JCI online early table of contents: Oct. 18, 2010

October 18, 2010

EDITOR'S PICK: The protein NOS2 isn't good for ER-negative breast cancer patients

Breast cancers can be divided into different subtypes based on several criteria, including whether or not they express the protein to which the female hormone estrogen binds; that is, the estrogen receptor (ER). Patients with ER-negative breast tumors have a worse outlook than those with ER-positive breast tumors. However, even among ER-negative breast tumors, those characterized as basal-like are the most aggressive and difficult to treat. New therapeutic targets for this subtype of breast cancer are urgently needed. Now, a team of researchers, led by Stefan Ambs, at the National Cancer Institute, Bethesda, report data that suggest that the protein NOS2 could be a good drug target in this context. The data, generated by analysis of human breast cancer samples and cell lines, lead the authors to conclude that high levels of NOS2 are a predictor of survival in patients with ER-negative breast tumors and to suggest that selective NOS2 inhibitors might be of benefit to these individuals.

TITLE: Increased NOS2 predicts poor survival in estrogen receptor-negative breast cancer patients

Stefan Ambs
National Cancer Institute, Bethesda, Maryland, USA.
Phone: 301.496.4668; Fax: 301.480.4676; E-mail: ambss@mail.nih.gov.

View this article at: http://www.jci.org/articles/view/42059?key=e19810fc296c1ecf1474

DERMATOLOGY: Blistering analysis reveals disease cause in autoimmune skin condition

Pemphigus is an autoimmune condition (i.e., it is caused by an individual's immune system turning on their own body) that can be fatal if left untreated. It is characterized by skin blisters, which arise because immune molecules in the body known as antibodies start targeting the desmoglein proteins that are key to maintaining the integrity of the skin.

A team of researchers, led by John Stanley, at the University of Pennsylvania, Philadelphia, set out to understand whether the antibodies that cause disease in different patients share any features that could ultimately be targeted by a specific therapy. Analysis of the disease-causing antibodies from 5 patients indicated that a region of these antibodies known as the H-CDR3 shared a similar amino-acid sequence (i.e., the protein building blocks making up this region of the antibody were similar). Importantly, changing the building blocks in H-CDR3 eliminated their ability to cause blistering in human skin organ cultures. Thus, the team suggests that targeting therapy to the H-CDR3 might reduce the ability of the pemphigus-causing antibodies to elicit disease.

TITLE: Homologous regions of autoantibody heavy chain complementarity-determining region 3 (H-CDR3) in patients with pemphigus cause pathogenicity

John R. Stanley
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: 215.898.3240; Fax: 215.573.2033; E-mail: jrstan@mail.med.upenn.edu.

View this article at: http://www.jci.org/articles/view/44425?key=cb0bebbcdf1456d7f6b4

CARDIOLOGY: Genetic inactivation fails to confirm role for microRNA-21 in heart failure

Persistent high blood pressure puts stress on the heart, which responds by remodeling its walls to withstand the extra pressure. This remodeling can lead to heart failure. It is hoped that identifying the key molecules that induce this remodeling will provide new therapeutic targets. Recent data suggest that a therapeutic (specifically an antagomir) that inhibits a molecule known as miR-21 alleviates remodeling and heart failure in a rodent model of high blood pressure. However, a team of researchers, led by Eric Olson, at the University of Texas Southwestern Medical Center at Dallas, and Eva van Rooij, at miRagen Therapeutics, Inc., Boulder, has now shown that genetic deletion of miR-21 does not have a similar effect -- mice lacking miR-21 showed the same heart remodeling in models of high blood pressure as did normal mice -- questioning its utility as a therapeutic target in this context.

miR-21 is a microRNA, i.e., it is a small RNA molecule with a potent ability to regulate protein expression. MicroRNAs can be inhibited quickly and easily using antagomirs, which are small inhibitory molecules that target a specific microRNA. They can also be genetically deleted. In an accompanying commentary, Edward Morrisey, at the University of Pennsylvania, discusses the distinct data obtained using the miR-21 antagomir and miR-21 genetic deletion and suggests that genetic inactivation should be the gold standard by which experiments using antagomirs are measured.

TITLE: Stress-dependent cardiac remodeling occurs in the absence of microRNA-21 in mice

Eric N. Olson
University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.
Phone: 214.648.1187; Fax: 214.648.1196; E-mail: eric.olson@utsouthwestern.edu.

Eva van Rooij,
miRagen Therapeutics, Inc., Boulder, Colorado, USA.
Phone: 303.531.5952; Fax: 303.531.5094; E-mail: evanrooij@miragenrx.com.

View this article at: http://www.jci.org/articles/view/43604?key=261b03f0a2e7850d746a

ACCOMPANYING COMMENTARY TITLE: The magic and mystery of miR-21

Edward E. Morrisey
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: 215.573.3010, Fax: 215.573.2094; E-mail: emorrise@mail.med.upenn.edu.

View this article at: http://www.jci.org/articles/view/44596?key=4304e5eea9ceffdf4e1b

HEMATOLOGY: Understanding treatment failure after bone marrow transplantation

Some forms of cancer are treated by transplantation with blood or bone marrow from a genetically non-identical individual (i.e., treated by allogeneic BMT). The idea behind this is that immune cells known as T cells, in particular CTLs, from the donor will attack and destroy the cancer. The main cause of treatment failure is tumor recurrence due to loss of functional donor CTLs that target the tumor. A team of researchers, led by Ronjon Chakraverty, at University College London, United Kingdom, has now identified two mechanisms by which loss of functional donor CTLs occurs in mouse models of allogeneic BMT. Furthermore, they identified a way to overcome one of these mechanisms -- disrupting interactions between the proteins PD-1 and PD-L1 -- such that donor CTL function was partially restored. They therefore suggest that these data define a potential approach to prevent or treat tumor recurrence following allogeneic BMT.

TITLE: Nonhematopoietic antigen blocks memory programming of alloreactive CD8+ T cells and drives their eventual exhaustion in mouse models of bone marrow transplantation

Ronjon Chakraverty
University College London, London, United Kingdom.
Phone: 44.207.317.7513; Fax: 44.207.830.2092; E-mail: r.chakraverty@medsch.ucl.ac.uk.

View this article at: http://www.jci.org/articles/view/41446?key=600b45fdb2c3f6f905ac

NEPHROLOGY: Slowing progression of chronic kidney disease

Chronic kidney disease is the ninth leading cause of death in the United States. It is the term given to the progressive loss of kidney function over many months or years culminating in end-stage renal disease, which requires treatment with dialysis or a kidney transplant. A team of researchers, led by Katalin Susztak, at Albert Einstein College of Medicine, New York, has now generated new data, by analysis of a mouse model of chronic kidney disease and kidney samples from patients with the condition, that lead them to suggest that inhibiting activation of the Notch signaling pathway might provide a way to reduce progression to end-stage renal disease.

TITLE: Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans

Katalin Susztak
Albert Einstein College of Medicine, New York, New York, USA.
Phone: 718.430.3498; Fax: 718.430.8963; E-mail: katalin.susztak@einstein.yu.edu.

View this article at: http://www.jci.org/articles/view/43025?key=57c3da7d127adbe6b9ab

HEPATOLOGY: Ameliorating scarring of the liver

Chronic liver damage, such as that caused by chronic infection with hepatitis C virus or by chronic alcohol abuse, leads to scarring of the liver tissue (a condition also known as liver fibrosis) and ultimately end-stage liver disease. A team of researchers, led by Hermann Wasmuth, at University Hospital Aachen, Germany, has now found a way to ameliorate experimental liver fibrosis in mice. Specifically, the team found that an antagonist of the proteins to which the molecule Ccl5 binds ameliorated liver fibrosis in two mouse models of the condition and was able to accelerate fibrosis regression. These results are likely to have clinical implications because in patients with liver fibrosis, high levels of CCL5 mRNA (the template from which CCL5 protein is made) in the liver were observed to be associated with severe disease.

TITLE: Antagonism of the chemokine Ccl5 ameliorates experimental liver fibrosis in mice

Hermann E. Wasmuth
University Hospital Aachen, Aachen, Germany.
Phone: 49.241.8080861; Fax: 49.241.8082455; E-mail: hwasmuth@ukaachen.de.

View this article at: http://www.jci.org/articles/view/41732?key=b3472a613a49bb57191a

CARDIOVASCULAR DISEASE: Role for the protein S1PR2 in hardening of the arteries

One of the major causes of heart attack and stroke is atherosclerosis -- a disease of the major arterial blood vessels that is sometimes known as hardening of the arteries. New data, generated in mice, by a team of researchers led by Yoh Takuwa and Yasuo Okamoto, at Kanazawa University, Japan, indicates that the protein S1PR2 is important in the development of atherosclerosis, leading the team to suggest that it might provide a new therapeutic target for this prevalent condition. Of critical importance to this conclusion and suggestion was the observation that mice lacking both S1PR2 and ApoE developed less atherosclerotic disease when fed a high fat diet than did mice lacking ApoE but expressing S1PR2 normally.

TITLE: Sphingosine-1-phosphate receptor-2 deficiency leads to inhibition of macrophage proinflammatory activities and atherosclerosis in apoE-deficient mice

Yoh Takuwa
Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan.
Phone:; Fax:; E-mail: ytakuwa@med.kanazawa-u.ac.jp.

Yasuo Okamoto
Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan.
Phone:; Fax:; E-mail: linakura@med.kanazawa-u.ac.jp.

View this article at: http://www.jci.org/articles/view/42315?key=93bbccb990881af23874

NEPHROLOGY: Understanding the mechanism of a classic experimental model of kidney disease

A team of researchers, led by Ali Gharavi, at Columbia University College of Physicians and Surgeons, New York, has provided new insight into the underlying mechanism of kidney injury in a classic experimental model of kidney disease.

Administration of Adriamycin, a chemotherapeutic drug commonly used in the treatment of a wide range of cancers, to certain mouse strains leads to the development of kidney disease. Susceptibility to kidney disease has been mapped to a specific region of mouse chromosome 16. In the study, Gharvi and colleagues were able to more finely map susceptibility to the Prkdc gene. Consistent with this, overexpression of Pkrdc in mouse kidney cells known as podocytes improved their survival after exposure to Adriamycin. Further analysis suggested that Pkrdc helps maintain mitochondrial DNA and that Prkdc might be a modifier gene in human mitochondrial DNA depletion syndromes.

TITLE: Prkdc participates in mitochondrial genome maintenance and prevents Adriamycin-induced nephropathy in mice

Ali G. Gharavi
Columbia University College of Physicians and Surgeons, New York, New York, USA.
Phone: 212.851.5556; Fax: 212.305.5520; E-mail: ag2239@columbia.edu.

View this article at: http://www.jci.org/articles/view/43721?key=2b5bd382a45e8bafe6c8

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