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JCI online early table of contents: Dec. 1, 2010

EDITOR'S PICK: Designing safer glucocorticoid drugs

Glucocorticoid drugs are used widely to treat numerous conditions, including rheumatoid arthritis, allergic reactions, asthma, and some forms of cancer, and transplant recipients. The beneficial effects of these drugs are their potent antiinflammatory and immunosuppressive properties. However, their long-term use is limited by severe side effects, including high blood levels of glucose, fatty liver, and type 2 diabetes. A team of researchers, led by Carolyn Cummins, at the University of Toronto, Ontario, has now shown that the protein LXR-beta is required in mice for glucocorticoid drugs to elicit many of their negative side effects. Importantly, although mice lacking LXR-beta did not develop high levels of blood glucose or fatty liver when administered a glucocorticoid drug, they did show all the signs of immunosuppression. The authors therefore suggest that glucocorticoid drugs designed to selectively target the glucocorticoid receptor and not LXR-beta should be safer than those currently in clinical use.

TITLE: LXR-beta is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice

Carolyn L. Cummins
University of Toronto, Toronto, Ontario, Canada.
Phone: 416.946.3466; Fax: 416.978.8511; E-mail:

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EDITOR'S PICK: The protein TXNL2 provides human breast cancer cells with protection

Some individuals supplement their diet with antioxidants to try to ensure that they maintain their health and prevent disease. A key target of antioxidants is reactive oxygen species (ROS), which have been linked to tumor development and progression. A team of researchers led by Xiaojiang Cui, at the John Wayne Cancer Institute, Santa Monica; Ning-Hui Cheng, Baylor College of Medicine, Houston; and Ning Zhang, at Tianjin Medical University, China have now determined that the protein TXNL2 helps protect human breast cancer cells from high levels of ROS. Of interest, knocking down TXNL2 levels in human breast cancer cells inhibited their ability to form tumors upon transplantation into mice. Furthermore, enhanced TXNL2 expression in primary breast cancer samples correlated with cancer spread to the lung and brain and with decreased survival. The authors therefore suggest that TXNL2 could be a new therapeutic target for the treatment of breast cancer.

TITLE: Thioredoxin-like 2 regulates human cancer cell growth and metastasis via redox homeostasis and NF-kB signaling

Xiaojiang Cui
John Wayne Cancer Institute, Santa Monica, California, USA.
Phone: 310.998.3916; Fax: 310.582.7390; E-mail:

Ning-Hui Cheng
Baylor College of Medicine, Houston, Texas, USA.
Phone: 713.798.9326; Fax: 713.798.7101; E-mail:

Ning Zhang
Tianjin Medical University, Tianjin, China.
Phone: 86.13502179648; Fax: 86.22.23542068; E-mail:

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NEPHROLOGY: Genetic mutations underlying rare human kidney disorder identified

Dicarboxylic aminoaciduria is a rare inherited disorder for which the affected gene has not yet been identified. Individuals with this disorder excrete extremely high levels of the protein building blocks glutamate and aspartate in their urine, due to inefficient handling of these molecules by the kidney. Many also show mental retardation. A team of researchers, led by John Rasko, at Centenary Institute, Australia, has now identified two specific mutations in the SLC1A1 gene as causing dicarboxylic aminoaciduria in humans. Further analysis indicated that the mutations abrogated the ability of SLC1A1 protein to transport glutamate in the human kidney. The authors therefore suggest that impaired uptake of protein building blocks via SLC1A1 in nerve cells likely accounts for the impaired neurological capabilities of individuals with dicarboxylic aminoaciduria accompanied by mental retardation.

TITLE: Loss-of-function mutations in the glutamate transporter SLC1A1 cause human dicarboxylic aminoaciduria

John E.J. Rasko
Royal Prince Alfred Hospital and Centenary Institute, Camperdown, New South Wales, Australia.
Phone: 61.2.95656156; Fax: 61.2.95656101; E-mail:

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AUTOIMMUNITY: A new view of type 1 diabetes

Individuals develop type 1 diabetes when their immune system attacks and destroys cells in their pancreas that produce the hormone insulin. A major obstacle to advances in understanding, preventing, and curing type 1 diabetes has been the inability to "see" the disease initiate, progress, or regress, especially during the very early phases of the disease. However, Diane Mathis, Ralph Weissleder, and colleagues, at Harvard Medical School, Boston, have now developed a way to noninvasively image pancreatic islets (the regions of the pancreas that house the cells that produce insulin) and defined certain events that allowed them to distinguish patients recently diagnosed with diabetes from healthy individuals. They hope that their approach can be exploited to follow the progression of type 1 diabetes and to monitor the ability of different therapeutic agents to clear early stage disease.

TITLE: Noninvasive imaging of pancreatic islet inflammation in type 1A diabetes patients

Diane Mathis
Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617.432.7742; Fax: 617.432.7744; E-mail:

Ralph Weissleder
Massachusetts General Hospital, Boston, Massachusetts, USA.
Phone: 617.726.8226; Fax: 617.726.5708; E-mail:

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METABOLIC DISEASE: Warming up to brown fat

Fat is divided into two types: the white adipose (WAT), which stores energy, and the brown adipose (BAT), which burns energy to generate heat. WAT can be further divided into the layer under the skin (subcutaneous) and intra-abdominal (visceral) deposits. Excess visceral WAT is associated with increased risk of diseases such as diabetes and heart disease, but excess subcutaneous WAT is not. In addition, brown-like cells can appear within WAT during adaptation to cold and in response to anti-diabetic drugs. These cells are thought to increase heat production at the expense of energy storage, and mice with more brown-like cells are resistant to diet-induced obesity. Although the genes that control BAT and WAT generation have been described, it is not known what genes are required for "brown-like" cells to form.

In collaborative work from researchers at the University of Pennsylvania and the Dana-Farber Cancer Institute, Patrick Seale, Bruce Spiegelman, and colleagues investigated the molecular mechanisms that give rise to these brown-like cells. They found that Prdm16, a gene known to promote BAT development, was expressed in sub-cutaneous but not visceral WAT. Mice engineered to over-express Prdm16 in fat tissue had increased brown-like cell accumulation, and had reduced weight gain when placed on a high fat-diet. The researchers believe that these results show that Prdm16 is a critical factor for brown-like cell development, and that controlling its expression in subcutaneous WAT may be a promising therapeutic strategy in fighting obesity and diabetes.

TITLE: Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice

Patrick Seale
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: 215.573.8856 Fax: 215.898.5408; E-mail:

Bruce M. Spiegelman
Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Phone: 617.632.3567; Fax: 617.632.5363; E-mail:

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ONCOLOGY: New insights into Wilms tumor

Wilms tumor is a childhood kidney tumor. Many different genetic alterations have been identified in Wilms tumors, with some tumors having one detectable genetic alteration and others having multiple. How individual or combinations of genetic alterations cause tumors to arise has been difficult to determine because there is no mouse model of the condition. However, Vicki Huff and colleagues, at the University of Texas M.D. Anderson Cancer Center, Houston, have now generated a mouse model of the subset of Wilms tumors in which the WT1 gene is inactivated and the IGF2 gene is expressed at higher than normal levels. Increased activity of the signaling molecules ERK1/2 was observed in these mice, leading the authors to look at this in human Wilms tumor. As increased ERK1/2 activity was also observed in some human Wilms tumors, the authors suggest that their new mouse model of Wilms tumor will provide a useful tool to study the initiation and progression of Wilms tumor and to investigate potential new therapeutic strategies.

TITLE: Wt1 ablation and Igf2 upregulation in mice result in Wilms tumors with elevated ERK1/2 phosphorylation

Vicki Huff
University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
Phone: 713.834.6384; Fax: 713.834.6380; E-mail:

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ENDOCRINOLOGY: Hormone deficiency is the pits

The pituitary is a gland at the base of the brain that produces a number of hormones that regulate growth, reproduction, and metabolism. PIT-1 is a gene that controls the expression of many of those hormones, including growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH). Human mutations in PIT-1 are linked to short stature and multiple hormone deficiency. In new research, Yukaka Takahashi and colleagues at Kobe University Graduate School of Medicine in Kobe, Japan, investigated several patients who exhibited normal growth but adult-onset deficiency of GH, PRL, and TSH. They found that although these patients did not have mutations in PIT-1, each had PIT-1specific antibodies in their blood. The researchers believe that these patients suffer from a unique autoimmune disorder that results in the immune system attacking PIT-1expressing cells in the pituitary.

TITLE: Adult combined GH, prolactin, and TSH deficiency associated with circulating PIT-1 antibody in humans

Yutaka Takahashi
Kobe University Graduate School of Medicine, Kobe, Japan.
Phone: 81.78.382.5861; Fax: 81.78.382.2080; E-mail:

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ONCOLOGY: From failed DNA repair, to altered energy generation, to tumor cell

Individuals with the genetic disorder xeroderma pigmentosum are extremely sensitive to light from the sun and have an increased risk of developing skin cancer. In a subset of individuals, the condition is caused by mutations in the XPC gene, which generates a protein known to be important in repairing damaged DNA. A team of researchers led by David Bickers, at Columbia University, New York, and Hamid Reza Rezvani, at INSERM U876, France have now provided new insight into how loss of XPC might lead to the formation of skin cancer in patients with xeroderma pigmentosum.

In the study, knocking down levels of XPC in human skin cells (keratinocytes) generated cells capable of causing skin cancer when injected into mice. Analysis of the cells showed that XPC knockdown led to the accumulation of damaged DNA. This, in turn, changed the way in which the keratinocytes generated energy such that they used the same energy-generating pathways used by cancer cells. This led to increased production of damaging molecules known as ROS, the gradual accumulation of mutations in mitochondrial DNA, and the formation of a tumor cell. These data delineate a new pathway by which mutations in a DNA repair gene can lead to tumor formation via effects on cellular energy generation.

TITLE: XPC silencing in normal human keratinocytes triggers metabolic alterations that drive the formation of squamous cell carcinomas

David R. Bickers
College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Phone: 212.305.5565; Fax: 212.851.4540; E-mail:

Hamid Reza Rezvani
INSERM U876, Bordeaux, F-33000 France.
Phone: 33.557.571.373; Fax: 33.556.983.348; E-mail:

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HEMATOLOGY: A tale of unwanted blood clots

Antiphospholipid syndrome is a medical condition that causes blood clots to form within the arteries and veins, causing blockages that can damage tissues and organs. The blood clots are triggered by immune molecules known as antibodies. Specifically, antibodies that recognize proteins in the blood rather than invading microbes. Exactly how these antibodies trigger blood clot formation, is, however, not clear. But now, a team of researchers, led by Chieko Mineo, at the University of Texas Southwestern Medical Center, Dallas, has identified in mice a molecular pathway by which a subset of antibodies that cause antiphospholipid syndrome trigger blood clot formation. The team suggests that targeting this pathway might provide insight into new approaches for developing treatments for individuals with antiphospholipid syndrome.

TITLE: Antiphospholipid antibodies promote leukocyteendothelial cell adhesion and thrombosis in mice by antagonizing eNOS via beta-2GPI and apoER2

Chieko Mineo
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: 214.648.2015; Fax: 214.648.2098; E-mail:

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HEPATOLOGY: The proteins FXR and SHP work together to regulate bile acid levels

Bile acids, which are made in the liver, are involved in numerous biological processes, including digestion of fats, liver regeneration, and energy expenditure. Levels of bile acid are tightly regulated by a feedback loop. Current models place the protein FXR upstream of SHP in a linear pathway within this feedback loop. Now, a team of researchers, led by David Moore, at Baylor College of Medicine, Houston, has shown that in mice FXR and SHP act in parallel within the feedback loop that regulates bile acid levels. Of particular interest was the observation that mice lacking both FXR and SHP showed substantially more severe defects in regulation of bile acid levels than did mice lacking either of the proteins alone. Furthermore, as mice lacking both FXR and SHP developed cholestasis (the accumulation of bile acids in the liver) and liver injury at just 3 weeks of age, the authors suggest that these animals could provide a model for juvenile onset cholestasis, a term that encompasses several genetic diseases including progressive familial intrahepatic cholestasis.

TITLE: Combined deletion of Fxr and Shp in mice induces Cyp17a1 and results in juvenile onset cholestasis

David D. Moore
Baylor College of Medicine, Houston, Texas, USA.
Phone: 713.798.3313; Fax: 713.798.3017; E-mail:

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HEPATOLOGY: Uncovering the in vivo function of the protein Fbxw7 in the liver

Uncovering the in vivo function of the protein Fbxw7 has been difficult because mice lacking Fbxw7 die in utero. However, by selectively deleting Fbxw7 in mouse liver cells, a team of researchers, led by Keiichi Nakayama, at Kyushu University, Japan, has now determined that Fbxw7 has key roles in the liver, where it regulates the formation of lipids (fats) and the proliferation and differentiation of liver cells.

The team used two approaches to delete the gene responsible for generating Fbxw7 specifically in mouse liver cells. The resulting mice had massively enlarged livers and developed steatohepatitis (inflammation of the liver accompanied by fat accumulation in the same organ). Additional analysis indicated that the enlarged liver was associated with markedly increased cell proliferation and that Fbxw7-deficient liver stem cells were skewed to become bile duct cells rather than liver cells. The authors therefore conclude that Fbxw7 contributes to distinct biological functions in a tissue-specific manner.

TITLE: Fbxw7 regulates lipid metabolism and cell fate decisions in the mouse liver

Keiichi I. Nakayama
Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Phone: 81.92.642.6815; Fax: 81.92.642.6819; E-mail:

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Contact: Karen Honey
Journal of Clinical Investigation

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