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

A team of researchers, led by Yizheng Wang, at the Chinese Academy of Sciences, China, has identified a way to preserve nerve cells in a rat model of stroke.

Stroke is most commonly caused by impaired delivery of oxygen to part of the brain as a result of disruption to the blood supply (a condition known as ischemia). This leads to nerve cell death, although the exact mechanisms underlying ischemic nerve cell death have not been clearly determined. Yang and colleagues, set out to test in rats the idea that disruption to pathways involved in protecting nerve cells from death contributes to nerve cell death in stroke and generated data consistent with this idea. Specifically, they found that degradation of the protein TRPC6 preceded nerve cell death in the rat model of stroke and that suppressing TRPC6 degradation prevented nerve cell death and subsequent brain damage. The authors therefore suggest that preventing TRPC6 degradation could be a way to limit nerve cell death after stroke.

TITLE: Inhibition of TRPC6 degradation suppresses ischemic brain damage in rats

AUTHOR CONTACT:
Yizheng Wang
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Phone: 86.21.5492.1793; Fax: 86.21.5492.1735; E-mail: yzwang@ion.ac.cn.

View this article at: http://www.jci.org/articles/view/43165?key=da4fd780e07be0ce5d1d

Malaria kills more than 1 million individuals each year. Despite intensive research, there is still no malaria vaccine approved for use. A team of researchers, led by Moriya Tsuji, at the Aaron Diamond AIDS Research Center, New York, has now designed a new vaccine that provides protection from malaria in mice. The team hopes its approach to vaccine design will help in the future development of a malaria vaccine.

One way to design a malaria vaccine is to use a modified virus to deliver immune-stimulating malaria proteins to the body. Adenovirus is considered an ideal virus for this. However, adenovirus-based vaccines tend to induce only weak antibody-mediated immune responses and many individuals harbor immune molecules that neutralize the adenovirus delivery vehicle, thereby dampening immune responses to the proteins it carries. The authors modified an adenovirus carrying a malaria protein such that it also contained a fragment of a malaria protein that would induce a strong antibody immune response in place of the adenovirus protein that is most targeted by neutralizing immune responses. This modified adenovirus induced a substantially increased level of protection against malaria in mice, indicating that it is an improvement on the old adenovirus vaccine candidate.

TITLE: Replacing adenoviral vector HVR1 with a malaria B cell epitope improves immunogenicity and circumvents preexisting immunity to adenovirus in mice

AUTHOR CONTACT:
Moriya Tsuji
Aaron Diamond AIDS Research Center, New York, New York, USA.
Phone: 212.448.5021; Fax: 212.725.1126; E-mail: mtsuji@adarc.org.

View this article at: http://www.jci.org/articles/view/39812?key=ad717d6f517985a0f625

For many different types of cancer, including testicular cancer, platinum-based chemotherapeutic drugs such as cisplatin are the treatment of choice. Although such treatments are often effective, a sizeable fraction of patients eventually relapse with disease that is resistant to these drugs. Understanding the mechanisms of resistance might provide clues as to how to overcome this problem. A team of researchers, led by Steven de Jong, at the University of Groningen, The Netherlands, has now determined that high levels of expression of the protein p21 in the cytoplasm of tumor cells are a determinant of cisplatin-resistance in human testicular cancer cells known as testicular embryonal carcinoma cells. The team therefore suggests that targeting p21 in the cytoplasm might provide a way to treat testicular cancer that is resistant to platinum-based chemotherapeutics.

TITLE: Cytoplasmic p21 expression levels determine cisplatin resistance in human testicular cancer

AUTHOR CONTACT:
Steven de Jong
University Medical Center Groningen, Groningen, The Netherlands.
Phone: 31.0.50.3612964; Fax: 31.0.50.3614862; E-mail: s.de.jong@int.umcg.nl.

View this article at: http://www.jci.org/articles/view/41939?key=df301cc16f1792b9f7fa

Individuals who have mutations in one of their two PDX1 genes are highly likely to develop diabetes. Understanding how levels of PDX1 are regulated is therefore of intense interest in the study and treatment of diabetes. A team of researchers, led by Doris Stoffers, at the University of Pennsylvania School of Medicine, Philadelphia, has now determined that the protein Pcif1 has a key role in regulating Pdx1 protein levels in mice. Specifically, Pcif1 was found to target Pdx1 for degradation. Interestingly, the signs of diabetes observed in mice lacking one Pdx1 gene were absent if one Pcif1 gene was also deleted, because Pdx1 protein levels became normalized. These data, which provide new insight into the regulation of Pdx1 protein levels, lead the authors to suggest that targeting PCIF1-mediated degradation of PDX1 could provide a way to treat diabetes.

TITLE: Pcif1 modulates Pdx1 protein stability and pancreatic beta cell function and survival 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 this article at: http://www.jci.org/articles/view/40440?key=5dd89705ebc349a1a8bf

Individuals with mutations in genes that generate proteins that make up the contractile unit of muscles (including heart muscle) can develop hypertrophic cardiomyopathy, a condition that causes the heart muscle to thicken, predisposing patients to heart failure. One characteristic of the thickened heart muscle in individuals with hypertrophic cardiomyopathy is scar tissue, which forms by a process known as fibrosis. A team of researchers, led by Jonathan Seidman, at Harvard Medical School, Boston, has now determined that the soluble factor Tgf-beta has a central role in the fibrosis that occurs in the hearts of mice with a disease that models hypertrophic cardiomyopathy. The team therefore suggests that preemptively treating individuals with the genetic mutations that can lead to hypertrophic cardiomyopathy with TGF-beta inhibitors might be warranted.

TITLE: Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-beta

AUTHOR CONTACT:
Jonathan G. Seidman
Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617.432.7871; Fax: 617.432.7832; E-mail: seidman@genetics.med.harvard.edu.

View this article at: http://www.jci.org/articles/view/42028?key=abc50d0de674281463f1

Key to the immune system responding to invading microbes is a group of proteins known as TLRs. These proteins trigger immune responses when they detect the presence of microbial products. Each TLR recognizes a distinct set of microbial products. As triggers of mouse TLR8 have not been identified, it has been suggested that it is inactive. However, a team of researchers, led by Lena Alexopoulou, at Centre d'Immunologie de Marseille-Luminy, France, has now determined that mouse TLR8 has a role in preventing the immune system attacking the body, that is, in preventing autoimmunity.

In the study, mice lacking TLR8 were found to have signs of the autoimmune disease lupus. This was associated with increased levels of TLR7 on immune cells known as dendritic cells and with increased responsiveness to molecules that trigger TLR7. The authors therefore conclude that mouse TLR8 has an important role in limiting TLR7 expression and that this is crucial for preventing the development of lupus-like autoimmunity.

TITLE: TLR8 deficiency leads to autoimmunity in mice

AUTHOR CONTACT:
Lena Alexopoulou
Centre d'Immunologie de Marseille-Luminy, Université de la Méditerranée, Marseille, France.
Phone: 33.491.269199; Fax: 33.491.269430; E-mail: alexopoulou@ciml.univ-mrs.fr.

View this article at: http://www.jci.org/articles/view/42081?key=cb8bf48e147d2e5aa6ec

Inflammatory mediators such as the complement system that are key to host defense against microbes must be suppressed in the absence of invading microbes so that they do not cause unwanted tissue damage. Indeed, dysfunction of proteins that negatively regulate the alternative pathway of complement activation has been linked to several human inflammatory disorders. Wen-Chao Song and colleagues, at the University of Pennsylvania School of Medicine, Philadelphia, have now determined that the protein properdin has a key role in tissue injury caused by alternative pathway complement activation in mice. For example, properdin deficiency reduced the severity of disease in a mouse model of arthritis. The authors therefore suggest that targeting properdin could be a way to treat human inflammatory diseases caused by alternative pathway complement activation.

TITLE: Genetic and therapeutic targeting of properdin in mice prevents complement-mediated tissue injury

AUTHOR CONTACT:
Wen-Chao Song
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: 215.573.6641; Fax: 215.746.8941; E-mail: songwe@upenn.edu.

View this article at: http://www.jci.org/articles/view/41782?key=586c429ae17e0189f66f