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PUBLIC RELEASE DATE:
1-Jun-2009

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Contact: Karen Honey
press_releases@the-jci.org
215-573-1850
Journal of Clinical Investigation
@jclinicalinvest

JCI online early table of contents: June 1, 2009

EDITOR'S PICK: The immune response to influenza virus isn't 'all good'

Complications following infection with the virus that causes flu (influenza virus) are one of the top ten causes of death in the United States. Although infection with influenza virus can directly cause death, many deaths following infection with influenza virus occur because the individual develops pneumonia due to secondary infection with bacteria such as Streptococcus pneumoniae. How influenza makes individuals more sensitive to pneumonia-causing secondary bacterial infections is not well understood. However, Jane Deng and colleagues, at the University of California, Los Angeles, have now determined, through studies in mice, one mechanism by which influenza might sensitize individuals to secondary bacterial pneumonia.

In the study, it was found that molecules known as type I IFNs, which are key mediators of the antiviral immune response initiated by infection with influenza virus, impaired the ability of mice to mount an adequate immune response to subsequent pneumonia-causing bacterial infection. In particular, the type I IFNs decreased production of soluble factors that attract neutrophils, immune cells central to the initial antibacterial immune response, to sites of bacterial infection. The authors therefore suggest that the pathway uncovered in their study might provide a new avenue of research for those developing ways to combat pneumonia following infection with influenza virus.

TITLE: Type I IFNs mediate development of postinfluenza bacterial pneumonia in mice

AUTHOR CONTACT:
Jane C. Deng
David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
Phone: (310) 983-3446; Fax: (310) 206-8622; E-mail: jdeng@mednet.ucla.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35412


EDITOR'S PICK: Enhancing the effects of platinum-based anticancer drugs

Daqing Li and colleagues, at the University of Pennsylvania School of Medicine, Philadelphia, have identified in vitro and in mice a way to enhance the anticancer effects of the commonly used platinum-based drug cisplatin.

For many forms of cancer, including testicular, ovarian, and lung cancer, platinum-based drugs that cause DNA damage are the first choice treatment. However, the utility of these drugs is often limited by the enhanced ability of cancer cells to repair their DNA. As the MRN protein complex, which contains the protein RAD50, has a key role in the molecular pathways that control DNA repair in human cells, Li and colleagues set out to test the hypothesis that attenuating the function of the MRN protein complex might sensitize cancer cells to the effects of cisplatin. The hypothesis was proven using a genetic approach to disrupt MRN function. Specifically, human squamous cell carcinoma cells resistant to the toxic effects of cisplatin became sensitive to the drug when it was combined with an adenoviral vector that drove expression of a dominant-negative RAD50 protein in the cancer cells. Importantly, the combination therapy had potent anti-cancer cell effects in vitro and in mice transplanted with human squamous cell carcinoma cells resistant to cisplatin. The authors therefore hope that it might be possible to develop a clinical strategy to attenuate MRN function and enhance the anticancer effects of platinum-based drugs.

TITLE: Molecular disruption of RAD50 sensitizes human tumor cells to cisplatin-based chemotherapy

AUTHOR CONTACT:
Daqing Li
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: (215) 615-0854; Fax: (215) 573-1934; E-mail: lidaqing@mail.med.upenn.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33816


IMMUNOLOGY: Chronic prostatitis is an autoimmune condition

Chronic prostatitis/chronic pelvic pain syndrome is a common disease that causes pelvic pain in men. The cause of chronic prostatitis is unknown and there are no specific treatments for the condition. However, insight into the cause of chronic prostatitis has now been provided by Lawrence Fong and colleagues, at UCSF, San Francisco, who have determined that it is an autoimmune disease.

In this study, the researchers initially analyzed mice lacking the protein Aire because they develop spontaneous prostatitis. These mice were found to mount an immune response, mediated by cells known as B and T cells, that was directed toward the prostate protein SVS2. The importance of this immune response was highlighted by the observation that normal mice injected with SVS2 developed prostatitis. Of clinical relevance, immune molecules (specifically antibodies) that target the human SVS2-like seminal vesicle protein semenogelin were detected in patients with chronic prostatitis. The authors hope that defining chronic prostatitis as an autoimmune disease and semenogelin as the target of the immune system might provide new approaches to the diagnosis and treatment of the condition.

TITLE: An aberrant prostate antigen-specific immune response causes prostatitis in mice and is associated with chronic prostatitis in humans

AUTHOR CONTACT:
Lawrence Fong
University of California, at San Francisco, San Francisco, California, USA.
Phone: (415) 514-3160; Fax: (415) 514-3165; E-mail: lfong@medicine.ucsf.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=38332


PULMONARY: New pathway underlying pulmonary hypertension

Pulmonary hypertension is an unremitting disease caused by a progressive increase in blood pressure in the blood vessels of the lung; it leads to heart failure and ultimately death. Currently there are limited treatment options. However, You-Yang Zhao and colleagues, at the University of Illinois College of Medicine, Chicago, have identified in mice a new molecular pathway underlying pulmonary hypertension that they hope might provide novel therapeutic targets.

In the study, mice lacking either caveolin 1, eNOS, or both proteins were used to determine that chronic eNOS activation, secondary to loss of caveolin-1, can lead to pulmonary hypertension. Further analysis revealed that the chronic eNOS activation that induced pulmonary hypertension was associated with impaired activity of the protein PKG because it was modified by a process known as nitration. As lung tissue from patients with a form of pulmonary hypertension known as idiopathic pulmonary arterial hypertension exhibited evidence of increased eNOS activation and PKG nitration and reduced caveolin-1 expression, the authors suggest that preventing and/or reversing PKG nitration might be of benefit to individuals with idiopathic pulmonary arterial hypertension.

TITLE: Persistent eNOS activation secondary to caveolin-1 deficiency induces pulmonary hypertension in mice and humans through PKG nitration

AUTHOR CONTACT:
You-Yang Zhao
University of Illinois College of Medicine, Chicago, Illinois, USA.
Phone: (312) 355-0238; Fax: (312) 996-1225; E-mail: yyzhao@uic.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33338


VASCULAR BIOLOGY: New function for the peptides ANP and BNP

Michaela Kuhn and colleagues, at the University of Würzburg, Germany, have identified in mice a new function for the molecules ANP and BNP: they help coordinate the formation of new blood vessels following tissue stress.

In the heart, ANP and BNP have a role in regulating blood pressure and volume. In the study, the researchers analyzed mice lacking the molecule to which ANP and BNP bind (GC-A) in every cell, in endothelial cells, or in smooth muscle cells. The formation of new blood vessels in a hind leg muscle stressed after its blood supply was experimentally restricted was severely impaired in both mice lacking GC-A in all cells and mice lacking GC-A in endothelial cells, but it was normal in mice lacking GC-A in smooth muscle cells. A similar reduction in the formation of new blood vessels was observed in the heart of mice lacking GC-A in endothelial cells after being exposed to the stress of high blood pressure. As BNP expression was increased in hind leg muscle and heart muscle under these stress conditions, the authors suggest that BNP acts on endothelial cells to regulate blood vessel formation.

TITLE: The natriuretic peptide/guanylyl cyclase-A system functions as a stress-responsive regulator of angiogenesis in mice

AUTHOR CONTACT:
Michaela Kuhn
Physiologisches Institut der Universität Würzburg, Würzburg, Germany.
Phone: 49-931-31-2721; Fax: 49-931-31-2741; E-mail: michaela.kuhn@mail.uni-wuerzburg.de.

View the PDF of this article at: https://www.the-jci.org/article.php?id=37430


METABOLIC DISEASE: Developing insulin-producing cells

Underlying the progression of both type 1 and type 2 diabetes is decreased levels of the hormone insulin. This insulin defect is due to decreased numbers of beta-cells in the pancreas, suggesting that beta-cell replacement therapies might be of clinical benefit. Understanding how beta-cells develop is of prime importance for developing such approaches. New insight into this has now been provided by Doris Stoffers and colleagues, at the University of Pennsylvania School of Medicine, Philadelphia, who have discerned the molecular mechanism by which the protein Pdx1 governs early embryonic development of the mouse pancreas. The information obtained from this study is likely to help determine the requirements for manipulating multipotent cells to generate insulin-producing beta-cells. In addition, these data suggest a mechanism to explain why mutations in one of an individual's two copies of the PDX1 gene are associated with both type 2 diabetes and an inherited form of diabetes known as MODY4.

TITLE: The diabetes gene Pdx1 regulates the transcriptional network of pancreatic endocrine progenitor cells in mice

AUTHOR CONTACT:
Doris A. Stoffers
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: (215) 573-5413; Fax: (215) 898-5408; E-mail: stoffers@mail.med.upenn.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=37028

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