JCI online early table of contents: July 11, 2011

(Press-News.org) EDITOR'S PICK: Do-it-yourself brain repair following stroke

Stroke is a leading cause of long-term disability and death in the United States. A team of researchers — led by Gregory Bix, at Texas A&M College of Medicine, College Station — has identified a way to exploit one of the brain's self-repair mechanisms to protect nerve cells and enhance brain repair in rodent models of stroke. The authors suggest that this approach could provide a nontoxic treatment for stroke.

The most common form of stroke (ischemic stroke) occurs when a blood vessel that brings oxygen and nutrients to the brain becomes clogged, for example with a blood clot, causing nerve cells in the affected area to die rapidly. In their study, Bix and colleagues detected in rodent models of stroke elevated levels of domain V, a naturally occurring fragment of the molecule perlecan, suggesting it might have a natural role in repairing the brain after a stroke. When administered in these models 24 hours after stroke, perlecan domain V protected nerve cells from death and promoted blood vessel growth, a key component of brain repair. The authors therefore suggest that perlecan domain V could provide a therapy that improves stroke outcome by protecting nerve cells and enhancing brain repair.

TITLE: Perlecan domain V is neuroprotective and proangiogenic following ischemic stroke in rodents

AUTHOR CONTACT:
Gregory J. Bix
Texas A&M College of Medicine, College Station, Texas, USA.
Phone: 979.862.7613; Fax: 979.847.9481; E-mail: gjbix@medicine.tamhsc.edu.

View this article at: http://www.jci.org/articles/view/46358?key=975ca4af1b533bd95895

EDITOR'S PICK: PXR: a stepping stone from environmental chemical to cancer?

Several chemicals that can accumulate to high levels in our body (for example BPA and some pesticides) have been recently linked to an increased risk of cancer and/or impaired responsiveness to anticancer drugs. A team of researchers, led by Sridhar Mani, at Albert Einstein College of Medicine, New York, has now identified a potential mechanistic link between environmental exposure to these foreign chemicals (xenogens) and cancer drug therapy response and survival.

PXR is one protein by which cells (including tumor cells) can sense xenogens. In their study, Mani and colleagues determined that activation of PXR was sufficient to enhance the cancerous characteristics of human colon tumor cell lines and primary human colon cancer tissue xenografted into immune system–deficient mice. Further analysis indicated FXR activation leads to colon cancer growth through the induction of the growth factor FGF19. The authors therefore suggest that it will be important to investigate further the extent to which the environment might play a role in tumor recurrence through PXR activation.

TITLE: Pregnane X receptor activation induces FGF19-dependent tumor aggressiveness in humans and mice

AUTHOR CONTACT:
Sridhar Mani
Albert Einstein College of Medicine, New York, New York, USA.
Phone: 718.430.2871; Fax: 718.904.2830; E-mail: sridhar.mani@einstein.yu.edu.

View this article at: http://www.jci.org/articles/view/41514?key=d5f620785644dd3ba8e6

METABOLIC DISEASE: Sex hormone protection from type 2 diabetes

The incidence of obesity and its common complication, type 2 diabetes, is approaching epidemic proportions in the developed world. A key event in the development of type 2 diabetes is the failure of beta-cells in the pancreas to produce enough of the hormone insulin to meet the body's demands. The fact that both human and rodent females are relatively protected from beta-cell failure suggests that the sex hormone estradiol (the second most prevalent sex hormone in females) has beneficial effects in this context. Now, a team of researchers, led by Franck Mauvais-Jarvis, at Northwestern University Feinberg School of Medicine, Chicago, has determined in a rat model of obestity-associated type 2 diabetes that estradiol protects male rats against beta-cell failure. Detailed analysis indicated that these effects of estradiol were mediated directly on pancreatic beta-cells via estrogen receptors and identified the underlying downstream mechanisms. The authors therefore suggest that estrogen receptors might be viable therapeutic targets to prevent beta-cell failure in individuals at high risk of developing or already diagnosed with type 2 diabetes.

TITLE: Estrogen receptor activation reduces lipid synthesis in pancreatic islets and prevents beta-cell failure in rodent models of type 2 diabetes

AUTHOR CONTACT:
Franck Mauvais-Jarvis
Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Phone: 312.503.1293; Fax: 312.908.9032; E-mail: f-mauvais-jarvis@northwestern.edu.

View this article at: http://www.jci.org/articles/view/44564?key=e3a715f3d0406a16a2e2

ONCOLOGY: A Rock(in') target for treating breast cancer

Invasive lobular carcinoma is the second most commonly diagnosed form of breast cancer. It refers to tumors that began in the milk-producing lobules of the breast but have subsequently broken through the wall of the lobule and begun to invade the tissues of the breast. A team of researchers, led by Patrick Derksen, at University Medical Center Utrecht, the Netherlands, has now gained new insight into the development of invasive lobular carcinoma and its spread to distant sites (metastasis) that they hope could provide new targets to treat invasive and metastatic lobular carcinoma.

Loss of expression of the protein E-cadherin is a key event in the development and progression of invasive lobular carcinoma. Derksen and colleagues identified in a mouse model of invasive lobular carcinoma a signaling pathway that regulates tumor growth upon loss of E-cadherin. This pathway involved activation of signaling via the protein Rock. As primary human invasive lobular carcinoma samples showed signs of active Rock signaling, the authors suggest that inhibition of Rock could be combined with conventional chemotherapeutics to treat invasive and metastatic lobular carcinoma.

TITLE: Cytosolic p120-catenin regulates growth of lobular carcinoma through Rock1-mediated anoikis resistance

AUTHOR CONTACT:
Patrick W.B. Derksen
University Medical Center Utrecht, Utrecht, the Netherlands.
Phone: 31.88.7568068; Fax: 31.88.7568479; E-mail: pderksen@umcutrecht.nl.

View this article at: http://www.jci.org/articles/view/41695?key=358a4f1f9b3de71fdce1

ONCOLOGY: Opposing forces at work in lung cancer

In patients with cancer, the spread of their tumor to a distant site (a process known as metastasis) is a common cause of death. A team of researchers — led by Pan-Chyr Yang, at National Taiwan University College of Medicine, Taiwan, and Tse-Ming Hong, at National Chung Hsing University, Taiwan — has now identified two proteins with opposing functions in regulating metastasis in patients with non-small-cell lung cancer. The team hopes that this pathway might provide a new target for anticancer therapeutics.

Yang, Hong, and colleagues found that the protein LCRMP-1 promoted the metastasis of human lung cancer cells transplanted into mice, while the protein CRMP-1 decreased human lung cancer cell metastasis in mice by antagonizing the function of LCRMP-1. Importantly, high-level expression of LCRMP-1 and low-level expression of CRMP-1 were associated with metastasis to lymph nodes and poor survival in patients with non-small-cell lung cancer. The authors therefore suggest that targeting LCRMP-1 could provide a new approach to treating non-small-cell lung cancer.

TITLE: The ability of LCRMP-1 to promote cancer invasion by enhancing filopodia formation is antagonized by CRMP-1

AUTHOR CONTACT:
Pan-Chyr Yang
National Taiwan University College of Medicine, Taipei, Taiwan.
Phone: 886.2.23562185; Fax: 886.2.23224793; E-mail: pcyang@ntu.edu.tw.

Tse-Ming Hong
National Chung Hsing University, Tainan City, Taiwan.
Phone: 886.6.2353535, ext. 4259; Fax: 886.6.3028162; E-mail: tmhong@mail.ncku.edu.tw.

View this article at: http://www.jci.org/articles/view/42975?key=92e715f1288bc1cfb183

ONCOLOGY: Molecular explanation of why liver cancer is more prevalent in men than women

Hepatocellular carcinoma (HCC), which is the most common form of liver cancer and the third most common cause of cancer-related death worldwide, occurs more frequently in men than women. Consistent with this, recent studies have linked the protein AR, which is the protein to which the hormone testosterone binds, to the development of HCC. A team of researchers — led by Alfred Cheng and Joseph Sung, at The Chinese University of Hong Kong, China — has now identified a molecular mechanism underlying this association. Specifically, the team found that in human HCC cell lines, AR induced expression of the gene CCRK. In turn, the protein templated by this gene promoted human HCC cell lines to form tumors when they were transplanted into mice via upregulation of β-catenin/TCF signaling. The clinical significance of these data was highlighted by the observation that AR, CCRK, and β-catenin were concordantly overexpressed in human primary HCC cells. These data provide important insight into the factors causing the sex-related disparity of HCC.

TITLE: Cell cycle–related kinase is a direct androgen receptor–regulated gene that drives β-catenin/T cell factor–dependent hepatocarcinogenesis

AUTHOR CONTACT:
Alfred S.L. Cheng
The Chinese University of Hong Kong, Hong Kong, China.
Phone: 852.37636100; Fax: 852.21445330; E-mail: alfredcheng@cuhk.edu.hk.

Joseph J.Y. Sung
The Chinese University of Hong Kong, Hong Kong, China.
Phone: 852.26098600; Fax: 852.26036197; E-mail: jjysung@cuhk.edu.hk.

View this article at: http://www.jci.org/articles/view/45967?key=a13e556e15a9ea17b862

CARDIOLOGY: The proteins RhoA and PKD provide the heart with protection

A heart attack occurs when blood flow to a section of the heart muscle suddenly becomes blocked. This starves that region of the heart muscle of oxygen (and it is said to be ischemic) and the heart muscle cells begin to die. Surprisingly, even if blood flow is restored to that region of the heart (a process known as reperfusion) the heart muscle cells can be further damaged, such damage is known as ischemia/reperfusion injury. A team of researchers, led by Joan Heller Brown, at the University of San Diego, La Jolla, has now identified a molecular pathway that protects mouse heart muscle cells from ischemia/reperfusion injury. Specifically, they find that signaling downstream of the protein RhoA involves the protein PKD and that these proteins work together to promote mouse heart muscle cell survival after ischemia/reperfusion. The team therefore suggests that therapeutics that activate RhoA could provide protection to the heart following a heart attack.

TITLE: RhoA protects the mouse heart against ischemia/reperfusion injury

AUTHOR CONTACT:
Joan Heller Brown
University of California San Diego, La Jolla, California, USA.
Phone: 858.822.5858; Fax: 858.822.0041; E-mail: jhbrown@ucsd.edu.

View this article at: http://www.jci.org/articles/view/44371?key=fd2af9acd4f73ac551f9

HEPATOLOGY: The liver is scarred for life by the protein p53

Scarring of the liver (liver fibrosis) is a severe consequence of most chronic diseases of the liver. It leads to cirrhosis of the liver, for which the only effective available treatment is transplantation. However, a team of researchers, led by Tetsuo Takehara, at Osaka University Graduate School of Medicine, Japan, has now identified a molecular pathway that could provide a target for therapeutics designed to treat individuals with liver fibrosis.

In the study, Takehara and colleagues found that increased levels of the protein p53 in mice led to liver fibrosis and that this was caused by p53 inducing upregulation of liver cell production of the protein CTGF, a known master regulator of fibrotic liver diseases. The clinical significance of these data was highlighted by the observation that levels of the gene CTGF and genes regulated by p53 were both increased in fibrotic human liver samples. The authors therefore suggest that the p53/CTGF pathway could provide a therapeutic target for the treatment of individuals with fibrosis of the liver.

TITLE: Increases in p53 expression induce CTGF synthesis by mouse and human hepatocytes and result in liver fibrosis in mice

AUTHOR CONTACT:
Tetsuo Takehara
Osaka University Graduate School of Medicine, Osaka, Japan.
Phone: 81.6.6879.3621; Fax: 81.6.6879.3629; E-mail: takehara@gh.med.osaka-u.ac.jp.

View this article at: http://www.jci.org/articles/view/44957?key=2d4b5eef0796c175c7cb

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