[ Back to EurekAlert! ] Public release date: 1-Dec-2009
[ | E-mail Share Share ]

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

JCI online early table of contents: Dec. 1, 2009

EDITOR'S PICK: High urea levels in chronic kidney failure might be toxic afterall

It is thought that the elevated levels of urea (the byproduct of protein breakdown that is excreted in the urine) in patients with end-stage kidney failure are not particularly toxic. However, a team of researchers, at Albert Einstein College of Medicine, New York, and Università degli Studi di Foggia, Italy, has now generated evidence in mice that high levels of urea are indeed toxic. They therefore suggest that blocking the effects of high levels of urea might benefit patients with end-stage kidney disease.

The team, led by Michael Brownlee and Ida Giardino, found that fat cells cultured in the presence of disease-relevant levels of urea produced toxic molecules known as reactive oxygen species (ROS). These caused the fat cells to take on characteristics of fat cells in patients with end-stage kidney disease (such as an inability to respond to the hormone insulin, which is also a key feature of type 2 diabetes). In a mouse model of end-stage kidney disease, increased ROS levels were detected, as was resistance to the effects of insulin. As treatment with an antioxidant (which will act to mop up the ROS) restored the ability of mice to respond to insulin, the authors suggest that drugs targeting ROS might help improve the quality of life and lifespan of individuals with end-stage kidney disease.

AUTHOR CONTACT:
Michael Brownlee
Albert Einstein College of Medicine, Bronx, New York, USA.
Phone: (718) 430-3636; Fax: (718) 430-8570; E-mail: brownlee@aecom.yu.edu.

Ida Giardino
Università degli Studi di Foggia, Foggia, Italy.
Phone: 39-0881-736006; Fax: 39-0881-733718; E-mail: ig@unifg.it.

View this article at: http://www.jci.org/articles/view/37672?key=0Qep53Rl8tUvugD0O2jY


EDITOR'S PICK: Human Mdm2: a new molecular link to late-stage metastatic breast cancer

A large proportion of late-stage breast cancers that have spread to other parts of the body (metastatic breast cancers) are characterized by overexpression of the protein Mdm2. Lindsey Mayo and colleagues, at Indiana University School of Medicine, Indianapolis, have now determined what drives this increased Mdm2 expression and found that Mdm2 helps promote cancer cells take on more aggressive characteristics, making it a potential target for drugs to treat late-stage metastatic breast cancer.

In the study, a signaling pathway triggered by the molecule TGF-beta-1 was found to increase Mdm2 expression in human cancer cell lines. Expression of activated molecules involved in this pathway correlated with Mdm2 expression in many late-stage breast cancer samples analyzed. The increased level of Mdm2 in the human cancer cell lines led to decreased expression of the key tumor suppressor p53. More importantly, it enabled the cells to gain the ability to move freely in vitro after exposure to TGF-beta-1 (a key feature of cells that cause metastatic tumors). As an antagonist of the effects of Mdm2 on p53 prevented TGF-beta-1 from enabling cells to move freely in culture, the authors suggest that targeting Mdm2 might help prevent progression of late-stage breast cancer.

TITLE: TGF-β1–induced expression of human Mdm2 correlates with late-stage metastatic breast cancer

AUTHOR CONTACT:
Lindsey D. Mayo
Indiana University School of Medicine, Indiana University Simon Cancer Center, Indianapolis, Indiana, USA.
Phone: (317) 278-3173; Fax: (317) 274-8046; E-mail: ldmayo@iupui.edu.

David A. Boothman
University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.
Phone: (214) 645-6371; Fax: (214) 645-6347; E-mail: David.Boothman@utsouthWestern.edu.

View this article at: http://www.jci.org/articles/view/39194?key=EC7lQbgq0ivAliJkn5z3


EDITOR'S PICK: Death-inducing proteins key to complications of bone marrow transplantation

Treatment for a number of cancers and other medical conditions is transplantation with bone marrow from a genetically nonidentical individual (a process known as allogeneic bone marrow transplantation [allo-BMT]). The treatment often causes an extended period of immune deficiency, resulting in susceptibility to infections and recurrence of cancers. Damage to the thymus (the part of the body where immune cells known as T cells develop) elicited by T cells from the donor bone marrow (a medical condition known as thymic GVHD [tGVHD]) contributes to the deficit in T cell immunity. Using mouse models of allo-BMT, Marcel van den Brink and colleagues, at Memorial Sloan-Kettering Cancer Center, New York, have now identified several of the molecules required by donor-derived T cells to mediate tGVHD, some of which might prove good drug targets to improve the outcome of allo-BMT.

In the study, one series of experiments determined that donor-derived T cells required the cell death–inducing proteins FasL and TRAIL to damage the thymus and mediate tGVHD. These molecules bound to the death receptors Fas and DR5, respectively, expression of which was upregulated on thymic cells by radiation, a key step in preparing for BMT. The results identifying Fas/FasL and TRAIL/DR5 interactions as critical to tGVHD induction led the authors to suggest that targeting these pathways may provide a way to attenuate tGVHD and improve T cell reconstitution in allo-BMT recipients.

TITLE: The cytolytic molecules Fas ligand and TRAIL are required for murine thymic graft-versus-host disease

AUTHOR CONTACT:
Marcel R.M. van den Brink
Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Phone: (646) 888-2304; Fax: (917) 432-2375; E-mail: vandenbm@mskcc.org.

View this article at: http://www.jci.org/articles/view/39395?key=vtxU3XV6azsy7m3y7tJn


METABOLIC DISEASE: Life in the Fas(t) lane: role for the protein Fas in obesity-associated type 2 diabetes?

Obesity is associated with inflammation of the excess fat tissue. It is thought that the effects of inflammation on excess fat cells in individuals who are obese contribute to the development of resistance to the hormone insulin, a condition that often progresses to type 2 diabetes. A team of researchers, led by Daniel Konrad, at University Children's Hospital, Switzerland, has now identified a protein in fat cells that has a key role in obesity-associated development of fat tissue inflammation and insulin resistance in mice. The authors therefore conclude that determining whether the protein, which is known as Fas, has a similar role in human fat cells is important. If it does, Fas might provide a new therapeutic target in the treatment of insulin resistance and type 2 diabetes.

TITLE: Deletion of Fas in adipocytes relieves adipose tissue inflammation and hepatic manifestations of obesity in mice

AUTHOR CONTACT:
Daniel Konrad
University Children's Hospital, Zurich, Switzerland.
Phone: 41-44-266-7966; Fax: 41-44-266-7983; E-mail: daniel.konrad@kispi.uzh.ch.

View this article at: http://www.jci.org/articles/view/38388?key=Mvy266BKXVSZ9c8MHgm1


METABOLIC DISEASE: The protein C/EBP-beta stresses out pancreatic beta-cells

A key event in the development of type 2 diabetes is failure of the beta-cells in the pancreas (the cells that produce the hormone insulin) to function normally. One aspect of this failure is a reduction in beta-cell mass. A cellular process known as ER stress is thought to contribute to beta-cell failure, largely through loss of beta-cell mass. A team of researchers, led by Masato Kasuga, at the International Medical Center of Japan, has now determined that the protein C/EBP-beta enhances susceptibility to ER stress and thereby contributes to β cell failure in mice. By identifying the molecular mechanism by which C/EBP-beta mediates these effects in mice, the authors have defined a molecular pathway that might underlie pancreatic failure in type 2 diabetes and that could be investigated as a therapeutic target for the prevention or treatment of type 2 diabetes.

TITLE: Ablation of C/EBP-beta alleviates ER stress and pancreatic beta-cell failure through the GRP78 chaperone in mice

AUTHOR CONTACT:
Masato Kasuga
Research Institute, International Medical Center of Japan, Tokyo, Japan.
Phone: 81-3-3202-7181; Fax: 81-3-5273-4526; E-mail: kasuga@ri.imcj.go.jp

View this article at: http://www.jci.org/articles/view/39721?key=BQ302fE1Jpgi01jPeguH


IMMUNOLOGY: Survival of the T cell: role for the protein CD27

If the immune system is to mount an effective response to a virus infection, cells known as CD8+ T cells must be activated, expanded, and maintained as killer cells. A team of researchers, led by Jannie Borst, at The Netherlands Cancer Institute, has identified a key role for stimulation of the protein CD27 on killer CD8+ T cells for sustaining their survival in virus-infected lung. Detailed analysis indicated that when CD27 on killer CD8+ T cells was stimulated, by binding to the protein CD70, the killer CD8+ T cells produced the immune molecule IL-2, which enabled them to survive. These data have implications for the development of vaccines against viruses.

TITLE: CD27 sustains survival of CTLs in virus-infected nonlymphoid tissue in mice by inducing autocrine IL-2 production.

AUTHOR CONTACT:
Jannie Borst
The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Phone: 31-20-5122056; Fax: 31-20-5122057; E-mail: j.borst@nki.nl.

View this article at: http://www.jci.org/articles/view/40178?key=oFjtxc06OX483cIW9mNR

###



[ Back to EurekAlert! ] [ | E-mail Share Share ]

 


AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.