JCI table of contents: Sept. 20, 2007

Currently, prenatal diagnosis of genetic diseases and genetic monitoring of fetal development require invasive procedures. New data generated by Jill Maron and colleagues, at Tufts — New England Medical Center, Boston, has indicated that it might be possible to perform these processes non-invasively.

In the study, it was shown that a common pattern of fetal mRNAs, the molecules that hold the “blueprints” for proteins, was detectable in the blood of pregnant women. After birth, these mRNAs were no longer detected or were detected at substantially lower levels. These data have two important implications: first, the common pattern of fetal mRNAs found in the blood of the pregnant women could serve as a baseline to compare fetuses affected by various pathologic conditions; and second, monitoring specific fetal mRNAs in the blood of pregnant women could be used for prenatal diagnosis of genetic diseases.

TITLE: Gene expression analysis in pregnant women and their infants identifies unique fetal biomarkers that circulate in maternal blood

AUTHOR CONTACT:
Jill L. Maron
Tufts — New England Medical Center, Boston, Massachusetts, USA.
Phone: (617) 636-1468; Fax: (617) 636-1469; E-mail: jmaron@tufts-nemc.org.

View the PDF of this article at: https://www.the-jci.org/article.php?id=29959

New data, generated in mice by Richard Proia and colleagues at the National Institutes of Health, Bethesda, provides a potential reason for early pregnancy loss in humans.

Female mice lacking a protein known as sphingosine kinase 1 (Sphk1) and expressing reduced levels of Sphk2 (Sphk1-/-Sphk2+/- mice) were found to be infertile. Although embryos implanted into the womb, the womb failed to respond correctly to this — the structures that support the developing embryo before a functional placenta is established (the decidua) were defective. In particular, there was increased death of decidual cells and breakage of decidual blood vessels, which led to hemorrhaging and early pregnancy loss. As Sphk1 and Sphk2 are involved in metabolizing a group of fats known as sphingolipids, the authors suggested that disturbances in sphingolipid metabolism might be a cause of early pregnancy loss in humans.

TITLE: Maternal disturbance in activated sphingolipid metabolism causes pregnancy loss in mice

AUTHOR CONTACT:
Richard L. Proia
National Institutes of Health, Bethesda, Maryland, USA.
Phone: (301) 496-4391; Fax: (301) 496-0839; E-mail: proia@nih.gov.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30674

Air pollution is caused by any particulate matter, chemical, or biological agent that changes the natural characteristics of the atmosphere. Exposure to particulate matter has been linked to an increased risk of heart problems, including increased risk of heart attack. In a new study, Gökhan Mutlu and colleagues at Northwestern University Feinberg School of Medicine, Chicago, have identified in mice a mechanism by which exposure to particulate matter leads to accelerated blood clotting and thrombosis, something that can precipitate heart attacks and stroke.

Mice exposed to particulate matter were shown to have decreased bleeding times, accelerated blood clotting, and accelerated formation of an arterial thrombus. As these effects of exposure to particulate matter were not observed in mice lacking IL-6 or depleted of lung macrophages, the authors suggested that particulate matter triggers lung macrophages to produce IL-6 that then mediates altered blood clotting and enhanced thrombus formation. This study provides evidence to suggest that targeting IL-6 might decrease the risk of heart problems caused by exposure to particulate matter.

TITLE: Ambient particulate matter accelerates coagulation via an IL-6–dependent pathway

AUTHOR CONTACT:
Gökhan Mutlu
Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Phone: (312) 908-8163; Fax: (312) 908-4650; E-mail: g-mutlu@northwestern.edu.

Marla Paul
Senior Health Sciences Editor
Northwestern University, Chicago, Illinois, USA.
Phone: (312) 503-8928; E-mail: marla-paul@northwestern.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30639

Huntington disease (HD) is a genetic disease that causes the death of brain cells (neurons) in certain parts of the brain, including a region known as the striatum. There is no cure for HD but medication and specific care methods can reduce or alleviate symptoms. In a new study, Steven Goldman and colleagues at the University of Rochester Medical Center, Rochester, have identified a treatment strategy that slows disease progression in a mouse model of HD (R6/2 huntingtin transgenic mice), leading them to suggest that similar approaches might be of benefit to individuals with HD.

Adenoviral vectors carrying the BDNF and Noggin genes were injected into the brain of R6/2 mice and increased survival times compared with R6/2 mice not receiving this treatment. Increased survival was associated with a delay in the development of impaired function and was caused by the recruitment of new neurons to the striata. The authors therefore suggested that the use of BDNF and Noggin to stimulate the development of new brain cells might be combined with current approaches for reducing and alleviating the symptoms of HD to benefit individuals with HD.

TITLE: Induction of neostriatal neurogenesis slows disease progression in a transgenic murine model of Huntington disease

AUTHOR CONTACT:
Steven A. Goldman
University of Rochester Medical Center, Rochester, New York, USA.
Phone: (585) 275-9550; Fax: (585) 276-0232; E-mail: Steven_Goldman@urmc.rochester.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=31778

A new study by Shobha Ghosh and colleagues from Virginia Commonwealth University, Richmond, has uncovered an important role for a protein known as cholesteryl ester hydrolase (CEH) in the development of atherosclerosis (hardening or furring of the arteries).

Atherosclerosis is a chronic inflammatory disease of the arteries that often leads to heart attacks. It is caused by cholesterol being deposited in the walls of the arteries and being taken up by cells known as macrophages that congregate at the site of cholesterol deposition and form an atherosclerotic plaque. In the study, mice prone to atherosclerosis if fed a high-fat diet (Ldlr–/– mice) developed much smaller atherosclerotic plaques if they expressed high levels of CEH in their macrophages. The overexpression of CEH in the macrophages enhanced their ability to pump out cholesterol, preventing them from dying. These data led the authors to suggest that targeting macrophage CEH might provide a new approach to attenuate atherosclerosis.

TITLE: Macrophage-specific transgenic expression of cholesteryl ester hydrolase significantly reduces atherosclerosis and lesion necrosis in Ldlr–/– mice

AUTHOR CONTACT:
Shobha Ghosh
Virginia Commonwealth University, Richmond, Virginia, USA.
Phone: (804) 827-1012; Fax: (804) 827-1782; E-mail: shobha@hsc.vcu.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30485

Immune responses are essential for keeping our bodies free from infectious agents, but if they persist they cause unwelcome tissue damage. The persistence of Th2-type immune responses is what causes problems for individuals with asthma and for individuals who become chronically infected with parasites. Surprisingly, although the soluble factor IL-10 limits Th2 inflammation, it does not prevent the associated tissue damage. New insight into this conundrum has now been provided by Thomas Wynn and colleagues at the National Institutes of Health, Bethesda, who have shown that in mice IL-10 and the decoy receptor IL-13R-alpha2 regulate Th2 inflammation and Th2-associated tissue damage, respectively.

In both a model of acute Th2-mediated allergic airway inflammation and a model of chronic Th2 responses (chronic infection with the parasite Schistosoma mansoni), inflammation was increased in IL-10–deficient mice but tissue damage was decreased. By contrast, for both the acute and chronic disease, if mice lacked IL-10 and IL-13R-alpha2 the inflammatory response and tissue damage were increased. This data led the authors to suggest that modulating the activity of both IL-10 and IL-13 might be a good approach to treat various Th2-driven diseases, including asthma and chronic infection with parasites.

TITLE: IL-13R-alpha2 and IL-10 coordinately suppress airway inflammation, airway-hyperreactivity, and fibrosis in mice

AUTHOR CONTACT:
Thomas A. Wynn
National Institutes of Health, Bethesda, Maryland, USA.
Phone: (301) 594-4758; Fax: (301) 480-5025; E-mail: twynn@niaid.nih.gov.

Laurie K. Doepel
Chief, News and Public Information Branch
National Institutes of Health, Bethesda, Maryland, USA.
Phone: (301) 402-1663; Fax: (301) 402-0120; E-mail: niaidnews@niaid.nih.gov. or ldoepel@niaid.nih.gov.

View the PDF of this article at: https://www.the-jci.org/article.php?id=31546

Many tumors express unique proteins that the immune system should recognize as foreign (tumor-associated antigens; TAAs) and therefore attack. However, without therapeutic help the immune system usually fails to attack tumors expressing TAAs. A study in mice by Claudio Bordignon and colleagues from Università Vita-Salute San Raffaele, Italy, has now described a new way to induce the immune system to respond to TAAs and to attack tumors.

In the study, immune cells known as lymphocytes were genetically modified so that they expressed a specific TAA. The administration of three doses of the modified lymphocytes to mice that had already been infused with tumor cells resulted in markedly increased survival. Impaired tumor growth in these mice was associated with a strong CD8+ T cell immune response specific for the TAA. The authors therefore concluded that the administration of genetically modified lymphocytes might provide a way to induce therapeutically effective antitumor immune responses.

TITLE: Lymphocytes genetically modified to express tumor antigens target DCs in vivo and induce antitumor immunity

AUTHOR CONTACT:
Claudio Bordignon
Università Vita-Salute San Raffaele, Milan, Italy.
Phone: 39-02-26432351; Fax: 39-02-26432285; E-mail: claudio.bordignon@hsr.it.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30605

New data produced by Gary Gallick and colleagues at The University of Texas MD Anderson Cancer Center, Houston, has provided evidence of a role for the protein AFAP-110 in prostate cancer.

Expression of AFAP-110 was shown to be increased in nearly all prostate tumors compared with both normal prostate tissue and benign prostate tumors. Furthermore, the level of expression correlated directly with the aggressiveness of the cancer. Functionally, downregulation of AFAP-110 expression in human prostate cancer cell lines was found to abrogate their ability to grow in vitro and to grow when transplanted into mice. Mechanistically, further analysis indicated that AFAP-110 required PKC to mediate its effects on tumor growth. These data led the authors to suggest that AFAP-110 could be a good diagnostic and prognostic marker for prostate carcinoma.

TITLE: AFAP-110 is overexpressed in prostate cancer and contributes to tumorigenic growth by regulating focal contacts

AUTHOR CONTACT:
Gary E. Gallick
The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Phone: (713) 563-4919; Fax: (713) 563-5489; E-mail: ggallick@mdanderson.org.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30710

New data generated by Seiji Takashima and colleagues at Osaka University Graduate School of Medicine, Japan, have identified an important role in heart development for a new protein (cardiac-MLCK) whose expression is upregulated in the hearts of individuals with chronic heart failure (CHF).

Expression of cardiac-MLCK was shown to be increased in heart tissue from individuals with CHF compared with normal heart tissue, as well as in rat models of heart failure. In vitro, knocking down cardiac-MLCK expression in rat heart cells impaired sarcomere assembly; normal sarcomere assembly is essential for optimal heart function. Furthermore, knocking down cardiac-MLCK expression in zebrafish led to heart abnormalities, indicating a role for cardiac-MLCK in heart development.

TITLE: A cardiac myosin light chain kinase regulates sarcomere assembly in the vertebrate heart

AUTHOR CONTACT:
Seiji Takashima
Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Phone: 81-68-679-3472; Fax: 81-68-679-3473; E-mail: takasima@medone.med.osaka-u.ac.jp.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30804