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JCI online early table of contents: April 13, 2009

EDITOR'S PICK: Enhancing the effects of the drug used to treat chronic myeloid leukemia

Individuals with chronic myeloid leukemia (CML) are first treated with a drug known as imatinib mesylate. Although very effective, as the disease progresses it often becomes resistant to the drug. However, a team of researchers, at the University of Leicester, United Kingdom, and Thomas Jefferson University, Philadelphia, has identified a class of drugs that might enhance the therapeutic effects of imatinib mesylate and other drugs that target the same molecule.

The team, led by Paolo Salomoni and Bruno Calabretta, observed that for several different CML cell lines and primary cells, although imatinib mesylate killed the majority of cells, a marked proportion underwent a process known as autophagy. Consistent with studies indicating that the induction of autophagy can provide a mechanism of cellular survival, suppression of autophagy using either drugs or RNA interference enhanced imatinib mesylateinduced death of CML cell lines, primary CML cells, and CML stem cells. The authors therefore suggest that inhibitors of autophagy might be used with imatinib mesylate or other drugs that target the same molecule to enhance their therapeutic benefits.

Paolo Salomoni
University of Leicester, Leicester, United Kingdom.
Phone: 44-116-2525568; Fax: 44-116-2525616; E-mail:

Bruno Calabretta
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Phone: (215) 503-4522; Fax: (215) 923-0249; E-mail:

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NEUROBIOLOGY: A novel zebrafish model for screening drugs for Alzheimer disease

Neurodegenerative diseases such as Alzheimer disease and frontotemporal dementia (FTD) are associated with the modification and accumulation of a protein called TAU in the brain. These diseases are therefore known as tauopathies and they have no cure. In a new study, Christian Haass and his colleagues at Ludwig-Maximilians-University, Germany, have developed a zebrafish model for tauopathies that they hope will be helpful in screening for therapies for such diseases.

Zebrafish larvae are transparent and small, which makes them ideal for in vivo imaging studies. In the study, the researchers generated zebrafish expressing a mutant form of human TAU associated with FTD and fluorescently labeled the cells expressing this protein, which enabled them to image the brain cell death accompanying TAU accumulation. A compound that could inhibit the TAU-related protein GSK3-beta was also identified and shown to reduce TAU modification. The authors therefore conclude that this zebrafish model of tauopathies may enable more rapid and systematic evaluation of pharmacologic therapies for neurodegenerative diseases.

TITLE: A zebrafish model of tauopathy allows in vivo imaging of neuronal cell death and drug evaluation

Christian Haass
Ludwig-Maximilians-University, Munich, Germany.
Phone: 49-89-2180-75472; Fax: 49-89-2180-75415; E-mail:

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ONCOLOGY: Distinguishing aggressive prostate cancer from nonaggressive disease

Prostate cancer is the second most common cancer in men worldwide. However, a sizeable proportion of men diagnosed with the disease have a tumor that will never cause a problem. Currently there is no good way to distinguish these individuals, who really do not require treatment and should not be exposed to the considerable side effects of therapy, from men who have disease that requires treatment. However, Antonella Farsetti and colleagues, at Regina Elena Cancer Institute, Italy, hope that by using cultured cells from men with prostate cancer to define a molecular mechanism underlying the most aggressive form of prostate cancer, specifically a pathway involving the proteins eNOS, HIF-2-alpha, and ER-beta, they might have generated data that will help develop diagnostic approached that can determine which individuals have aggressive disease.

TITLE: Endothelial NOS, estrogen receptorbeta, and HIFs cooperate in the activation of a prognostic transcriptional pattern in aggressive human prostate cancer

Antonella Farsetti
Regina Elena Cancer Institute, Rome, Italy.
Phone: 39-06-5266-2531; Fax: 39-06-41805-26; E-mail:

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METABOLIC DISEASE: New insights into hardening of the arteries

Atherosclerosis, or hardening of the arteries, is a disease of the major arterial blood vessels that is a common cause of heart attack and stroke. The uptake of molecules comprised of both protein and fat-soluble substances such as cholesterol (lipoproteins) by cells known as macrophages is vital to the development of atherosclerosis; however, the method of lipoprotein uptake in vivo remains poorly defined. In a new study, Howard S. Kruth and his colleagues at the National Heart, Lung, and Blood Institute, Maryland, found that cultured human and mouse macrophages took up fluorescent lipoprotein-sized nanoparticles by a process known as pintocytosis. They also found that when mice susceptible to atherosclerosis were injected with these particles, they developed atherosclerotic lesions with massive nanoparticle accumulation. The authors therefore conclude from these results that targeting lipoprotein pintocytosis should be considered when developing novel atherosclerotic therapies that prevent macrophage uptake of lipoproteins.

TITLE: Fluorescent pegylated nanoparticles demonstrate fluid-phase pinocytosis by macrophages in mouse atherosclerotic lesions

Howard S. Kruth
NHLBI, National Institutes of Health, Bethesda, Maryland, USA.
Phone: (301) 496-4826; Fax: (301) 402-4359; E-mail:

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METABOLIC DISEASE: Adding insight into nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease associated with conditions such as obesity, type 2 diabetes, and high blood pressure. It covers a spectrum of disease states, beginning with hepatic steatosis, which leads to steatohepatitis, cirrhosis, and ultimately liver cancer. Fabienne Foufelle and colleagues, at INSERM UMRS 872, Paris, have now provided new insight into the mechanisms underlying hepatic steatosis in obese insulin-resistant rodents. Specifically, they find that ER stress activates the protein SREBP-1c, which is intimately involved in hepatic lipogenesis (and thereby hepatic steatosis), explaining why ER stress has a role in hepatic steatosis. Further, they show that overexpression of the protein GRP78 inhibits both insulin and ER stressinduced activation of SREBP-1c.

TITLE: GRP78 expression inhibits insulin and ER stressinduced SREBP-1c activation and reduces hepatic steatosis in mice

Fabienne Foufelle
INSERM UMR-S 872, Centre de Recherche des Cordeliers, Paris, France.
Phone: 33-1-42-34-69-23; Fax: 33-1-40-51-85-86; E-mail:

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METABOLIC DISEASE: New role for immune system in hardening of the arteries

Atherosclerosis, or hardening of the arteries, is a chronic inflammatory disease of the major arterial blood vessels that is a common cause of heart attack and stroke. New insight into the role of the immune system in atherosclerosis has now been provided through the study of mice and humans by a team of researchers, at the University of California at San Diego, La Jolla, and the Medical University of Vienna, Austria.

The team, led by Joseph Witztum and Christoph Binder, found that immune factors known as natural Abs (NAbs) from both mice and humans recognize portions of lipoproteins, molecules that accumulate in regions of blood vessels affected by atherosclerosis. Detailed analysis in mice indicated that NAbs that bind lipoproteins also bind atherosclerotic regions of blood vessels and cells that have died by a process known as apoptosis. The authors therefore suggest that future studies should determine the role of NAbs in the development of atherosclerosis.

TITLE: Oxidation-specific epitopes are dominant targets of innate natural antibodies in mice

Joseph L. Witztum
University of California at San Diego, La Jolla, California, USA.
Phone: (858) 534-4347; Fax: (858) 534-2005; E-mail:

Christoph J. Binder
Medical University of Vienna, Vienna, Austria.
Phone: 43-1-40400-6441; Fax: 43-1-40400-2097; E-mail:

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Contact: Karen Honey
Journal of Clinical Investigation

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