News Release

JCI table of contents -- April 5, 2007

Peer-Reviewed Publication

JCI Journals

EDITOR'S PICK: Tumors stopped from spreading to new sites

For several types of cancer, persistently high levels of the soluble factor TGF-beta in the blood after surgery, chemotherapy, or radiation therapy correlate with increased risk of early metastasis and a poor prognosis. Using a mouse model of breast cancer, researchers from Vanderbilt University have now generated evidence to suggest that treatment with TGF-beta inhibitors might help such patients.

In the study, which appears online on April 5 in advance of publication in the May print issue of the Journal of Clinical Investigation, Carlos Arteaga and colleagues show that treating mice with mammary tumors with either radiation or the chemotherapeutic drug doxorubicin increased the level of TGF-beta in their blood, the number of cancer cells in their blood, and the development of lung metastases. Treatment with an inhibitor of TGF-beta blocked the increased lung metastases. Furthermore, mice whose tumors did not express the receptor for TGF-beta did not develop increased incidence of lung metastases after treatment with radiation, indicating that TGF-beta affects the cancer cells directly, enhancing their metastatic function. This study has important clinical implications as it suggests that monitoring TGF-beta levels after primary therapy might indicate the patients most at risk of developing tumor metastases and that treatment with TGF-beta inhibitors might be of clinical benefit to these individuals.

TITLE: Inhibition of TGF-beta with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression

AUTHOR CONTACT:
Carlos L. Arteaga
Vanderbilt University School of Medicine, Nashville, Tennessee, USA
Phone: (615) 936-3524; Fax: (615) 936-1790; E-mail: carlos.arteaga@vanderbilt.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30740


METABOLIC DISEASE: Leptin gives itself some negative feedback

Leptin is an important regulator of the amount of fuel that our bodies store. It acts in the brain to tell the body that fuel stores have been restocked and that it can stop feeding. Many individuals who are obese exhibit leptin resistance, that is, they do not respond appropriately to high levels of leptin in their blood. One possible cause of leptin resistance is that leptin only poorly activates the leptin receptor (LRb).

In a study that appears online on April 5 in advance of publication in the May print issue of the Journal of Clinical Investigation, Martin Myers and colleagues from the University of Michigan, Ann Arbor, used mice expressing a mutant form of LRb to characterize a leptin-mediated LRb signaling pathway that inhibits further leptin-mediated LRb signaling. Female mice, but not male mice, expressing only forms of LRb in which a single amino acid, tyrosine 985, had been mutated weighed less than normal mice, did not become obese when fed a high-fat diet, ate less, and produced lower amounts of neuropeptides that stimulate appetite. In addition, these female mice were more sensitive to leptin administration than wild-type female mice. These data indicate that leptin-mediated signaling through LRb tyrosine 985 inhibits leptin-mediated LRb signaling in female mice. The authors therefore propose that this negative feedback pathway might contribute to leptin resistance in some obese individuals, in particular females.

TITLE: Mice lacking inhibitory leptin receptor signals are lean with normal endocrine function

AUTHOR CONTACT:
Martin G. Myers Jr.
University of Michigan Medical School, Ann Arbor, Michigan, USA.
Phone: (734) 647-9515; Fax: (734) 936-6684; E-mail: mgmyers@umich.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30688


CARDIOLOGY: Role for STARS in heart failure illuminated

Thickening of the walls of the heart (cardiac hypertrophy) can cause heart failure if it is sustained. Understanding the molecular processes that lead to cardiac hypertrophy are therefore an area of intensive research.

In a study that appears online on April 5, in advance of publication in the May print issue of the Journal of Clinical Investigation, Eric Olson and colleagues from the University of Texas Southwestern, Dallas, show that expression of a protein known as STARS is increased in hearts from humans suffering from heart failure and mice suffering from experimental cardiac hypertrophy. Furthermore, compared with normal mice, mice engineered to express high levels of STARS in their heart muscle cells showed accelerated heart failure under conditions that led to cardiac hypertrophy. At the molecular level, a protein known as MEF2 was shown to induce the expression of STARS, which, in turn, induced the expression of genes controlled by a protein known as SRF. This molecular pathway that couples cardiac hypertrophy to deteriorating heart function requires further dissecting to determine more fully its role in development and disease before it can be considered as a target for the development of treatments to prevent heart failure as a result of cardiac hypertrophy.

TITLE: Modulation of adverse cardiac remodeling by STARS, a mediator of MEF2 signaling and SRF activity

AUTHOR CONTACT:
Eric N. Olsen
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: (214) 648-1187; Fax: (214) 648-1196; E-mail: Eric.Olson@utsouthwestern.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=31240


PHYSIOLOGY: Learning the normal functions of EWS

Dysregulation of the gene EWS has been implicated in various types of cancer, but the normal physiologic function of the EWS protein has yet to be fully determined. So, researchers from the National Institutes of Health generated mice lacking EWS and identified a role for this protein in the development of immune cells known as B cells and in meiosis, the process by which sperm and eggs are produced.

In the study, which appears online on April 5 in advance of publication in the May print issue of the Journal of Clinical Investigation, Sean Bong Lee and colleagues show that mice lacking EWS had a decreased number of B cells in their blood compared with normal mice. Further analysis revealed a block in B cell development at the transition between the pro-B cell and the pre-B cell stages of development. In addition, the testes and ovaries of EWS-deficient mice were reduced in size compared with these organs in normal mice. In the sperm cell precursors this was, in part, because the X and Y sex chromosomes failed to pair up and because there was no meiotic recombination. This study therefore identifies specific physiological functions for EWS and further analysis of the mice is likely to reveal further functions and might help elucidate some of the mechanisms underlying EWS-related cancers.

TITLE: Ewing sarcoma gene EWS is essential for meiosis and B lymphocyte development

AUTHOR CONTACT:
Sean Bong Lee
National Institutes of Health, Bethesda, Maryland, USA.
Phone: (301) 496-9739; Fax: (301) 480-0638; E-mail: seanL@intra.niddk.nih.gov.

View the PDF of this article at: https://www.the-jci.org/article.php?id=31222


PULMONARY: To inhibit or not to inhibit Gi proteins in asthma?

The symptoms of asthma, shortness of breath, chest tightness etc., are caused by narrowing (also known as constriction) of the airways that lead to the lungs and are relieved by drugs (such as beta-agonists) that reverse airway constriction (also known as dilation). Airway constriction and dilation are caused by the airway smooth muscle (ASM) cells contracting and relaxing, processes that are controlled by triggering proteins on the surface of the ASM cells known as G protein–coupled receptors, with the G proteins to which they are coupled determining the intracellular signals initiated. However, the role of Gi proteins in these processes has remained ill-defined

In a study appearing online on April 5 in advance of publication in the May print issue of the Journal of Clinical Investigation, Stephen Liggett and colleagues from the University of Maryland, Baltimore, show that the ASM cells from mice over expressing G-alpha-i2 contracted less than ASM cells from normal mice when stimulated with a chemical that induces asthma-like symptoms, whereas ASM cells from mice expressing a G-alpha-i2 inhibitor contracted more. By contrast, overexpression of G-alpha-i2 decreased airway relaxation by beta-agonists and inhibition of G-alpha-i2 increased the effectiveness of these drugs. This study indicates that Gi proteins have many different roles in regulating airway constriction and dilation, leading the authors to suggest that “pharmacologic or genetic methods to modulate Gi [proteins] could have limited clinical utility.�

TITLE: Crosstalk between Gi and Gq/Gs pathways in airway smooth muscle regulates bronchial contractility and relaxation

AUTHOR CONTACT:
Stephen B. Liggett
University of Maryland School of Medicine, Baltimore, Maryland, USA.
Phone: (410) 706-6256; Fax: (410) 706-6262; E-mail: sligg001@umaryland.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30489

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