[ Back to EurekAlert! ] Public release date: 19-Apr-2007
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Journal of Clinical Investigation

JCI table of contents -- April 19, 2007

EDITOR'S PICK

Why cisplatin kills breast cancer cells when other drugs fail

The cancerous cells of some individuals with breast cancer lack expression of two cell surface proteins, the estrogen and progesterone receptors, and do not express increased amounts of HER2. Individuals with such breast cancer (known as triple-negative breast cancer) do not respond to treatment with commonly used chemotherapeutic drugs and their prognosis is relatively poor. But now, a new study from researchers at Massachusetts General Hospital Cancer Center, Boston, has indicated that triple-negative breast cancer cell lines are sensitive to exposure to the chemotherapeutic cisplatin.

In the study, which appears online on April 19 in advance of publication in the May print issue of the Journal of Clinical Investigation, Leif Ellisen and colleagues show that triple-negative breast cancer specimens express increased amounts of two proteins, delta-Np63 and TAp73. Delta-Np63 was shown to bind TAp73 and prevent it from killing the cancerous cells. Importantly, the chemotherapeutic drug cisplatin, but not other commonly used chemotherapeutic drugs, was found to release TAp73 from delta-Np63, causing the cells to be killed. This study indicates that individuals with triple-negative breast cancer might benefit from early treatment with cisplatin if their cancerous cells express increased amounts of delta-Np63 and TAp73.

TITLE: The p63/p73 network mediates chemosensitivity to cisplatin in a biologically defined subset of primary breast cancers

AUTHOR CONTACT:

Leif W. Ellisen
Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 726-4315; Fax: (617) 726-8623; E-mail: ellisen@helix.mgh.harvard.edu.

Sue McGreevey
Massachusetts General Hospital Public Affairs, Boston, Massachusetts, USA.
Phone: (617) 724-2764; E-mail: smcgreevey@partners.org.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30866


PHYSIOLOGY

Why don’t mothers’ bodies reject their fetus?

The immune system is designed to attack anything that is not the body’s own tissues, such as pathogens and genetically nonidentical organ transplants, so why does the maternal immune system not attack a developing fetus? Several answers to this question are provided by a new study of mice from researchers at New York University School of Medicine.

In the study, which appears online on April 19 in advance of publication in the May print issue of the Journal of Clinical Investigation, Adrian Erlebacher and colleagues show that when maternal immune cells known as T cells interact with fetal cells they can’t "see" proteins that only their fetus expresses. By contrast, the same maternal T cells were able to "see" the fetal proteins when other maternal immune cells began picking up the fetal proteins around mid-gestation. However, this did not result in the T cells being primed to attack the fetus, rather, it induced the T cells to die. Surprisingly, even when the T cells were isolated from the female mice and exposed to the fetal proteins in vitro, under conditions that normally stimulate T cell activation, the maternal T cells did not become activated. This study therefore describes three reasons why maternal T cells do not attack a developing fetus and the authors suggest that immune-mediated early pregnancy loss might occur if maternal T cells become able to "see" fetal proteins when they interact with fetal cells.

TITLE: Constraints in antigen presentation severely restrict T cell recognition of the allogeneic fetus

AUTHOR CONTACT:

Adrian Erlebacher
New York University School of Medicine, New York, New York, USA.
Phone: (212) 263-8926; Fax: (212) 263-8211; Email: adrian.erlebacher@med.nyu.edu.

Pam McDonnell
Director, Media Relations
New York University School of Medicine, New York, New York, USA.
Phone: (212) 404-3555 ; E-mail: Pamela.McDonnell@nyumc.org

View the PDF of this article at: https://www.the-jci.org/article.php?id=28214


DERMATOLOGY

Understanding how glucocorticoids work to stop skin irritation

Individuals who are allergic to some things that their skin comes in contact with (a condition called contact dermatitis), such as metals or poison ivy, are treated with glucocorticoids, which can be applied to the skin as a cream or taken orally. Glucocorticoids work by dampening the inflammatory response to the allergen, but precisely which cells they affect and in what way have not been determined for contact dermatitis.

In a study appearing online on April 19 in advance of publication in the May print issue of the Journal of Clinical Investigation, Günther Schütz and colleagues from the German Cancer Research Institute, Heidelberg, show that glucocorticoids do not dampen inflammation induced by contact with an allergen in mice lacking expression of the glucocorticoid receptor in immune cells known as macrophages and neutrophils. Furthermore, for glucocorticoids to dampen inflammation the glucocorticoid receptor had to bind DNA and repress the production of several proinflammatory soluble factors, including IL-1-beta, MIP-2, MCP-1, and IP-10. Conversely, administration of these soluble factors to mice abrogated the protective effects of glucocoticoids following the induction of an allergic response in the skin. The authors therefore suggest that targeting macrophage and neutrophil production of these soluble factors might provide a more specific treatment for individuals with contact dermatitis than glucocorticoids and avoid the side-effects that are associated with long-term administration of glucocorticoids.

TITLE: Macrophages and neutrophils are the targets for immune suppression by glucocorticoids in contact allergy

AUTHOR CONTACT:

Günther Schütz
German Cancer Research Institute, Heidelberg, Germany.
Phone: +49-6221-423411; Fax: +49-6221-423470; E-mail: g.schuetz@dkfz.de.

Jan P. Tuckermann
Fritz Lipmann Institute, Jena, Germany.
Phone: +49-3641-656134; Fax: +49-3641-656133; E-mail: jan@fli-leibniz.de.

Eberhard Fritz
Scientific Coordinator
Fritz Lipmann Institute, Jena, Germany
Phone: +49-3641-656371; Fax: +49-3641-656335; E-mail: efritz@fli-leibniz.de

View the PDF of this article at: https://www.the-jci.org/article.php?id=28034


CARDIOLOGY

Filling in the blanks: MAPKs mediate heart function defects in Emery-Dreifuss muscular dystrophy

Emery-Dreifuss muscular dystrophy (EDMD) is characterized mainly by defects in heart and muscle function and is caused by mutations in one of two genes LMNA and EMD. But how mutations in LMNA lead to heart disease had not been determined.

In a study appearing online on April 19 in advance of publication in the May print issue of the Journal of Clinical Investigation, Howard Worman and colleagues from Columbia University, New York, used a mouse model of EDMD to define the signaling proteins activated in cells expressing mutated Lmna. Heart muscle cells isolated from these mice expressed high levels of signaling proteins known as MAPKs and high levels of MAPK activity. Importantly, overexpression of the protein made by the mutated Lmna gene in cultured heart muscle cells also induced the activation of MAPKs. This study indicates that activation of MAPKs is likely to contribute substantially to the defects in heart function in individuals with EDMD caused by mutations in LMNA, leading the authors to suggest that drugs inhibiting these signaling proteins might be of benefit for individuals with EDMD.

TITLE: Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophy

AUTHOR CONTACT:

Howard J. Worman
Columbia University, New York, New York, USA.
Phone: (212) 305-8156; Fax: (212) 305-6443; E-mail: hjw14@columbia.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=29042


CARDIOLOGY

Not all beta-adrenergic receptors cause heart disease along the same pathway

Individuals with some forms of heart failure are treated with drugs that are known as beta-blockers because they target proteins known as beta-adrenergic receptors (beta-ARs). Now, a potential alternative strategy to treating heart failure by targeting molecules downstream of beta-ARs is suggested by mouse studies conducted by researchers from the University of Medicine and Dentistry of New Jersey.

Mice overexpressing either beta1-AR or beta2-AR develop heart disease as they age. In the study, which appears online on April 19 in advance of publication in the May print issue of the Journal of Clinical Investigation, Dorothy Vatner and colleagues show that if mice overexpressing beta2-AR also express an inhibitor of the downstream signaling molecule p38-alpha MAPK (dominant-negative p38-alpha) they are protected from developing heart disease. By contrast, mice overexpressing beta1-AR were not protected by the presence of dominant-negative p38-alpha, even though they exhibited increased p38-alpha expression. This study indicates that p38-alpha has an important role downstream of beta2-AR, but not beta1-AR, in development of heart disease. Other signaling molecules must therefore be activated downstream of beta1-AR, and the authors suggest that targeting the signaling molecules downstream of beta-ARs might provide a new approach to treating individuals with heart failure.

TITLE: Inhibition of p38-alpha MAPK rescues cardiomyopathy induced by overexpressed beta2-adrenergic receptor, but not beta1-adrenergic receptor

AUTHOR CONTACT:

Dorothy E. Vatner
University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA
Phone: (973) 972-8920; Fax: (973) 972-7489; E-mail: vatnerdo@umdnj.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=29576


AUTOIMMUNITY

Autoantibodies help T cells "see" their target

Autoimmune diseases such as type I diabetes and rheumatoid arthritis are caused by the immune system attacking the body’s own tissues. Determining the factors that trigger the immune system to attack is an area of intensive research. In a new study appearing online on April 19, in advance of publication in the May print issue of the Journal of Clinical Investigation, Raphael Clynes and colleagues from Columbia University show that autoantibodies are required to induce disease in a mouse model of autoimmune diabetes mediated by immune cells known as T cells. When CD8+ T cells that recognize ovalbumin were transplanted into mice expressing ovalbumin in the pancreas (the organ targeted by the immune system in type I diabetes) they caused diabetes only if the mice were also transplanted with IgG antibodies that recognize ovalbumin. The antibodies were shown to enable immune cells known as dendritic cells to take up dying pancreatic cells expressing ovalbumin and present the ovalbumin to CD8+ T cells (a process known as cross-presentation) in a form that they could "see". Cross-presentation required that the dendritic cells express activating IgG1 receptors. Because ovalbumin-specific antibodies were required for the activation of disease-causing T cells the authors suggest that developing approaches to prevent autoantibodies from enabling dendritic cells to cross-present self antigen to T cells might provide a new approach to treat autoimmune diseases.

TITLE: Antibody-enhanced cross-presentation of self antigen breaks T cell tolerance

AUTHOR CONTACT:

Raphael Clynes
Columbia University, New York, New York, USA.
Phone: (212) 305-5289; Fax: (212) 305-1392; E-mail: rc645@columbia.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=29470

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