News Release

JCI online early table of contents: Feb. 13, 2012

Peer-Reviewed Publication

JCI Journals

EDITOR'S PICK: Enhancing the effectiveness of a breast cancer treatment

Breast cancers expressing the protein HER2 have a particularly poor prognosis. Treatment with trastuzumab (Herceptin) benefits some patients with HER2-positive breast cancer, but it is not as effective as had been hoped. Researchers are therefore seeking ways to enhance the effectiveness of trastuzumab. In this context, a team of researchers led by Ronald Levy, at Stanford University, Stanford, has identified a sequential treatment regimen that enhances the effectivenss of trastuzumab in xenotransplant models of breast cancer.

Trastuzumab is a molecule known as an antibody that binds to HER2. Binding of trastuzumab to HER2-positive tumor cells recruits immune cells such as natural killer cells to the tumor cells. Upon encountering encountering trastuzumab-coated, HER2-overexpressing tumor cells, natural killer cells become activated and kill the tumor cells. Levy and colleagues found that upon encountering trastuzumab-coated, HER2-overexpressing breast cancer cells, human NK cells upregulated expression of the protein CD137. Moreover, stimulating trastuzumab-activated human NK cells with an agonistic antibody specific for CD137 led to breast cancer cell killing in vitro and in xenotransplant models of breast cancer. They therefore suggest that trastuzumab treatment followed by administration of an antibody that activates natural killer cells (for example, an antibody that targets CD137) could provide a more effective way to treat patients with HER2-positive breast cancer than trastuzumab alone.

TITLE: Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer

AUTHOR CONTACT:
Ronald Levy
Stanford University Medical Center, Stanford, California, USA.
Phone: 650.725.6452; Fax: 650.736.1454; E-mail: levy@stanford.edu.

View this article at: http://www.jci.org/articles/view/61226?key=e73b4d46e3bcddb314c8


EDITOR'S PICK: The leading cause of death for diabetics: getting to the heart of problem

Millions of people suffer from type 2 diabetes. The leading cause of death in these patients is heart disease. Joseph Hill and colleagues, at the University of Texas Southwestern Medical Center, Dallas, have now identified, through their work in mice, a potential new therapeutic approach to reduce the prevalence of heart failure and improve the long-term survival of patients with type 2 diabetes.

Although diabetes-associated heart disease is caused by a multitude of factors, it is typified by changes in heart structure and function independent of high blood pressure and disease in the major arterial blood vessels. This condition is known as diabetic cardiomyopathy. The molecular mechanism(s) that links diabetes to cardiomyopathy are not well understood. Hill and colleagues found that FoxO proteins were persistently activated in the heart of mice with a condition that models type 2 diabetes and that FoxO activity was linked with the development of cardiomyopathy. Importantly, deletion of FoxO1 in heart muscle cells markedly reduced the development of cardiomyopathy. These data led Hill and colleagues to conclude that activation of FoxO1 is critical for the development of diabetic cardiomyopathy and suggest that FoxO1 could be a promising therapeutic target for diabetic cardiomyopathy.

TITLE: Metabolic stress–induced activation of FoxO1 triggers diabetic cardiomyopathy in mice

AUTHOR CONTACT:
Joseph A. Hill
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: 214.648.1400; Fax: 214.648.1450; E-mail: joseph.hill@utsouthwestern.edu.

View this article at: http://www.jci.org/articles/view/60329?key=4d5e9386184f450fc9a2


METABOLIC DISEASE: A direct hit from the hormone leptin has potential therapeutic consequences

The number of people who suffer from one or more of the adverse complications of obesity, including type 2 diabetes, is rapidly increasing. The hormone leptin decreases food intake and increases energy expenditure. As such, it was hoped that it could be developed as an anti-obesity agent. However, the results of early clinical trials were disappointing. Now, Joel Elmquist and colleagues, at the University of Texas Southwestern Medical School, Dallas, have generated data in mice that suggest that leptin could have therapeutic utility in the treatment of type 2 diabetes.

Elmquist and colleagues suggest this therapeutic potential of leptin because they found that it had effects in mice that ameliorated symptoms of this disease in humans, including high blood sugar and lack of liver cell sensitivity to the hormone insulin. These effects of leptin were a result of direct action of the hormone on a subset of nerve cells in the brain known as POMC neurons. Moreover, it occurred independently of the effects of leptin on food intake, as direct leptin action on POMC neurons did not reduce food intake.

TITLE: Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice

AUTHOR CONTACT:
Joel K. Elmquist
The University of Texas Southwestern Medical School, Dallas, Texas, USA.
Phone: 214.648.2911; Fax: 214.648.5612; E-mail: joel.elmquist@UTSouthwestern.edu.

View this article at: http://www.jci.org/articles/view/59816?key=edec7d2613b54da12600


METABOLIC DISEASE: Regulating the regulator of food intake

The number of people who are obese and suffer from one or more of its associated adverse complications is reaching epidemic proportions. Much excitement accompanied the discovery of a hormone (leptin) that could decrease food intake and increase energy expenditure, as it was hoped that it could be harnessed as an anti-obesity agent. Although the results of early clinical trials were disappointing, recent studies have indicated that there might be ways to utilize leptin therapeutically. Given the physiologic importance and therapeutic potential of leptin, researchers continue to study the hormone. One aspect of leptin biology about which surprisingly little is known is what factors regulate expression of the leptin gene. A team of researchers — led by Evan Rosen, at Beth Israel Deaconess Medical Center, Boston; and Shao-En Ong, at the Broad Institute, Cambridge — has now answered this question by showing that the protein FOSL2 is a critical regulator of leptin gene expression in human and mouse fat cells.

TITLE: FOSL2 promotes leptin gene expression in human and mouse adipocytes

AUTHOR CONTACT:
Evan D. Rosen
Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Phone: 617.735.3221; Fax: 617.735.3323; E-mail: erosen@bidmc.harvard.edu.

Shao-En Ong
University of Washington, Seattle, Washington, USA.
Phone: 206.616.6962; Fax: 206.616.4230; E-mail: shaoen@u.washington.edu.

View this article at: http://www.jci.org/articles/view/58431?key=da470b89658e83215d03


HEMATOLOGY: Working together to identify a new candidate therapeutic target for leukemia

Acute myeloid leukemia (AML) is a blood cell cancer that most commonly affects adults. The prognosis for individuals diagnosed with AML has changed little over the past decade, and only a minority of patients are long-term survivors. New candidate therapeutic targets are therefore much needed. By integrating several approaches, Kimberly Stegmaier and colleagues, at Harvard University, Boston, have identified a role for the protein GSK-3-alpha in AML, leading them to suggest that targeting GSK-3-alpha could provide therapeutic benefit.

TITLE: The intersection of genetic and chemical genomic screens identifies GSK-3-alpha as a target in human acute myeloid leukemia

AUTHOR CONTACT:
Kimberly Stegmaier
Dana-Farber Cancer Institute and Harvard University, Boston, Massachusetts, USA.
Phone: 617.632.4438; Fax: 617.632.4850; E-mail: kimberly_stegmaier@dfci.harvard.edu.

View this article at: http://www.jci.org/articles/view/46465?key=15829540b61107b3adb1


DEVELOPMENT: One pathway to cleft palate uncovered

Abnormal growth of the head and facial bones in utero causes what are known as congenital craniofacial deformities. These deformities, which include cleft palate, are among the most common congenital birth defects in humans. In some patients, genetic mutations that result in altered signaling by the molecule TGF-beta cause the craniofacial deformities. Yang Chai and colleagues, at the University of Southern California, Los Angeles, have now delineated a previously undefined TGF-beta signaling pathway as responsible for the cleft palate in mice mutant for the gene responsible for generating the protein TGF-beta receptor type II (Tgfbr2). These data have important clinical implications, as prior to this study, the precise TGF-beta signaling pathways responsible for abnormal craniofacial development in patients, including those with TGFBR2 mutations, had not been determined.

TITLE: Modulation of noncanonical TGF-beta signaling prevents cleft palate in Tgfbr2 mutant mice

AUTHOR CONTACT:
Yang Chai
University of Southern California, Los Angeles, California, USA.
Phone: 323.442.3480; Fax: 323.442.2981; E-mail: ychai@usc.edu.

View this article at: http://www.jci.org/articles/view/61498?key=7591486f950e6c111be5


IMMUNOLOGY: A molecular way to divide and conquer T cells

T cells are key components of the immune system. They come in different 'flavors', with distinct subtypes contributing to particular forms of immune response. A team of researchers led by Eyal Raz, at the University of California, San Diego, La Jolla, has now determined that distinct subtypes of T cells in mice have different molecular requirements for their generation and inflammatory function. Raz and colleagues hope that such information could ultimately lead to the development of therapeutic approaches to target particular T cell subsets.

Distinct T cell subtypes are involved in the immune response to different invading microbes. For example, T cells known as Th1 cells predominate in the immune response following viral infection. However, they are also linked to inflammatory diseases such as colitis. Defining differences in the molecular pathways leading to the activation of distinct T cell subsets might provide targets to specifically modulate the given T cell subset linked to a disease. In this context, Raz and colleagues found that the generation and function of Th2 cells was less dependent on the signaling molecules G-alpha-s and cAMP than was the generation and function of Th1 and Th17 cells, T cell subsets associated with inflammatory diseases. They therefore suggest that targeting cAMP could provide ways to specifically target Th1 and Th17 cells.

TITLE: Divergent requirement for G-alpha-s and cAMP in the differentiation and inflammatory profile of distinct mouse Th subsets

AUTHOR CONTACT:
Eyal Raz
University of California, San Diego, La Jolla, California, USA.
Phone: 858.534.5444; Fax: 858.534.0409; E-mail: eraz@ucsd.edu.

View this article at: http://www.jci.org/articles/view/59097?key=6a019981d6c55f325e32


IMMUNOLOGY: Controlling numbers of immune first responders: a complex job

One of the first immune cells to respond to an invading microbe is the neutrophil. However, they also cause tissue damage during inflammation. Numbers of these cells are therefore tightly regulated. In healthy individuals, more than 1 × 109 neutrophils per kilogram body weight are released from the bone marrow every day; an equivalent number must be cleared from the circulation to ensure numbers remain constant. A team of researchers — led by Junjie Mei and Scott Worthen, at Children's Hospital of Philadelphia, Philadelphia — has now determined how the protein CXCR2 helps keep neutrophil numbers constant in healthy mice. Interestingly, commensal bacteria (the good bacteria that colonize our bodies) were also found to have a role in keeping neutrophil numbers constant in healthy mice. Mei, Worthen, and colleagues therefore suggest that the local bacterial environment contributes to the control of neutrophil numbers in healthy mice and that changes in the commensal bacteria (for example, in response to severe stress, antibiotic treatment, etc) might impact neutrophil numbers in heretofore unexpected ways.

TITLE: CXCR2 and CXCL5 regulate the IL-17/G-CSF axis and neutrophil homeostasis in mice

AUTHOR CONTACT:
Junjie Mei
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Phone: 267.426.7228; Fax: 215.590.4267; E-mail: meij@email.chop.edu.

G. Scott Worthen
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Phone: 267.426.0198; Fax: 215.590.4267; E-mail: worthen@email.chop.edu.

View this article at: http://www.jci.org/articles/view/60588?key=70ffd37f3c33b1527fbd


HEPATOLOGY: A mere role in liver cell proliferation for miR-21

The liver has the remarkable ability to rapidly regenerate after tissue injury or partial removal. 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 better understand the mechanisms controlling natural liver regeneration. In this context, a team of researchers led by Holger Willenbring, at the University of California, San Francisco, has now determined that the gene regulatory molecule miR-21 enables rapid liver cell proliferation during liver regeneration in mice who have had 2/3 of their liver removed. This gene regulatory molecule has been previously shown to promote cancer cell proliferation. Thus, Willenbring and colleagues suggest that the mechanism they uncovered as underlying the effects of miR-21 on liver cell proliferation could be involved in the rapid proliferation of other regenerative cell types and cancer cells.

TITLE: A microRNA-21 surge facilitates rapid cyclin D1 translation and cell cycle progression in mouse liver regeneration

AUTHOR CONTACT:
Holger Willenbring
University of California, San Francisco, San Francisco, California, USA.
Phone: 415.476.2417; Fax: 415.514.2346; E-mail: willenbringh@stemcell.ucsf.edu.

View this article at: http://www.jci.org/articles/view/46039?key=40e2f46411387541375a

###


Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.