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JCI table of contents: Dec. 20, 2007

EDITOR'S PICK: You can teach an old dog new tricks: antimalarial prevents cancer in mice

New data generated by a team of researchers from St Jude Childrens Research Hospital, Memphis, and Scripps Research Institute, Jupiter, have indicated that the antimalarial drug chloroquine effectively prevents cancer in mouse models of two distinct human cancer syndromes, Burkitt lymphoma and ataxia telangiectasia. As discussed in the accompanying commentary by Chi Dang, from Johns Hopkins University School of Medicine, Baltimore, these results complement an old epidemiology study suggesting that malarial prophylaxis with chloroquine diminished the incidence of Burkitt lymphoma.

In the study, chloroquine was shown to inhibit the development of Myc-induced lymphomas (a mouse model of Burkitt lymphoma) and to inhibit the development of lymphomas in ATM-deficient mice (a mouse model of ataxia telangiectasia). By contrast, chloroquine did not inhibit the development of lymphomas in p53-deficient mice. Further analysis indicated that chloroquine induced cellular features of autophagy (self-eating) and mediated its effects by inducing lysosomal stress and provoking a p53-dependent cell death. The authors therefore suggested that modulating autophagy, either using chloroquine or other approaches, might provide a new avenue for the development of anticancer therapeutics.

TITLE: Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis

Michael B. Kastan
St. Jude Childrens Research Hospital, Memphis, Tennessee, USA.
Phone: (901) 495-3968; Fax: (901) 495-3966; E-mail:

John L. Cleveland
The Scripps Research Institute, Jupiter, Florida, USA.
Phone: (561) 799-8808; E-mail:

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ACCOMPANYING COMMENTARY TITLE: Antimalarial therapy prevents Myc-induced lymphoma

Chi V. Dang
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Phone: (410) 955-2411; Fax: (410) 955-0185; E-mail:

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EDITOR'S PICK: How an Atkins-like diet can treat epilepsy: leptin attenuates rodent seizure severity

Not all individuals who have epilepsy respond to traditional treatments and these individuals are said to have medically refractory epilepsy. Strict use of a ketogenic diet high in fats and extremely low in carbohydrates is sometimes used for treatment of refractory epilepsy, and is effective about half of the time. However, the mechanisms whereby ketogenic diets suppress epileptic symptoms have long been a mystery. New data generated by Kelvin Yamada and colleagues at the Washington University School of Medicine, St. Louis, has revealed that intranasal delivery of leptin, a hormone important in feeding and energy metabolism, delayed the onset of convulsions in a rodent model of seizures. As indicated by Tamas Horvath and Sabrina Diano in an accompanying commentary, these data suggest that leptin-triggered signaling may be a key to how a ketogenic diet combats epilepsy.

In the study, when focal seizures were induced by injection of the chemical 4AP into rat brains, co-injection of leptin reduced both the length and the frequency of these seizures. Intranasal administration permitted leptin to cross the blood-brain barrier and delay the onset of chemical-induced generalized seizures in mice. Additional experiments revealed that leptin may assert these antiseizure effects via interaction with the JAK2/PI3K signaling pathway. The authors concluded that successful epilepsy treatments may include dietary changes to increase leptin levels, intranasal administration of the compound, and pharmacological targeting of JAK2/PI3K signaling pathways.

TITLE: Leptin inhibits 4-aminopyridine and pentylenetetrazole-induced seizures and AMPAR-mediated synaptic transmission in rodents

Kelvin A. Yamada
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: (314) 454-6120; Fax: (314) 454-2523; E-mail:

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ACCOMPANYING COMMENTARY TITLE: Anticonvulsant effects of leptin in epilepsy

Tamas L. Horvath
Yale School of Medicine, New Haven, Connecticut, USA.
Phone: (203) 785-2525; Fax: (203) 785-7499; Email:

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NEUROBIOLOGY: A new potential target in the treatment of a fatal brain disease

Hypertensive encephalopathy is an often-fatal disease of the brain that results from extremely high blood pressure. This disorder can lead to a breakdown of the blood-brain barrier (BBB), resulting in fluid accumulation in the brain, a condition known as cerebral edema. The mechanisms underlying the breakdown of the BBB were previously unknown. However, a new study by Daria Mochly-Rosen and colleagues from Stanford University School of Medicine has revealed a role for activation of the protein PKC in dysregulation of the integrity of the BBB leading to hypertensive encephalopathy. Furthermore, their studies suggest that delta-PKC may be a useful therapeutic target in patients at risk for developing hypertensive encephalopathy.

Dahl salt-sensitive (DS) rats, when fed a high-salt diet from a young age, often develop severely high blood pressure, encephalopathy, and cerebral edema. The authors found that encephalopathy, BBB disruption, and mortality rates all decreased when PKC was inhibited in hypertensive DS rats. These effects seemed to be due to decreased disruption of the small blood vessels located in the brain. In an accompanying commentary, Robert Messing and Wen-Hai Chou from the University of California at San Francisco, Emeryville, suggest that these results provide incentive to investigate whether PKC signaling pathways mediate BBB dysfunction in other disease states.

TITLE: Sustained pharmacological inhibition of delta-PKC protects against hypertensive encephalopathy through prevention of blood-brain barrier breakdown in rats

Daria Mochly-Rosen
Stanford University School of Medicine, Stanford, California, USA.
Phone: (650) 725-7720; Fax: (650) 723-4686; E-mail:

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ACCOMPANYING COMMENTARY TITLE: Hypertensive encephalopathy and the blood-brain barrier: is delta-PKC a gatekeeper?

Robert O. Messing
University of California at San Francisco, Emeryville, California, USA.
Phone: (510) 985-3950; Fax: (510) 985-3101; Email:

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VASCULAR BIOLOGY: What AM I? AM is a regulator of vascular system functionality

The two vascular systems in mammals develop sequentially during embryonic life. The blood vascular system, which is essential for the delivery of oxygen and nutrients to the tissues, develops first. This is followed by the lymphatic vascular system that returns extracellular fluid and proteins back to the blood vascular system from the spaces between the tissues. New data reported in two studies in the Journal of Clinical Investigation has identified signaling by a peptide known as AM in the development of both the blood and lymphatic vascular systems in mice. How the two groups observe similar mouse phenotypes but one concludes they are due to lymphatic vascular system defects and the other to blood vascular defects is discussed in an accompanying commentary by Mark Kahn from the University of Pennsylvania, Philadelphia.

Kathleen Caron and colleagues at the University of North Carolina, Chapel Hill, showed that mice lacking AM or either one of the two components of its receptor (Calcrl and RAMP2) died mid-gestation after developing interstitial lymphedema without hemorrhage. Detailed analysis indicated a defect in these mice in lymphatic vascular development, and in vitro experiments demonstrated that AM signaling through Calcrl/RAMP2 drives the proliferation of lymphatic endothelial cells. The authors therefore suggested, that lack of lymphatic proliferative signals during lymphangiogenesis results in smaller, lower-capacity jugular lymphatic vessels that are unable to accommodate the normal uptake of extravasated fluid and thus exacerbates massive interstitial edema.

Similarly, Takayuki Shindo and colleagues from the Shinshu University Graduate School of Medicine, Japan, established that mice lacking RAMP2 died mid-gestation due to severe edema and hemorrhage. However, they observed that the arterial walls of these mice were abnormally thin and their typical structure was severely disrupted. Furthermore, overexpression of RAMP2 in endothelial cells enhanced their ability to form blood capillaries in vitro. The authors therefore concluded that, RAMP2 is a key determinant of the effects of AM on the vasculature and is essential for angiogenesis and vascular integrity in mice.

TITLE: Adrenomedullin signaling is necessary for murine lymphatic vascular development

Leslie H. Lang
Director, Research Communications
University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Phone: (919) 843-9687; E-mail:

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RELATED MANUSCRIPT TITLE: The GPCR modulator protein RAMP2 is essential for angiogenesis and vascular integrity

Takayuki Shindo
Shinshu University Graduate School of Medicine, Nagano, Japan.
Phone: 81-263-37-3192; Fax: 81-263-37-3437; E-mail:

Nobuko Mishima
Japan Science and Technology Agency Public Relations Division, Tokyo, Japan.
Phone: 81-3-5214-8404; Fax: 81-3-5214-8432; E-mail:

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ACCOMPANYING COMMENTARY TITLE: Blood is thicker than lymph

Mark L. Kahn
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: (215) 898-9007; Fax: (215) 573-2094; E-mail:

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GENETICS: What tips the balance? Understanding why X chromosome inactivation can be skewed

To ensure that women and men express equivalent levels of the genes found on X chromosomes, one of the two X chromosomes in the cells of a women is inactive. X chromosome inactivation (XCI) occurs early in development, at approximately the time an embryo implants in the womb, and all cells stemming from a given cell have the same X chromosome inactivated. Which X chromosome is inactivated is random and most females have approximately equal numbers of cells with each X chromosome inactivated. However, some individuals have a much greater proportion of their cells with a given X chromosome inactivated. Such skewing of XCI can have clinical implications, for example, increased XCI skewing has been linked to premature ovarian failure and recurrent spontaneous abortion. To use XCI skewing effectively as a clinical tool more information is needed about the underlying mechanisms. In a new study, Lambert Busque and colleagues at the University of Montreal, have shown that XCI skewing is a complex trait determined by secondary events and selection biases rather than being the result of an inherited tendency to inactivate a particular X chromosome. Carolyn Brown and colleagues from the University of British Columbia, Vancouver, highlight the importance of these observations in an accompanying commentary.

TITLE: No evidence that skewing of X chromosome inactivation patterns is transmitted to offspring in humans

Lambert Busque
University of Montreal, Montreal, Quebec, Canada.
Phone: (514) 252-3404; Fax: (514) 254-5094; E-mail:

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ACCOMPANYING COMMENTARY TITLE: A skewed view of X chromosome inactivation

Carolyn J. Brown
University of British Columbia, Vancouver, British Columbia, Canada.
Phone: (604) 822-0908; Fax: (604) 822-5348; E-mail:

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Contact: Karen Honey
Journal of Clinical Investigation

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