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JCI online early table of contents: Aug. 1, 2008

EDITOR'S PICK: Overcoming inhibitors of cell death improves cancer therapy efficacy

Individuals with glioblastoma multiforme (GBM), one of the most aggressive types of brain tumor, have an extremely poor prognosis. Although pre-clinical studies indicated therapeutics inhibiting a group of proteins known as receptor tyrosine kinases (RTKs) would likely be beneficial to individuals with GBM, these RTK inhibitors have met with limited clinical success only a small proportion of patients respond to such treatment and most subsequently relapse after only a short time. New data, generated by Andrew Kung and colleagues, at the Dana-Farber Cancer Institute, Boston, have now provided insight into the mechanism by which GBM cells become resistant to RTK inhibitors and have suggested a way to improve the efficacy of RTK inhibitors in this clinical setting.

In the study, human GBM cells exposed in vitro to an inhibitor of the RTK PDGFR activated a cellular pathway that usually induces cells to undergo a form of cell death known as apoptosis, but the final steps of the pathway were not completed, meaning that the cells did not die. Further analysis revealed that the final steps of this pathway were blocked by a group of proteins known as IAPs. Consistent with this, if the PDGFR inhibitor was combined with an IAP inhibitor the GBM cells underwent apoptosis. Further, this drug combination showed enhanced efficacy at inhibiting tumor growth in an orthotopic mouse model of GBM. The authors therefore suggest that combining drugs targeting IAPs with RTK inhibitors might prove beneficial to individuals with GBM.

TITLE: Resistance of human glioblastoma multiforme cells to growth factor inhibitors is overcome by blockade of inhibitor of apoptosis proteins

Andrew L. Kung
Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Phone: (617) 632-5731; Fax: (617) 582-8096; E-mail:

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EDITOR'S PICK: A mechanism for the development of obesity-associated conditions

Endocannabinoids are substances produced by several cells in the body that are very similar to compounds found in cannabis plants. They have been implicated in the development of many effects of a high-fat diet, including many risk factors for type 2 diabetes: obesity, insulin resistance, leptin resistance, and dyslipidemia. It is important to determine whether these effects of endocannabinoids occur via activation of the protein CB1 in the brain, liver, or other tissues, as the therapeutic potential of agents that target CB1 is currently limited by the side effects of targeting CB1 in the brain, anxiety and depression. However, new insight into this issue has now been provided by George Kunos and colleagues, at the National Institutes of Health, Rockville, through analysis of mice lacking CB1 only in the liver.

Similar to normal mice, when the mice lacking CB1 only in the liver were fed a high-fat diet they became obese. However, they exhibited less severe insulin resistance, leptin resistance, and dyslipidemia than the normal mice. They also exhibited less severe high fat dietinduced fatty liver, something that increases the risk of developing cirrhosis of the liver. The data indicate that high fat dietinduced obesity is influenced by CB1 found in tissues other than the liver and that liver-specific CB1 is necessary for the development of high fat dietinduced fatty liver and the hormonal and metabolic changes that occur as a result of such a diet, increasing the risk of type 2 diabetes. The authors therefore suggest that targeting liver CB1 might provide an effective way to treat obesity-related medical conditions without the side effects of targeting CB1 in the brain.

TITLE: Hepatic CB1 receptor is required for development of diet-induced steatosis, altered lipid profile, and insulin and leptin resistance in mice

George Kunos
The National Institutes of Health, Rockville, Maryland, USA.
Phone: (301) 443-2069; Fax: (301) 480-0257; E-mail:

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METABOLISM: New panel of mice helps predict how drugs are broken down in humans

Humans express several proteins that breakdown the synthetic chemicals and drugs (collectively known as xenobiotics) that we ingest or are administered. Expression of these proteins is itself regulated by the xenobiotic-sensing proteins PXR and CAR. Developing animal models to determine the relative importance of PXR and CAR for humans to breakdown a specific drug has been difficult because the human and animal proteins sense different xenobiotics. However, Nico Scheer and colleagues, at TaconicArtemis, Germany, have now developed a panel of mice that will help researchers address this issue and enable them to predict more accurately how drugs are likely to be broken down in humans, providing important information regarding probable toxicity and efficacy.

In the study, four types of mouse were generated: mice that lacked PXR, mice that lacked CAR, mice that expressed human PXR in place of mouse PXR, and mice that expressed human CAR in place of mouse CAR. In addition, breeding these different mice in various combinations led to the generation of mice expressing both human PXR and human CAR and mice lacking both PXR and CAR. To prove that this panel of mice could be used to more effectively evaluate how PXR and CAR are likely to influence drug breakdown, they were used to demonstrate that upregulation of drug-destroying enzymes by the barbiturate Phenobarbital is mediated by only CAR, whereas previous in vitro studies had indicated a role for both PXR and CAR.

TITLE: A novel panel of mouse models to evaluate the role of human pregnane X receptor and constitutive androstane receptor in drug response

Nico Scheer
TaconicArtemis, Cologne, Germany.
Phone: 49-221-9645343; Fax: 49-221-9645321; E-mail:

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HEMATOLOGY: Some types of leukemia are addicted to Notch proteins

The leukemic cells in a large proportion of individuals with a form of leukemia known as T-ALL have mutations in the NOTCH1 gene. These mutations lead to the generation of Notch1 proteins that have increased activity, however, it is not known whether they have sufficient increased activity to actually initiate the disease. New data, generated by a team of researchers, at the University of Pennsylvania School of Medicine, Philadelphia, and Brigham and Women's Hospital, Boston, have now indicated that only uncommon T-ALLassociated NOTCH1 mutations have the ability to induce cells to become leukemic in mice (these uncommon mutations generated Notch1 proteins with far greater increased activity than the Notch1 proteins generated by the more common mutations). However, although the more common mutations were not themselves able to induce cells to become leukemic in mice, they were able to accelerate the onset of leukemia induced by other genetic mutations. The authors therefore suggest that all T-ALL leukemic cells with mutations in the NOTCH1 gene are "addicted" to Notch and that this study provides support for the evaluation of Notch signaling pathway inhibitors as a treatment for leukemia.

TITLE: Leukemia-associated NOTCH1 alleles are weak tumor initiators but accelerate K-rasinitiated leukemia

Warren S. Pear
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: (215) 573-7764; Fax: (215) 573-6725; E-mail:

Jon C. Aster
Brigham and Women's Hospital, Boston, Massachusetts, USA.
Phone: (617) 525-7329; Fax: (617) 264-5169; E-mail:

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INFLAMMATION: How inflammatory cells get from the blood to the site of injury

New insight into the way in which inflammatory cells known as macrophages leave the blood and access sites of injury has been provided by Jane Hoover-Plow and colleagues, at Cleveland Clinic Lerner Research Institute, Cleveland, who studied the process in mice. This information has particular clinical relevance to injury and inflammation of the major arterial blood vessels, one of the main causes of heart attack and stroke.

It was found that in mice lacking a protein known as plasminogen, macrophages were less able to leave the blood and access sites of injury than in normal mice. This was associated with decreased activation of a protein known as MMP-9, and addition of MMP-9 to the mice restored the ability of macrophages to access sites of injury. As this was also true in a mouse model of abdominal aortic aneurysm (AAA), a chronic degenerative condition of the aorta that is usually fatal if it ruptures, the authors suggest that targeting the plasminogen/MMP-9 pathway might be a viable approach to controlling disease-causing inflammation, such as occurs in the development of AAA.

TITLE: Inflammatory macrophage migration requires MMP-9 activation by plasminogen in mice

Jane Hoover-Plow
Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.
Phone: (216) 445-8207; Fax: (216) 444-9263; Email:

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BONE BIOLOGY: An odd pair important for cartilage formation: Sox9 and p54nrb

New data, generated in mice by Riko Nishimura and colleagues, at Osaka University Graduate School of Dentistry, Japan, have provided insight into the formation of cartilage, a process that is known as chondrogenesis and that is an important event in bone development.

Previous studies have indicated an essential role for the protein Sox9 in promoting chondrogenesis. In this study, the authors screened a mouse chondrogenic cell line to identify proteins that interacted with Sox9 to activate the expression of a gene important for chondrogenesis, Col2a1. A protein known as p54nrb was found to physically interact with Sox9 in cellular compartments known as nuclear paraspeckle bodies and to enhance expression of Col2a1. If the chondrogenic cell line was engineered to express a mutant form of p54nrb, the nuclear paraspeckle bodies had markedly altered appearance, and if precursor cells were engineered to express this mutant they could not develop into chondrocytes. Further, mice engineered to express the same mutant protein exhibited dwarfism, indicating that p54nrb has an important role in regulating the function of Sox9 during chondrogenesis.

TITLE: Paraspeckle protein p54nrb links Sox9-mediated transcription with RNA processing during chondrogenesis in mice

Riko Nishimura
Osaka University Graduate School of Dentistry, Osaka, Japan.
Phone: 81-6-6879-2887; Fax: 81-6-6879-2890; E-mail:

View the PDF of this article at:


Contact: Karen Honey
Journal of Clinical Investigation

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