News Release

JCI table of contents: July 26, 2010

Peer-Reviewed Publication

JCI Journals

EDITOR'S PICK: Reducing the health risks of obesity without serious side effects

The drug rimonabant was developed as a treatment for obesity and its myriad of serious health consequences (for example, type 2 diabetes). Despite having its desired effects on weight, which it decreased, and on levels of glucose and fats in the blood, rimonabant was never approved for use in the US because of serious neurological side effects including depression and anxiety. Now, a team of researchers, led by George Kunos, at the National Institutes of Health, Bethesda, and Alexandros Makriyannis, at Northeastern University, Boston, have developed a drug that has the same positive effects in mice on levels of glucose and fats in the blood as rimonabant but none of the neurological side effects.

Rimonabant targets the protein CB1R, the same molecule that mediates the effects of marijuana. CB1R is expressed in the brain and in organs such as the liver, pancreas, and fat tissue. The team developed a drug that inhibited CB1R in peripheral mouse organs but could not access the brain. This drug did not cause weight loss or neurological side effects, which rimonabant does, but did have effects on levels of glucose and fats in the blood that should reduce the risk of the serious health consequences of obesity. The authors therefore hope that this approach of targeting only peripheral CB1R can be translated into the clinic to reduce health risks in obese patients. However, in an accompanying commentary, Mary-Elizabeth Patti, at the Joslin Diabetes Center, Boston, cautions that it will be important to ensure that such drugs really do not access the brain to mediate neurological effects.

TITLE: Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity

AUTHOR CONTACT:
George Kunos
National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health, Bethesda, Maryland, USA.
Phone: 301.443.2069; Fax: 301.480.0257; E-mail: gkunos@mail.nih.gov.

Alexandros Makriyannis
Northeastern University, Boston, Massachusetts, USA.
Phone: 617.373.4200; Fax: 617.373.7493; E-mail: a.makriyannis@neu.edu.

View this article at: http://www.jci.org/articles/view/42551?key=6ce2dad54fc6a996740c

ACCOMPANYING COMMENTARY
TITLE: Rehashing endocannabinoid antagonists: can we selectively target the periphery to safely treat obesity and type 2 diabetes?

AUTHOR CONTACT:
Mary-Elizabeth Patti
Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617.735.1966; Fax: 617.732.2593; E-mail: mary.elizabeth.patti@joslin.harvard.edu.

View this article at: http://www.jci.org/articles/view/44099?key=0b54ba886fefa8c8c8f2


EDITOR'S PICK: Predicting drug responsiveness in cancer patients

Drugs such as everolimus that target the protein mTOR are used to treat several forms of cancer, but not all patients respond to the treatment. A team of researchers, led by Alberto Bardelli, at the University of Turin Medical School, Italy, has now identified a way to help predict which patients will respond to such drugs.

Specifically, the team found that human cancer cells with mutations in the PIK3CA gene responded to everolimus in vitro except when a KRAS gene mutation was also present. Importantly, in a cohort of metastatic cancer patients, the presence of KRAS gene mutations was associated with lack of response to treatment with everolimus therapy. These data suggest that by looking for the presence or absence of PIK3CA and KRAS mutations in a person's tumor it will be possible to predict whether or not that person will benefit from treatment with a drug that targets mTOR. However, as noted in an accompanying commentary, by Morassa Mohseni and Ben Ho Park, at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, while these data have enormous potential to change clinical practice, larger prospective studies are required to verify them.

TITLE: Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus

AUTHOR CONTACT:
Alberto Bardelli
IRCC, University of Turin Medical School, Turin, Italy.
Phone: 39.011.993.3235; Fax: 39.011.993.3225; E-mail: a.bardelli@unito.it.

View this article at: http://www.jci.org/articles/view/37539?key=fd893349707da2f3dddf

ACCOMPANYING COMMENTARY
TITLE: PIK3CA and KRAS mutations predict for response to everolimus therapy: now that's RAD001

AUTHOR CONTACT:
Ben Ho Park
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.
Phone: 410.502.7399; Fax: 410.614.8397; E-mail: bpark2@jhmi.edu.

View this article at: http://www.jci.org/articles/view/44026?key=e31261cd0926146a2435


CARDIOVASCULAR DISEASE: Flushing out key limitations to a drug that protects against heart attack

The drug niacin is used to modulate fat levels in the blood and thereby reduce the risk of a heart attack. However, noxious effects on the skin that have been termed 'flushing' limit its use in the clinic. Understanding the mechanisms underlying flushing might identify therapeutic targets that could suppress flushing and enable wider use of niacin. Insight into this has now been provided by a team of researchers, led by Stefan Offermanns, at the Max-Planck-Institute for Heart and Lung Research, Germany, that studied in mice the mechanisms underlying flushing caused by niacin, which targets the protein GPR109A.

Specifically, the team found that different molecular pathways in different cell types in the skin mediated the two phases of niacin-induced flushing. The early phase of flushing was mediated via GPR109A on Langerhans cells and involved the protein COX-1, while the late phase was mediated via GPR109A on skin cells (keratinocytes) and involved COX-2. Inhibitors of COX-1 and COX-2 selectively blocked the anticipated phases of flushing. The authors hope that these data will lead to the development of new approaches to mitigate the skin toxicity that limits the use of niacin in the clinic.

In an accompanying commentary, Richard Dunbar and Joel Gelfand, at the University of Pennsylvania, Philadelphia, note that these data bring us closer to understanding the noxious skin effects of niacin. However, they caution that the readouts of flushing assessed in mouse models (redness) might not correlate with some of the other noxious skin effects (such as pain and itching) that niacin induces.

TITLE: Nicotinic acid– and monomethyl fumarate–induced flushing involves GPR109A expressed by keratinocytes and COX-2–dependent prostanoid formation in mice

AUTHOR CONTACT:
Stefan Offermanns
Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
Phone: 49.6032.705.1201; Fax: 49.6032.705.1204; E-mail: stefan.offermanns@mpi-bn.mpg.de.

View this article at: http://www.jci.org/articles/view/42273?key=6d7f908cf8e1b502b593

ACCOMPANYING COMMENTARY
TITLE: Seeing red: flushing out instigators of niacin-associated skin toxicity

AUTHOR CONTACT:
Richard L. Dunbar
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: 215.662.9024; Fax: 215.243.1519; E-mail: richard.dunbar@uphs.upenn.edu.

View this article at: http://www.jci.org/articles/view/44098?key=56144c6536c87204f0e5


IMMUNOLOGY: Function of rare immune cell uncovered

Basophils are immune cells that are found in very small numbers in the blood. We currently have very little understanding of their function, but such information could be obtained by the development of a basophil-deficient mouse. A team of researchers, led by Hajime Karasuyama, at Tokyo Medical and Dental University Graduate School, Japan, has now generated mice in which basophils can be selectively deleted by administration of diptheria toxin. Furthermore, using these mice, they identified an essential and nonredundant role for basophils in the immune response to ticks that mediate babesiosis, Q fever, and Russian encephalitis in humans. The authors suggest that their data might open new avenues of research for the development of strategies for controlling tick-borne diseases and that their mice will be useful in determining the functions of basophils in health and disease, a sentiment echoed in an accompanying commentary by Booki Min, at the Cleveland Clinic Foundation, Cleveland.

TITLE: Selective ablation of basophils in mice reveals their nonredundant role in acquired immunity against ticks

AUTHOR CONTACT:
Hajime Karasuyama
Tokyo Medical and Dental University Graduate School, Tokyo, Japan.
Phone: 81.3.5803.5162; Fax: 81.3.3814.7172; E-mail: karasuyama.mbch@tmd.ac.jp.

View this article at: http://www.jci.org/articles/view/42680?key=e5e1612cd2bc1dbde29b

ACCOMPANYING COMMENTARY
TITLE: Mice that "conditionally" lack basophils, AT LAST

AUTHOR CONTACT:
Booki Min
Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
Phone: 216.445.3126; Fax: 216.444.8372; E-mail: minb@ccf.org.

View this article at: http://www.jci.org/articles/view/44058?key=28959b982be8abf8795c


ONCOLOGY: The protein Sema3E: the black sheep in the Sema3 family

Sema3 proteins are traditionally considered to be inhibitors of tumor growth and spread (metastasis). However, a team of researchers, led by Luca Tamagnone, at the University of Torino Medical School, Italy, and Massimiliano Mazzone, at Flanders Institute for Biotechnology, Belgium, has now determined that although the Sema3 protein Sema3E inhibits the growth of human tumor cells after transplantation into mice, it actually promotes their invasiveness and metastasis to distant sites. Consistent with this, expression of Sema3E and the protein to which it binds (Plexin D1) correlated with metastatic progression of human tumors. The authors therefore suggest that targeting Sema3E and the molecules to which it binds to mediate its effects might provide a way to block tumor metastasis. However, in an accompanying commentary, Michael Klagsbrun and Akio Shimizu, at Children's Hospital Boston, Boston, caution that more clinical data are needed to confirm that Sema3E has a central role in tumor metastasis in humans.

TITLE: Sema3E–Plexin D1 signaling drives human cancer cell invasiveness and metastatic spreading in mice

AUTHOR CONTACT:
Luca Tamagnone
Institute for Cancer Research, University of Torino Medical School, Candiolo, Italy.
Phone: 39.011.9933.204; Fax: 39.011.9933.225; E-mail: luca.tamagnone@ircc.it.

Massimiliano Mazzone
Flanders Institute for Biotechnology, Leuven, Belgium.
Phone: 32.16.34.61.76; Fax: 32.16.34.59.90; E-mail: massimiliano.mazzone@vib-kuleuven.be.

View this article at: http://www.jci.org/articles/view/42118?key=a1ec2a3ae3b1661b8e91

ACCOMPANYING COMMENTARY
TITLE: Semaphorin 3E, an exception to the rule

AUTHOR CONTACT:
Michael Klagsbrun
Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617.919.2157; Fax: 617.730.0233; E-mail: michael.klagsbrun@childrens.harvard.edu.

View this article at: http://www.jci.org/articles/view/44110?key=d5ad9fc631d0b90cfc89

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