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JCI online early table of contents: July 10, 2008

EDITOR'S PICK: Why men are more at risk of diseases caused by blood clots than women

Being male increases your risk of diseases caused by the inappropriate formation of a blood clot (a process known as thrombosis), such as heart attack and stroke, but the reasons for this are not completely understood. However, Ethan Weiss and colleagues at the University of California, San Francisco, have used a mouse model of thrombosis to shed new light on this matter.

Thrombosis-related proteins are made in the liver, where expression of the genes containing the information needed for their generation is regulated by growth hormone (GH), which is secreted in a sex-specific manner males secrete GH in a pulsatile fashion, whereas females secrete GH continuously. In this study, GH-deficient mice were protected from thrombosis in the model of disease. When female GH-deficient mice were given pulsatile GH (to mimic the manner in which GH is secreted in males) their ability to form blood clots resembled male mice. Conversely, when male GH-deficient mice were given continuous GH (to mimic the manner in which GH is secreted in females) their ability to form blood clots resembled female mice. The authors therefore conclude that sex-specific patterns of GH release mediate the gender-associated differences observed in susceptibility to diseases caused by inappropriate thrombosis, information that they hope will be of help in the development of sex-specific treatments for thrombosis.

TITLE: Sex differences in thrombosis in mice are mediated by sex-specific growth hormone secretion patterns

Ethan J. Weiss
University of California, San Francisco, San Francisco, California, USA
Phone: (415) 514-0819; Fax: (415) 476-0424; E-mail:

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ONCOLOGY: Prostate cancer cells cause disease in bones with the help of FGF9

Although prostate cancer is the second most common cause of death from cancer in the US, it is not the tumor in the prostate that usually causes death. Rather, death mainly occurs as a result of the tumor spreading to the bones, where it is known as an osteoblastic bone metastasis. Treatments that deprive the tumor of male sex hormones (androgens) are usually effective, but only briefly as the tumors typically develop the ability to grow in the absence of androgens and the diseases progresses. New data, generated using two prostate cancer cell lines that lack expression of androgen receptors and that were derived from the bones of an individual with osteoblastic bone metastases, by Nora Navone and colleagues, at The University of Texas MD Anderson Cancer Center, Houston, have provided new insight into the mechanisms by which prostate cancer osteoblastic bone metastases progress.

The androgen receptornegative prostate cancer cell lines generated by the authors grew when transplanted into immunocompromised mice and generated osteoblastic bone metastases. A protein known as FGF9 was found to be expressed at higher levels in these cells lines than in other bone-derived prostate cancer cells and induced bone formation in an in vitro organ culture assay. Further, as blocking FGF9 reduced the osteoblastic bone metastases in mice transplanted with the cell lines and FGF9 was found to be expressed in all human prostate cancer osteoblastic bone metastases analyzed, the authors suggest that FGF9 has an important role in prostate cancer progression to osteoblastic bone metastases. The cells lines generated are also likely to be an important preclinical model for researchers developing therapeutics for osteoblastic bone metastases in individuals with prostate cancer.

TITLE: Androgen receptornegative human prostate cancer cells induce osteogenesis in mice through FGF9-mediated mechanisms

Nora M. Navone
The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Phone: (713) 563-7273; Fax: (713) 745-9880; E-mail:

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ONCOLOGY: The protein Smad2 keeps skin cancer in check

Xiao-Jing Wang and colleagues, at Oregon Health & Science University, Portland, have provided new insight into the role of the signaling molecule Smad2 in skin cancer by analyzing human skin cancer tissue and a mouse model of skin cancer.

In the study, human squamous cell skin cancer samples were found to frequently lose expression of Smad2. In particular, Smad2 expression was lost in all samples characterized as "poorly differentiated" (which means they had progressed to become aggressive tumors). Consistent with this, mice lacking Smad2 in cells of the skin known as keratinocytes developed chemically induced skin cancer more rapidly than normal mice, and the cancers were all characterized as "poorly differentiated". The mouse cancers also underwent a process known as epithelial-mesenchymal transition (EMT) and this was found to contribute to the accelerated progression of the skin cancer to an aggressive form. These data identify Smad2 as a suppressor of skin cancer development and progression to an aggressive form, and future studies will investigate in more detail the mechanisms underlying the role of Smad2 loss in human skin cancer progression.

TITLE: Keratinocyte-specific Smad2 ablation results in increased epithelial-mesenchymal transition during skin cancer formation and progression

Xiao-Jing Wang
Portland VA Cancer Center, Portland, Oregon, USA.
Phone: (503) 220-8262, ext. 54273; Fax: (503) 402-2817; E-mail:

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METABOLIC DISEASE: A novel marker of hardening of the arteries

Atherosclerosis is a disease of the major arterial blood vessels that is often known as hardening of the arteries; it is one of the main causes of heart attack and stroke. An important first step in the disease is a process known as intimal thickening, whereby the intimal layer of arterial blood vessels becomes thicker because cells known as smooth muscle cells (SMCs) migrate to the area and proliferate. The protein sLRII is thought to play a key role in this process, although its specific mechanisms of action and significance are poorly understood. In a new study, Hideaki Bujo of the Chibe University Graduate School of Medicine, Japan, Wolfgang Schneider of the Medical University of Vienna, Austria, and their colleagues reveal that sLRII is important for SMC migration.

Levels of sLRII in the bloodstream were shown to be associated with intimal thickening in patients with poorly-regulated abnormal levels of fat in the blood. Furthermore, intimal thickening was markedly reduced in mice lacking sLRII. SMCs from these mice failed to migrate in response to stimulation, indicating that the reduced intimal thickening probably results from reduced SMC migration. The authors therefore suggest that sLRII may serve as a novel marker for intimal thickening and atherosclerosis

TITLE: Ang IIstimulated migration of vascular smooth muscle cells is dependent on LR11 in mice

Hideaki Bujo
Chiba University Graduate School of Medicine, Chiba, Japan.
Phone: 81-43-222-7171; Fax: 81-43-226-2095. E-mail:

Wolfgang J. Schneider
Medical University of Vienna, Vienna, Austria.
Phone: 43-1-4277-61803;
Fax: 43-1-4277-61804. E-mail:

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IMMUNOLOGY: APRIL showers bring mucosal antibody secreting cells long life

Antibodies are proteins that are a crucial component of the immune system. They are produced in large amounts by immune cells known as plasma cells, which live in just a few parts of the body, including the bone marrow and special areas of the various parts of the body that are exposed to the outside (e.g., the gut, nose, and airways). These areas are known as mucosa-associated lymphoid tissue (MALT) and include tissues such as the tonsils, but what regulates plasma cell survival in MALT has not been determined. Now, however, Bertrand Huard and colleagues, at Geneva University Medical Center, Switzerland, have provided new insight into the molecular mechanisms controlling plasma cell survival in MALT.

In the study, analysis of tonsils and MALT from the lower gut indicated that a protein known as APRIL is important for promoting the survival of plasma cells in human MALT. APRIL was found to work by increasing plasma cell expression of proteins that protect cells from a form of death known as apoptosis. Expression of APRIL was shown to be greater in tonsils infected with a microbe than in noninfected tonsils and the cells producing the increased APRIL were identified as immune cells known as neutrophils that had been recruited to the site of infection. APRIL from the neutrophils was retained in the tonsils bound to molecules known as heparan sulfate proteoglycans, creating an APRIL-rich niche for the plasma cells to survive in. The authors therefore suggest that the longevity of plasma cells in MALT is controlled, in part, by APRIL-secreting neutrophils recruited to sites of infection.

TITLE: APRIL secreted by neutrophils binds to heparan sulfate proteoglycans to create plasma cell niches in human mucosa

Bertrand Huard
Geneva University Medical Center, Geneva, Switzerland.
Phone: 41-22-379-58-11; Fax: 41-22-379-58-02; E-mail:

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METABOLIC DISEASE: Understanding how the brain can influence the effects of insulin

One of the characteristics of type 2 diabetes is insulin resistance, which refers to the inability of cells in the body to respond appropriately to the hormone insulin. Among the cells in the body that normally respond to insulin are nerves in a region of the brain known as the hypothalamus. New data, generated in rats, by Hiraku Ono and colleagues, at Albert Einstein College of Medicine, New York, has provided insight into a molecular pathway in the hypothalamus that contributes to the development of insulin resistance.

Insulin plays a key role in controlling the amount of glucose in the body through its ability to make cells, such as liver and fat cells, take up glucose from the blood and store it for future use. Insulin also prevents liver cells from releasing stored glucose, partly through its effects in the hypothalamus. In the study, if rats were fed a high-fat diet for a short period of time the ability of insulin to prevent liver cells releasing stored glucose was reduced. This was associated with both a decrease in insulin-induced signaling and an increase in activation of a protein known as SK6 in the hypothalamus. The importance of SK6 activation in the hypothalamus in suppressing the ability of insulin to prevent glucose release from liver cells was confirmed by two sets of experiments. First, it was shown that enforced SK6 activation in the hypothalamus had the same effects as feeding rats a high-fat diet; second, blocking the effects of SK6 activation restored the ability of insulin to prevent glucose release from liver cells, even when rats were fed a high-fat diet. These data lead the authors to speculate that the earliest stages of diet-induced insulin resistance might be prevented by inhibition of S6K in the hypothalamus.

TITLE: Activation of hypothalamic S6 kinase mediates diet-induced hepatic insulin resistance in rats

Hiraku Ono
Albert Einstein College of Medicine, New York, New York, USA.
Phone: (718) 430-2348; Fax: (718) 430-8557; E-mail:

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HEMATOLOGY: Shhhh: the protein Lnk keeps hematopoietic stem cells silent

Wei Tong and colleagues, at Children's Hospital of Philadelphia, have provided new insight into the molecular control of hematopoietic stem cells (HSCs), the cells that give rise to all types of blood cell, by explaining why mice lacking an inhibitory protein known as Lnk have more HSCs than normal mice.

In the study, it was observed that a greater proportion of HSCs in mice lacking Lnk were not undergoing cell division and were said to be quiescent (i.e., in a state of inactivity or in silent mode). Lnk was found to regulate HSC quiescence by binding a signaling protein known as JAK2 after it was activated following binding of the soluble factor TPO to its receptor Mpl. The authors therefore hypothesize that in the absence of the inhibitory molecule Lnk, TPO-initiated signaling from Mpl to JAK2 goes unchecked and the number of HSCs produced is increased to a level at which they do not need to undergo cell division as often to maintain their population.

TITLE: Lnk controls mouse hematopoietic stem cell self-renewal and quiescence through direct interactions with JAK2

Wei Tong
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Phone: (267) 426-0930; Fax: (267) 426-5476; E-mail:

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Contact: Karen Honey
Journal of Clinical Investigation

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