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JCI online early table of contents: May 9, 2011

EDITOR'S PICK: Sensitizing prostate cancer to radiotherapy

Men with prostate cancer whose disease has spread locally from inside the prostate to immediately outside it are primarily treated with radiation therapy. However, disease recurs in approximately half of these individuals. Strategies to enhance the efficacy of this treatment and thereby decrease the incidence of disease recurrence are clearly needed. Shawn Lupold and colleagues, at Johns Hopkins University School of Medicine, Baltimore, have now developed an approach that enhances the therapeutic effects of radiation therapy in mice bearing human prostate cancer xenografts. Specifically, they selectively sensitized the prostate cancer cells to radiation therapy by knocking down expression of the gene responsible for making the protein DNAPK, which is important for repairing damaged DNA. Lupold and colleagues hope that this approach can be developed for the treatment of locally advanced prostate cancer.

TITLE: Prostate-targeted radiosensitization via aptamer-shRNA chimeras in human tumor xenografts

Shawn E. Lupold
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Phone: 410.502.4822; Fax: 410.502.7711; E-mail:

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EDITOR'S PICK: Reducing the side effects of a multiple sclerosis drug

The drug FTY720 is approved for the treatment of multiple sclerosis. Although highly effective it can have serious side effects, including reduced lung function and fluid accumulation in the eye. Understanding the multiple molecular mechanisms by which the drug affects its target (the S1P receptor) could lead to the development of a drug with the same therapeutic efficacy but reduced side effects. In this context, a team of researchers, led by Timothy Hla, at Weill Cornell Medical College, New York, has now detailed the molecular mechanism by which FTY270 causes adverse effects in the lungs of mice.

Specifically, Hla and colleagues outlined a mechanism by which FTY270 causes S1P receptor degradation on the cells lining the blood vessels of the lungs and found that this reduction in S1P receptor levels causes leakage of the blood vessel contents into the lungs, impairing lung function. In contrast, S1P receptor degradation appears not to be required for the effects of FTY720 on immune cells, which are the effects that mediate its therapeutic efficacy. Hla and colleagues therefore suggest that developing a drug that does not act on S1P receptor on the cells lining the blood vessels of the lungs but does target S1P receptor on immune cells may provide a therapeutic with decreased side effects.

TITLE: Engagement of S1P1-degradative mechanisms leads to vascular leak in mice

Timothy Hla
Weill Cornell Medical College, Cornell University, New York, New York, USA.
Phone: 212.746.9953; Fax: 212.746.2830; E-mail:

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VIROLOGY: Stability critical to immune-stimulating capacity

Key to the success of vaccines that provide protection from infection with viruses is their ability to stimulate immune cells known as CD8+ T cells. By analyzing protein fragments (peptides) derived from HIV, a team of researchers, led by Sylvie Le Gall, at Harvard Medical School, Boston, has now generated data that suggest new ways to modify the CD8+ T cellstimulating components of a vaccine such that they trigger a more effective protective response.

CD8+ T cells are stimulated to respond to an invading virus when they see viral peptides bound to a cell surface protein complex known as MHC-I. The team analyzed the repertoire of HIV-derived peptides inside primary human cells and found that they persisted for different lengths of time before being degraded (i.e., showed different levels of stability). The sequence of the peptide determined its stability and this in turn determined how effectively it stimulated CD8+ T cells. Further analysis identified ways to modulate the stability of a peptide such that it enhanced CD8+ T cellrecognition and activity, providing a potential new approach to designing the CD8+ T cellstimulating components of a vaccine.

TITLE: Variable HIV peptide stability in human cytosol is critical to epitope presentation and immune escape

Sylvie Le Gall
Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617.726.1406; Fax: 617.726.5411; E-mail:

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TUMOR IMMUNOLOGY: Immune cells in tumors too exhausted to work

Immune cells known as CD8+ T cells are key components of the antitumor immune response. A team of researchers, led by Daniel Speiser, at the Ludwig Institute for Cancer Research, Lausanne, Switzerland, has now generated a gene expression profile of CD8+ T cells in the blood of patients with melanoma (the most dangerous form of skin cancer) and CD8+ T cells in the distant tumors of individuals with melanoma. Surprisingly, the cells in the blood have the characteristics of functional effector cells, whereas the cells in the tumors have the characteristics of exhausted cells that are functionally impaired. The molecular mechanisms underlying the functional impairment of the exhausted CD8+ T cells could provide new targets for anticancer therapies.

TITLE: Exhaustion of tumor-specific CD8+ T cells in metastases from melanoma patients

Daniel E. Speiser
Ludwig Institute for Cancer Research, Lausanne, Switzerland.
Phone: 41.21.314.0182; Fax: 41.21.314.7477; E-mail:

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CARDIOLOGY: The protein JMJD2A reprograms the heart for failure

Heart failure is a leading cause of death in Western countries. It is often preceded by a condition known as cardiac hypertrophy (thickening of the walls of the heart). Cardiac hypertrophy and heart failure are accompanied by a change in the genes expressed in the heart muscle cells and it is thought that understanding the mechanisms underlying this genetic reprogramming could provide new targets for drugs to treat these conditions. In this context, a team of researchers, led by Zhi-Ping Liu, at the University of Texas Southwestern Medical Center, Dallas, has now found that the protein JMJD2A promotes the genetic reprogramming that supports cardiac hypertrophy in mouse models of the human condition. Consistent with the mouse data, expression of JMJD2A was found to be upregulated in human patients with hypertrophic cardiomyopathy, leading the authors to suggest that the protein could be a potential target for drugs that treat cardiac hypertrophy and heart failure.

TITLE: The histone trimethyllysine demethylase JMJD2A promotes cardiac hypertrophy in response to hypertrophic stimuli in mice

Zhi-Ping Liu
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: 214.648.1485; Fax: 214.648.1450; E-mail:

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HIV/AIDS: Distinguishing progression to AIDS from nonprogression in HIV-1 infected individuals

The rate at which individuals infected with HIV-1 progress to AIDS differs dramatically: rapid progressors develop AIDS within 2𔃃 years of infection; typical progressors develop AIDS in approximately 10 years; while a small fraction of individuals remain asymptomatic despite high levels of virus being detectable in their blood. A team of researchers led by Javier Martinez-Picado, at the AIDS Research Institute, Barcelona, Spain, and Amalio Telenti, at University Hospital and University of Lausanne, Lausanne, Switzerland has now profiled the genes expressed differentially in individuals who progress rapidly to AIDS and those that remain asymptomatic in an attempt to understand more deeply the factors that determine progression to AIDS.

The team defined gene expression profiles characteristic of the two groups of patients and found that they were similar to those obtained from monkeys infected with SIV (the monkey equivalent of HIV) that do and do not develop AIDS-like disease. In addition, a short list of genes relevant to understanding progression to AIDS was identified. These data provide insight into two poorly understood clinical patterns of disease progression that have been minimally studied in the past. They also provide a springboard for future research, as they indicate that studying SIV infection of different species of monkey that do or do not develop AIDS-like disease provides a good model to understand HIV-1 progression to AIDS.

TITLE: Comparative transcriptomics of extreme phenotypes of human HIV-1 infection and SIV infection in sooty mangabey and rhesus macaque

Javier Martinez-Picado
AIDS Research Institute IrsiCaixa, Hospital Germans Trias i Pujol, Barcelona, Spain.
Phone: 34.93.4656374; Fax: 34.93.4653968; E-mail:

Amalio Telenti
Institute of Microbiology, University Hospital and University of Lausanne, Lausanne, Switzerland.
Phone: 41.79.556.0751; Fax: 41.21.314.4095; E-mail:

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METABOLIC DISEASE: Humans with rare genetic mutation point diabetes researchers in the right direction

The cells in the body of an individual with type 2 diabetes are resistant to the effects of the hormone insulin. A few individuals are born resistant to the effects of insulin as a result of mutations in their INSR gene, which templates the protein via which insulin mediates its effects. These individuals provide the unique opportunity to understand the relationship between features of type 2 diabetes and insulin resistance; that is, whether the insulin resistance or the given feature came first). For example, a longstanding question amongst diabetes researchers is whether mitochondrial dysfunction (i.e., dysfunction of the compartments of a cell that generate its energy) causes insulin resistance or vice versa. By studying individuals with INSR mutations, a team of researchers, led by David Savage, at the University of Cambridge, United Kingdom, have now answered this question: defects in insulin signaling can cause dysfunctional mitochondria (at least in these individuals). The team therefore concludes that it is likely that insulin resistance in individuals with type 2 diabetes can impair mitochondrial function.

TITLE: Mitochondrial dysfunction in patients with primary congenital insulin resistance

David B. Savage
University of Cambridge, Cambridge, United Kingdom.
Phone: 44.1223.767.923; Fax: 44.1223.330.598; E-mail:

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METABOLIC DISEASE: Clearing the wood from the trees on the function of growth hormone receptor on pancreatic beta-cells

Prior to an individual developing type 2 diabetes, the cells in their body stop responding efficiently to the hormone insulin (i.e., become insulin resistant). This causes a rise in the levels of the energy source glucose in the blood. This, in turn, acts on the insulin-producing cells of the body (pancreatic beta cells) causing them to increase in size and number so that more insulin is produced. Eventually insulin resistance overwhelms the ability of beta-cells to compensate in this way, and the individual becomes diabetic. A team of researchers, led by Derek LeRoith and Shoshana Yakar, at Mount Sinai School of Medicine, New York, has now determined that, in mice, beta-cell expression of the molecule to which growth hormone binds is important if the cells are to increase in number to compensate for conditions that promote type 2 diabetes. Expression of this molecule was also found to be important for glucose stimulation of insulin production. These data help dispel the controversy surrounding the function of growth hormone receptor on beta-cells by providing clear insight into its role on these cells.

TITLE: Growth hormone receptor regulates beta-cell hyperplasia and glucose-stimulated insulin secretion in obese mice

Derek LeRoith
Mount Sinai School of Medicine, New York, New York, USA.
Phone: 212.241.6306; Fax: 212.241.4218; E-mail:

Shoshana Yakar
Mount Sinai School of Medicine, New York, New York, USA.
Phone: 212.241.6306; Fax: 212.241.4218; E-mail:

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Contact: Karen Honey
Journal of Clinical Investigation

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