JCI online early table of contents: Dec. 27, 2011

December 27, 2011

EDITOR'S PICK
Another potential obstacle to developing an HIV vaccine

A clinical trial testing a candidate HIV vaccine known as the STEP study was halted in September 2007 after interim analysis indicated that the vaccine did not work. Moreover, subsequent analyses indicated that the vaccine made some individuals more susceptible to HIV, in particular individuals who had pre-existing immune effectors (antibodies) that recognized a component of the vaccine (adenovirus serotype 5 [Ad5]). A team of researchers led by Juliana McElrath, at the Fred Hutchinson Cancer Research Center, Seattle, has now determined that individuals from the STEP study in whom they could detect large numbers of immune cells (T cells) responsive to Ad5 generated a less robust immune response to HIV than those who had few Ad5-responsive T cells prior to vaccination. More worryingly, the Ad5-responsive T cells were found to also respond to other adenoviruses that are being considered as vaccine components in place of Ad5. This finding implies that vaccines based on adenoviruses other than Ad5 might not be effective in individuals with large numbers of Ad5-responsive T cells. As noted by McElrath and colleagues, this is something that will have to be carefully evaluated in any future clinical trial of any adenovirus-based vaccine, not just Ad5-based vaccines and not just adenovirus-based vaccines for HIV.

In an accompanying commentary, Nelson Michael, at the Walter Reed Army Institute of Research, Bethesda, expands on the implications of the work of McElrath and colleagues for HIV vaccine development.

TITLE: Human adenovirus-specific T cells modulate HIV-specific T cell responses to an Ad5-vectored HIV-1 vaccine

AUTHOR CONTACT:
Julie McElrath
Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Phone: 206 667-6704; E-mail: jmcelrat@fhcrc.org

ACCOMPANYING COMMENTARY

TITLE: Rare serotype adenoviral vectors for HIV vaccine development

AUTHOR CONTACT:
Nelson Michael
Walter Reed Army Institute of Research, Bethesda, MD, USA
Phone: 301-500-3601; E-mail: nmichael@hivresearch.org

EDITOR'S PICK
How obesity alters the brain area involved in body weight control

The number of people who suffer from one or more of the adverse complications of obesity, including type 2 diabetes and heart disease is rapidly increasing. Thus far, drugs designed to treat obesity have shown limited efficacy and have been associated with serious side effects. This is largely because we have limited understanding of the effects of obesity on our natural mechanisms of body weight control. For example, while great strides have been made in our understanding of how the brain controls our desire to feed, as well as the processes underlying the balancing of energy intake and expenditure, little is known about how the are altered by obesity. Two independent groups of researchers have now generated data that begin to address this issue.

In brief, a team of researchers led by Michael Schwartz, at the University of Washington, Seattle, has found that in both humans and rodents, obesity is associated with neuronal injury in an area of the brain crucial for body weight control (the hypothalamus). A second team of researchers, led by Jeffrey Flier, at Beth Israel Deaconess Medical Center, Boston, has determined that turnover of nerve cells in the hypothalamus is inhibited by obesity. Edward Lee and Rexford Ahima, at the University of Pennsylvania, Philadelphia, pull together these seemingly disparate strands of research in an accompanying commentary, highlighting the many questions that need to be answered before it can be determined whether targeting the structural changes in the hypothalamus could provide a treatment for obesity and related diseases.

TITLE: Remodeling of the arcuate nucleus energy-balance circuit is inhibited in obese mice

AUTHOR CONTACT:
Jeffrey Flier
Harvard Medical School, Boston, MA, USA
Phone: 617-432-1501; Fax: 617-432-3907; E-mail: jeffrey_flier@hms.harvard.edu

ACCOMPANYING ARTICLE

TITLE: Obesity is associated with hypothalamic injury in rodents and humans

AUTHOR CONTACT:
Michael W Schwartz
University of Washington, South Lake Union Campus, Seattle, WA, USA
Phone: 206-897-5288; Fax: 206 897 5293; E-mail: mschwart@u.washington.edu

ACCOMPANYING COMMENTARY

TITLE: Alteration of hypothalamic cellular dynamics in obesity

AUTHOR CONTACT:
Rexford S. Ahima
University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
Phone: 215-573-1872; E-mail: ahima@mail.med.upenn.edu

EDITOR'S PICK
Beneficial or not beneficial: that is the question for IL-1 inhibition in atherosclerosis

Atherosclerosis is a disease of the major arterial blood vessels. It is one of the major causes of heart attack and stroke. The proinflammatory molecule IL-1 has been linked to atherosclerosis and a clinical trial has been launched in which an antibody specific for IL-1-beta is being studied for its effects on the severe clinical complications of atherosclerosis (i.e., heart attack and stroke). However, a team of researchers led by Gary Owens, at the University of Virginia, Charlottesville, has now generated data in mice that raise potential concerns about this clinical trial -- Owens and colleagues find that IL-1 limits the features of advanced atherosclerosis that are linked to the severe complications of the disease in humans. In an accompanying commentary, Daniel Rader, at the University of Pennsylvania, Philadelphia, acknowledges that the data generated by Owens and colleagues could lead to concern about the clinical trial of the antibody specific for IL-1-beta but cautions that mice are not men and suggests that we need to wait for the results of the ongoing clinical trial.

TITLE: Genetic inactivation of IL-1 signaling enhances atherosclerotic plaque instability and reduces outward vessel remodeling in advanced atherosclerosis in mice

AUTHOR CONTACT:
Gary Owens
University of Virginia, Charlottesville, VA, USA
Phone: 434.924.2652; E-mail: gko@virginia.edu.

ACCOMPANYING COMMENTARY

TITLE: IL-1 and atherosclerosis: a murine twist to an evolving human story

AUTHOR CONTACT:
Daniel J. Rader
University of Pennsylvania Medical Center, Philadelphia, PA, USA
Phone: 215-898-4011; Fax: 215-573-8606; E-mail: rader@mail.med.upenn.edu

CARDIOLOGY
The protein TXNIP protects the heart

A heart attack occurs when the flow of blood to part of your heart muscle is blocked for long enough that some of the heart muscle is damaged. Prompt restoration of blood flow limits the size of the damaged area of heart muscle and reduces the patient's chance of dying. However, it also can cause additional damage to the heart muscle, a phenomenon referred to as ischemia-reperfusion (I-R) injury. There are currently no therapeutic approaches to effectively improve heart function after I-R injury. Emerging data suggest that the protein TXNIP could provide a new candidate therapeutic target, and clear rationale for this is now provided by the work of Richard Lee and colleagues, at Brigham and Women's Hospital, Boston. Of particular interest, Lee and colleagues found that mouse hearts lacking TXNIP showed greater recovery of function after I-R injury. Detailed analyses determined the mechanism underlying the beneficial effect of TXNIP deletion, and Bradford Berk and Oded Spindel highlight the importance of this in an accompanying commentary.

TITLE: Deletion of thioredoxin-interacting protein in mice impairs mitochondrial function but protects the myocardium from ischemia-reperfusion injury

AUTHOR CONTACT:
Richard Lee
Brigham and Women's Hospital, Boston, MA, USA
Phone: 617.768.8272; Fax: 617.768.8270; E-mail: rlee@partners.org

ACCOMPANYING COMMENTARY

TITLE: Redox redux: protecting the ischemic myocardium

AUTHOR CONTACT:
Bradford Berk
University of Rochester, Rochester, NY, USA
Phone: 585-276-9801; Fax: 585-276-9830; E-mail: Bradford_Berk@urmc.rochester.edu

ONCOLOGY
Stopping the HuR(t) of inflammation-induced cancer

Chronic inflammation has a critical role in the development of several forms of cancers. For example, inflammation of the lung as a result of smoking cigarettes is associated with lung cancer while inflammation of the intestine in individuals with inflammatory bowel diseases such as ulcerative colitis is associated with colon cancer. Defining the mechanisms responsible for regulating inflammation is important for identifying potential therapeutic targets for inflammation-associated cancers. In this context, a team of researchers led by Dimitris Kontoyiannis, at the Biomedical Sciences Research Center "Alexander Fleming," Greece, has now demonstrated in mice that expression of the protein HuR in myeloid cells provides protection against the onset of damaging intestinal inflammation (i.e., colitis) and colitis-associated cancer. Kontoyiannis and colleagues therefore suggest that strategies aimed at enhancing HuR activity in myeloid cells might have therapeutic benefit to individuals with pathologic inflammation and inflammation-associated cancer.

In an accompanying commentary, Charles Chalfant and Jacqueline Shultz, at Virginia Commonwealth University, Richmond, discuss both the clinical and biological implications of the data generated by Kontoyiannis and colleagues, highlighting the fact that we have much more to learn about the functions of HuR in distinct cell populations in vivo.

TITLE: Myeloid cell expression of the RNA-binding protein HuR protects mice from pathologic inflammation and colorectal carcinogenesi

AUTHOR CONTACT:
DIMITRIS KONTOYIANNIS
Biomedical Sciences Research Centre (BSRC) "Alexander FLEMING" Institute, Vari, Attiki, GRC
Phone: 0030210 9654335; Fax: 0030210 9654955; E-mail: kontoyiannis@fleming.gr

ACCOMPANYING COMMENTARY

TITLE: The flip-flop HuR: part of the problem or the solution in fighting cancer?


AUTHOR CONTACT: Charles Chalfant
Virginia Commonwealth University-School of Medicine, Richmond, VA, USA
Phone: 804-828-9526; E-mail: cechalfant@vcu.edu

NEPHROLOGY
Withstanding high pressure: a key role in the kidney for the protein CD151

A key function of our kidneys is to filter waste from our blood and to divert it into our urine. The filtration units in the kidneys are unique structures known as glomeruli. Key to the integrity of the filtration barrier in each glomerulus are specialized cells known as podocytes. A late event in many kidney diseases is scarring of the glomerulus, a condition known as glomerulosclerosis. Treatment with drugs known as ACE inhibitors often decreases the rate of progression of glomerulosclerosis to end-stage kidney disease. The mechanisms by which these inhibitors mediate their beneficial effects are incompletely understood. However, it has been suggested that they act, at least in part, by reducing blood pressure within each glomerulus and thereby pressure-induced loss of podocytes. A team of researchers led by Arnoud Sonnenberg, at The Netherlands Cancer Institute, has now confirmed in mice that tight adhesion of podocytes to the glomerular basement membrane is critical for maintaining glomerular integrity and provided evidence that suggests that ACE inhibitor reduce glomerulosclerosis, at least in mice with less tightly adherent podocytes, by reducing blood pressure within glomeruli. Roy Zent and Ambra Pozzi, at Vanderbilt University Medical Center, Nashville, highlight the importance of these data in an accompanying commentary.

TITLE: Blood pressure influences end-stage renal disease of Cd151 knockout mice

AUTHOR CONTACT:
Arnoud Sonnenberg
The Netherlands Cancer Institute, Amsterdam, NLD
Phone: +31 20 512 1942; Fax: +31 20 5121944; E-mail: a.sonnenberg@nki.nl

ACCOMPANYING COMMENTARY

TITLE: Hold tight or you'll fall off: CD151 helps podocytes stick in high-pressure situations

AUTHOR CONTACT:
Roy Zent
Vanderbilt University Medical Center, Nashville, TN, USA
Phone: 615-322-4632; E-mail: roy.zent@vanderbilt.edu

CARDIOLOGY
Starving hearts fail to function properly

There are about 5 million people in the US who suffer from heart failure. A person is said to suffer from heart failure when their heart is unable to pump sufficient blood to meet the needs of the body at normal filling pressures. It has long been suspected that the failing heart is starved of the fuel that the heart muscle cells need to function properly (i.e., it is "energy starved"), but this idea has never been proven. A team of researchers led by Robert Weiss, at Johns Hopkins University School of Medicine, Baltimore, has now proven this idea in mice and in doing so identified a potential new target for preventing and treating heart failure.

TITLE: Creatine kinase-mediated improvement of function in failing mouse hearts provides causal evidence the failing heart is energy starvedAUTHOR CONTACT:
Robert G. Weiss
The Johns Hopkins Hospital, Baltimore, MD, USA
Phone: 410 955-1703; Fax: 410 955 5996; E-mail: rweiss@jhmi.edu
-end-


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