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JCI online early table of contents: June 12, 2008

EDITOR'S PICK: New target to enhance anticancer drug sensitivity found in translation

The development of resistance to anticancer chemotherapeutic agents remains a large problem. In some cases, such resistance is associated with altered control of a cellular process known as translation, which is central to the generation of proteins. New data, generated by Jerry Pelletier and colleagues, at McGill University, Montreal, have identified a drug that can enhance the sensitivity of mouse cancer cells to standard anticancer chemotherapeutic agents.

In the study, small molecules were screened for their ability to inhibit the initiation of translation by modifying the function of a protein known as eIF4A, which has a central role in translation initiation. A class of natural drugs known as cyclopenta[b]benzofuran flavaglines were found to have the desired effects and one member of this class of compounds was shown to reverse the resistance of cancer cells to anticancer chemotherapeutic agents in a mouse model of lymphoma. The authors therefore suggest that developing approaches to inhibit translation initiation by targeting eIF4A might provide a way to altering drug resistance in cancers exhibiting altered control of translation initiation.

TITLE: Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma model

Jerry Pelletier
McGill University, Montreal, Quebec, Canada.
Phone: (514) 398-2323; Fax: (514) 398-7384; E-mail:

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EDITOR'S PICK: Fever may trigger heart failure in patients with the genetic disease LQT-2

The potentially fatal heart disease LQT-2, which is characterized by the prolongation of a specific interval of time (known as the QT interval) in the heart's electrical cycle, is caused by mutations in the HERG gene. What triggers the changes in the electrical activity in the heart (and therefore in the beating of the heart) has not been completely determined, although loud noises and emotional stress can be triggers. In a new study, a team of researchers from the Academic Medical Centre, The Netherlands, and the University of Wisconsin, Madison, has revealed that fever can also trigger life-threatening changes in the electrical activity in the heart of patients with LQT-2.

The team, led by Arthur Wilde and Craig January, measured the electrical activity in the heart over time (something that is recorded in an ECG) of two LQT-2 patients with the same HERG mutation (A558P), and found that fever was associated with prolonged QT intervals in these individuals. When this mutation was introduced into a cultured human cell line, the cells exhibited temperature-dependent characteristics, including altered electrical currents across their cell membranes at high temperatures. The authors therefore conclude that similar changes in electrical currents occur in heart cells at the high temperatures associated with fever and that fever is a potential trigger of the potentially lethal changes in the electrical activity in the heart of patients with LQT-2.

TITLE: Fever-induced QTc prolongation and ventricular arrhythmias in individuals with type 2 congenital long QT syndrome

Arthur A.M. Wilde
Academic Medical Centre, Amsterdam, The Netherlands.
Phone: 31-20-5662904; Fax: 31-20-6971385; E-mail:

Craig T. January,
University of Wisconsin Hospital and Clinics, Madison, Wisconsin, USA.
Phone: (608) 263-4856; Fax: (608) 263-0405; E-mail:

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EDITOR'S PICK: The nerves behind the pain relief provided by stressful situations

The increased beating of the heart that one experiences when in a stressful situation is just one part of the body's response to stress, something often known as the "fight-or-flight response". Another component of the fight-or-flight response is the suppression of pain, also known as stress-induced analgesia (SIA). Some of the nerves and nerve-produced peptides that are responsible for SIA have been identified, but much remains to be discovered. In a new study, a team of researchers in California, from AfaSci, Inc., Burlingame, and SRI International, Menlo Park, has revealed that nerves producing the peptide N/ORQ and nerves producing the peptide Hcrt are key in regulating SIA in mice.

The research team, which was led by Xinmin Xie and Thomas Kilduff, showed that in the brain of normal mice, Hcrt-producing nerve cells (Hcrt neurons) and N/ORQ-producing nerve cells interacted. N/ORQ affected the electrical current across Hcrt neurons and the release of neurotransmitters by these cells. Furthermore, administration of N/ORQ blocked SIA in normal mice, but this was overcome by administration of Hcrt at the same time. The authors therefore conclude that N/ORQ likely influences a variety of Hcrt-mediated processes, in addition to SIA, and suggest that these pathways might contribute to medical conditions caused by excessive stress, such as anxiety and post-traumatic stress disorder.

TITLE: Hypocretin/orexin and nociceptin/orphanin FQ coordinately regulate analgesia in a mouse model of stress-induced analgesia

Xinmin (Simon) Xie
AfaSci Inc., Burlingame, California, USA.
Phone: (650) 692-6051; Fax: (650) 6051; E-mail:

Thomas S. Kilduff
SRI International, Menlo Park, California, USA.
Phone: (650) 859-5509; Fax: (650) 859-3153; E-mail:

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HEMATOLOGY: Tumor cells want no contact with immune cells

As tumors progress they develop ways to escape recognition and attack by cells of the immune system. However, the mechanisms by which tumors modify the immune system have not been clearly determined. New insight into the way in which chronic lymphocytic leukemia (CLL) cells limit immune cell attack has now been provided by John Gribben and colleagues, at Barts and The London School of Medicine, United Kingdom.

For immune cells known as CD4+ and CD8+ T cells to become activated they must contact other cells known as APCs. The area of contact is known as the immunological synapse and it is highly organized. In the study, CD4+ and CD8+ T cells from patients with CLL were found to exhibit defective immunological synapse formation with APCs. Further, if CD4+ and CD8+ T cells from healthy individuals were cultured with CLL APCs, they also showed defective immunological synapse formation. As treatment with an immune systemmodifying drug improved immunological synapse formation, the authors suggest that approaches to overcoming immunological synapse defects might improve the efficacy of new ways to treat cancer that are currently being developed and that are based on enhancing the antitumor activity of CD4+ and CD8+ T cells.

TITLE: Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug

John G. Gribben
Barts and The London School of Medicine, London, United Kingdom.
Phone: 44-207-882-6126; Fax: 44-207-882-6126; E-mail:

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BONE BIOLOGY: How bone growth can be stunted in mice

Hiroshi Kawaguchi and colleagues, at the University of Tokyo, Japan, have provided new insight into the molecules that control the growth of the mouse skeleton.

Mice lacking a protein known as cGKII are dramatically smaller than mice expressing normal levels of this protein, because the bones of their legs and body are much shorter. In the study, it was found that the shorter bones were a result of a defect in bone growth, specifically in a process known as chondrocyte hypertrophy. Further analysis showed that in normal mouse chondrocytes, cGKII inhibited the function of a protein known as GSK-3-beta and that this was important for enhancing chondrocyte hypertrophy. In addition, the bone defects in mice lacking cGKII were partially rescued if the mice were engineered to express reduced levels of GSK-3-beta. These data indicate an important role for cGKII inhibition of GSK-3-beta function in skeletal growth and the authors are now investigating ways in which this information can be used to develop new therapeutics for skeletal disorders that result in dwarfism.

TITLE: Phosphorylation of GSK-3-beta by cGMP-dependent protein kinase II promotes hypertrophic differentiation of murine chondrocytes

Hiroshi Kawaguchi
University of Tokyo, Tokyo, Japan.
Phone: 81-33815-5411 ext. 30473; Fax: 81-33818-4082; E-mail:

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METABOLIC DISEASE: FABP molecules help link inflammation to obesity-related metabolic diseases

Individuals who are obese are predisposed to a variety of metabolic conditions, including type 2 diabetes. A characteristic of the fat tissue (adipose tissue) of individuals who are obese is that it is inflammed, and understanding the relationship between such inflammation and the onset of the metabolic conditions is of importance in combating what has become a large public health problem. In a new mouse study, Gkhan Hotamisligil and colleagues, at the Harvard School of Public Health, Boston, found that interactions between adipocytes (fat cells) and inflammatory cells called macrophages seem to underlie the inflammation-related metabolic deterioration associated with obesity.

In the study, when adipocytes isolated from mice lacking proteins known as FABPs, which are molecules that govern metabolic and inflammatory responses, were cultured with normal macrophages, the macrophages expressed reduced levels of inflammatory molecules. Likewise, when macrophages isolated from mice lacking FABPs were cultured with normal adipocyes, the adipocytes responded more to insulin and took up more glucose. Similar results, indicating that FABPs from both adipocytes and macrophages contribute to the inflammatory basis for metabolic deterioration, were obtained in vivo. The authors therefore suggest that this FABP-related pathway may be a novel target for metabolism-related disorders.

TITLE: Adipocyte/macrophage fatty acidbinding proteins contribute to metabolic deterioration through actions in both macrophages and adipocytes in mice

Gkhan S. Hotamisligil
Harvard School of Public Health, Boston, Massachusetts, USA.
Phone: (617) 432-1950; Fax: (617) 432-1941; E-mail:

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Contact: Karen Honey
Journal of Clinical Investigation

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