-beta and those cells responsive to the molecule. These gene expression signatures were then compared with four existing human breast cancer data sets containing gene expression profiles and associated clinical outcome data for 1,319 patients. The gene signature representative of no response to TFG-beta correlated with reduced, relapse-free survival in all patients. This association was particularly strong in patients with estrogen receptor–positive cancer, specifically those with the luminal A subtype of breast cancer. The authors therefore suggest that assessing TGF-beta responsiveness might provide an accurate prognosis to patients with estrogen receptor–positive breast cancer and indicate those patients that would benefit most from aggressive therapy.

TITLE: Abrogation of TGF-beta signaling enhances chemokine production and correlates with prognosis in human breast cancer

AUTHOR CONTACT:
Harold L. Moses
Vanderbilt University, Nashville, Tennessee, USA.
Phone: (615) 936-1782; Fax: (615) 936-1790; E-mail: hal.moses@vanderbilt.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=37480

Individuals with LigIV syndrome have any combination of a number of symptoms including immunodeficiency and growth retardation. It is caused by mutations in the LIG4 gene that decrease but do not eliminate gene expression. Mice with a Lig4 gene mutation that dramatically reduces LigIV activity (Lig4Y288C mice) have recently been identified and shown to recapitulate the immunodeficiency and growth retardation seen in human patients with LigIV syndrome. Richard Cornall and colleagues, at Oxford University, United Kingdom, have now characterized in these mice defects in the development, function, survival, and proliferation of immune cells known as lymphocytes that may well bring about the immunodeficiency observed in individuals with LigIV syndrome. They also observed an abnormally high incidence of cancers arising in the thymus, the organ where T cells develop, leading them to suggest that these tumors and the T cell leukemias reported in some patients with LigIV syndrome may arise through similar mechanisms.

TITLE: Impaired lymphocyte development and antibody class switching and increased malignancy in a murine model of DNA ligase IV syndrome

AUTHOR CONTACT:
Richard J. Cornall
Oxford University, Oxford, United Kingdom.
Phone: 44-1865-287790; Fax: 44-1865-287787; E-mail: richard.cornall@ndm.ox.ac.uk.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32743

A hormone cascade known as the renin-angiotensin system has a key role in regulating blood pressure and kidney function. Kenji Kadomatsu and his colleagues, at Nagoya University Graduate School of Medicine, Japan, have now identified a new regulator of the mouse renin-angiotensin system: the protein midkine.

In the study, both normal mice and mice lacking the protein midkine were studied after they had undergone a surgical procedure known as 5/6 nephrectomy, which is when one kidney is completely removed and two thirds of the other kidney is removed. Using this approach it was determined that midkine regulates the activity of ACE, a known controller of blood pressure that is the target of many drugs that lower blood pressure. Furthermore, midkine administration to midkine-deficient mice that had undergone 5/6 nephrectomy restored blood pressure and ACE activity to levels found in 5/6 nephrectomized normal mice. The authors conclude from these results that midkine is an important regulator of the renin-angiotensin system.

TITLE: The growth factor midkine regulates the renin-angiotensin system in mice

AUTHOR CONTACT:
Kenji Kadomatsu
Nagoya University Graduate School of Medicine, Nagoya, Japan.
Phone: 81-52-744-2059; Fax: 81-52-744-2065; E-mail: kkadoma@med.nagoya-u.ac.jp

View the PDF of this article at: https://www.the-jci.org/article.php?id=37249

Timothy Ley and colleagues, at Washington University Medical School, St. Louis, have used a newly developed high throughput digital technology (NanoString nCounter) to show that biomarkers of disease can be measured using very small amounts of clinical material.

In the study, traditional microarray approaches were used to identify a gene expression signature that is specific to a subtype (M3) of acute myeloid leukemia. The new high throughput technology was then used to validate the M3-specific gene signature because of the small size of the patient samples. Nearly all of the genes tested demonstrated highly significant statistical agreement with the microarray data and were enriched in a mouse model of the condition. The authors therefore conclude that the NanoString nCounter Analysis System is a useful tool to quantify the mRNA abundance of a large number of genes from an expression signature using very small amounts of clinical material and that this method will provide a valuable diagnositic tool.

TITLE: High throughput digital quantification of mRNA abundance in primary human acute myeloid leukemia samples

AUTHOR CONTACT:
Timothy J. Ley
Washington University Medical School, St. Louis, Missouri, USA.
Phone: (314) 362-8831; Fax: (314) 362-9333; E-mail: timley@wustl.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=38248