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Sun 1 Oct 2006 12:00 AM

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Research matters

News from the Harvard Medical School research community




Rapamycin shown to inhibit angiogenesis

Scientists have long known that the blood vessels of tumours differ markedly from normal blood vessels.

Now, a team led by scientists at Beth Israel Deaconess Medical Center (BIDMC) has identified a signaling pathway which, when activated, transforms otherwise healthy blood vessels into the leaky, misshapen vasculature that characterises cancerous tumours.

The findings, published in the August 2006 issue of Cancer Cell, additionally demonstrate that rapamycin, a compound used for immunosuppression in transplant patients and currently under investigation as a cancer treatment, can successfully block this signaling pathway—known as the Akt pathway in blood vessels.

This discovery further enhances the drug’s promise as a cancer therapy.

“There are three major hallmarks associated with tumour blood vessels,” explains the study’s senior author Laura Benjamin, PhD, an investigator in BIDMC’s Department of Pathology and associate professor of pathology at Harvard Medical School.

“First, unlike healthy blood vessels which are uniform in structure, a tumour’s blood vessels balloon and narrow, forming a highly irregular shape.

Second, the layer of smooth muscle that you would expect to find covering the blood vessels is inadequate, often resulting in only intermittent coverage. And last, a tumour’s blood vessels are overly permeable or leaky.”

The hypothesis that blood vessel formation in tumours is essential for the growth and spread of cancer was first proposed in the early 1970s, and in 1983, it was shown that tumours secrete VEGF (vascular endothelial growth factor) that induces the permeability associated with blood vessels in cancer.

In this new study, Benjamin and first author Dr Thuy Phung, a research fellow in BIDMC’s Department of Pathology, hypothesised that the Akt pathway was mediating many of the functions of VEGF in tumours, including the stimulation of blood vessels with abnormal structure and excessive leak.

Using a mouse model that enabled them to activate the Akt pathway in healthy blood vessel cells without the complicating influence of tumour cells they observed that Akt-induced blood vessels demonstrated the very same abnormalities that are seen in tumour blood vessels.

Benjamin adds, “We discovered that simply removing the activated Akt was sufficient to reverse these vasculature changes.”

The scientists then went on to treat the animals with rapamycin.

As predicted, the agent blocked the Akt-induced blood vessel changes.

In subsequent experiments, rapamycin reduced tumour growth and vascular leak in a mouse tumour model.

“This paper represents an impressive advance in our understanding of the mechanisms by which tumors generate the new blood vessels they need to survive and grow,” says Dr Harold Dvorak, director of the Vascular Biology Center at BIDMC.

“This suggests an attractive new molecular target for cancer therapy.”

“These new findings suggest that we should think about using rapamycin in regimens where anti-angiogenic therapy in cancer patients is desired,” says Benjamin.

“If human tumours respond in the same way that animal models have, rapamycin may normalise and diminish the tumour vasculature, and this is exciting because these findings are clinically relevant today.”



Study shows that smoking increases risk

Researchers in Boston studied elderly male twins and found that those who smoke or have a history of smoking had an increased risk of developing age-related macular degeneration as compared to those who never smoked.

At the same time, those who ate more fish and had diets with higher levels of omega-3 fatty acids reduced their risk of this blinding disease.

Their findings are published in the July 2006 issue of the Archives of Ophthalmology.

The team, combining researchers from Massachusetts Eye and Ear Infirmary and the Department of Biostatistics at Harvard Medical School, studied 681 male twins.

The participants were sourced from the National Academy of Sciences’ National Research Council World War II Veteran Twin Registry.

To determine genetic and environmental risk factors for AMD, twins were surveyed for a prior diagnosis of AMD and underwent an eye examination, fundus photography, and food frequency and risk factor questionnaires.

The study included 222 twins with intermediate and late stage AMD and 459 twins with no signs of the disease.

“Current smokers had a 1.9-fold increased risk of developing AMD, while past smokers had about a 1.7-fold increased risk,” said Dr Johanna M. Seddon, lead author on the study.

“We also found that increased intake of fish reduced the risk of AMD, particularly if they ate two more servings per week. Dietary omega-3 fatty intake was also inversely associated with AMD.

“This study of twins provides further evidence that cigarette smoking increases risk while fish consumption and omega-3 fatty acid intake reduce risk of AMD.”

Dr Seddon and her colleagues previously reported that the heritability of AMD is high (46% to 71%) in this same cohort of twins (Arch Ophthalmol 2005).

They also found that systemic markers of inflammation, including serum levels of C-reactive protein, as well as plasma homocysteine are associated with AMD (JAMA 2004, Am J Ophthalmol 2006).

A decade ago they reported the increased risk of AMD with cigarette smoking (JAMA 1996), and the decreased risk of this disease related to dietary intake of carotenoids and foods rich in lutein and zeaxanthin (JAMA 1994).

They also found in several of their study cohorts that fish intake appears beneficial and reduces risk of AMD (Arch Ophthalmol 2001, 2003, and current article), and high body mass index or obesity is also a risk factor for progression of the disease.

(Arch Ophthalmol 2003).



AEDs are recalled frequently

A new study shows that automated external defibrillators (AEDs), the devices used to resuscitate victims of sudden cardiac arrest, have a greater than 20% chance of being recalled for potential malfunction over the past decade.

The findings, reported in the Journal of the American Medical Association (JAMA), suggest the need for a more reliable system to locate and repair potentially defective devices in a more timely fashion.

“Though they are simple to use, AEDs are, in fact, complex medical devices,” explains the study’s senior author Dr William Maisel, director of the pacemaker and defibrillator service at Beth Israel Deaconess Medical Center (BIDMC) and assistant professor of medicine at Harvard Medical School.

“It is therefore not surprising that they may occasionally malfunction. An AED recall rate of one in five over the past decade, however, is too high.”

The portable units provide voice commands, automated heart rhythm analysis, and if necessary, shock delivery to resuscitate victims of cardiac arrest.

Their ease of operation, coupled with their clinically proven ability to improve the survival of cardiac arrest victims, has resulted in their widespread use in recent years.

“During the period we followed between 1996 and 2005 – the annual number of AEDs distributed increased almost 10-fold, from fewer than 20,000 in 1996 to nearly 200,000 in 2005,” says Maisel.

Many public areas such as airports, sports arenas, casinos, schools and churches are now routinely outfitted with AEDs, and certain AED models have even been approved by the US Food and Drug Administration (FDA) for use without a prescription, enabling consumers to purchase them more easily.

In their study, Maisel and coauthor Dr Jignesh Shah, of BIDMC’s cardiovascular division determined the number and rate of AED safety alerts and recalls (collectively referred to as “advisories”) as well as the number of actual AED malfunctions by analysing weekly FDA Enforcement Reports and reports of AED-related adverse events.

(The FDA routinely issues such “advisories” to notify the public about potentially defective medical devices.)

Their analysis showed that between 1996 and 2005, a total of 52 advisories affecting 385,922 AEDs or critical AED accessories were issued.

They also found that device malfunctions occurred during attempted resuscitation in 370 patients.

Device recalls were most often issued due to hardware malfunctions, which may result in a failure of the AED to power on, to charge, or to successfully deliver a shock.

Maisel explains: “Our study demonstrates that there is an urgent need to develop a more reliable system to identify and repair potentially defective AEDs in a timely fashion and to better notify AED owners when their devices are recalled.”



Being overweight as a teen associated with premature death in adulthood

Children and adolescents in the US and around the world are becoming more overweight.

A new study from the Harvard School of Public Health (HSPH) has found that there may be serious consequences to that trend.

Researchers found that being overweight at age 18 is associated with an increased risk of premature death in younger and middle-aged women. The study appears in the Annals of Internal Medicine.

“Our findings add to studies on overweight in middle-aged and older populations by providing insight into the impact of adolescent overweight on adult mortality,” said Rob van Dam, a research scientist in the Department of Nutrition at HSPH and lead author of the study.

Some previous studies had looked at the relationship between being overweight in childhood and adolescence and premature death in adulthood, but those studies tended to look at older cohorts (people born before 1945), in which few participants were overweight during their youth and the majority had smoked.

Van Dam and his colleagues examined data from 102,400 female nurses in the Nurses’ Health Study II, a prospective study launched in 1989.

At that time, study participants, all aged 24 to 44, reported their current height and weight and their weight at age 18, allowing researchers to calculate body mass index (BMI).

Participants answered questions in a number of other areas, including disease history, alcohol consumption, smoking and exercise.

Follow-up questionnaires were sent to participants until 1 July 2001, or to the date of death, whichever came first.

The results showed that women with a higher BMI at 18 consumed more alcohol, smoked more and were less likely to engage in vigorous physical activity during adolescence.

During the 12-year follow-up period (1989-2001), in which 710 participants died, the HSPH researchers found that women with a higher BMI at age 18 had a higher risk of dying prematurely.

That was true for even moderately overweight adolescents, the team reported.

Associations between overweight and premature mortality were similar for women who were younger and older than 40 during follow-up.

Major causes of death included cancer (258 deaths) and cardiovascular disease (55 deaths); of deaths due to external causes (144 deaths), suicide was the most common cause (61 deaths).

The researchers also found that women with a low BMI at age 18 did not have an increased risk of mortality.

This finding contrasts with several recent studies, in which both a low and high BMI in middle-aged and older adults was associated with excess mortality.

However, at older ages, a low BMI may reflect lifelong smoking habits or weight loss as a result of diseases, which may bias associations between BMI and mortality.

To adjust for smoking, van Dam and his colleagues looked at the results for women who never smoked.

They found the same results—women with a higher BMI during adolescence who never smoked had a significantly increased risk of premature death than those with a low BMI.

Another key finding was that BMI at age 18 was a strong predictor of BMI in 1989 when women were, on average, 34 years old.

Still, BMI in 1989 only partly explained the association between BMI at age 18 and premature death.

In other words, being overweight as an adult couldn’t fully explain why women died prematurely.

Health effects of overweight that are specific to younger ages, differences in location of fat deposition, or long-term exposure to metabolic effects of overweight may explain this finding.

Past studies have also shown that overweight children and adolescents have higher risks of cardiovascular problems and chronic diseases.

The results of this study, which show a risk of premature death for younger and middle-aged women, are in line with these findings.

“This paper underscores the importance of efforts to prevent excessive weight gain in children, not only to prevent obesity but also to prevent moderate overweight,” said Frank Hu, associate professor of nutrition and epidemiology at HSPH and a co-author of the study.



How a molecular switch regulates fat and cholesterol metabolism

Researchers at Harvard Medical School and Massachusetts General Hospital (MGH) have identified how a molecular switch regulates fat and cholesterol production, a step that may help advance treatments for metabolic syndrome, the constellation of diseases that includes high cholesterol, obesity, type II diabetes, and high blood pressure.

The study was published in the online version of the scientific journal Nature and will appear in the 10 August print edition.

“We have identified a key protein that acts together with a family of molecular switches to turn on cholesterol and fat (or lipid) production,” says principal investigator Anders Näär, PhD, assistant professor of cell biology at Harvard Medical School and the MGH Cancer Center.

“The identification of this protein interaction and the nature of the molecular interface may one day allow us to pursue a more comprehensive approach to the treatment of metabolic syndrome.”

High levels of cholesterol and lipids are linked to a number of interrelated medical conditions and diseases, including obesity, type II diabetes, fatty liver, and high blood pressure.

This set of conditions and diseases, known as metabolic syndrome, are afflicting a rapidly increasing portion of society and serve as a major risk factor for heart disease, the leading cause of death in the developed world.

Treatments for diseases associated with metabolic syndrome have focused primarily on individual elements, such as high LDL-cholesterol (targeted by the cholesterol-lowering statin drugs).

However, more effective ways to treat all of the components of metabolic syndrome are needed.

One attractive approach might be to target the genetic switches that promote cholesterol and lipid synthesis, but it would require a detailed understanding of the regulatory mechanisms before drug targets can be identified.

After eating a meal, SREBPs, or sterol regulatory element binding protein prompt cholesterol and fat (or lipid) production.

Between meals, the production of cholesterol and lipids should be turned off.

However, excess intake of foods coupled with lack of exercise, appear to disturb the normal checks and balances that control SREBPs, resulting in overproduction of cholesterol and lipids.

In the Nature paper, the HMS and MGH Cancer Center team has shown that a protein called ARC105, which binds to SREBPs, is essential in controlling the activity of the SREBP family of proteins.

“ARC105 represents a lynchpin for SREBPs control of cholesterol and lipid biosynthesis genes, which may provide a potential molecular Achilles heel that could be targeted by drugs,” says Dr Näär.

The researchers initially found that after removing ARC105 from human cells, SREBPs were no longer able to activate cholesterol and lipid biosynthesis genes.

To validate these findings in a physiological setting, the researchers turned to the microscopic worm C. elegans.

This is a favourite model organism among those studying evolutionarily conserved biological processes because of its rapid generation time and relative simplicity of genetics.

Through a collaborative effort with the worm genetics group of Anne Hart, PhD, HMS associate professor of pathology at the MGH Cancer Center, the team demonstrated that the C. elegans homologues of SREBP and ARC105, known as SBP-1 and MDT-15, respectively, are necessary for production and storage of fat.

The worms had regular fat production when SBP-1 and MDT-15 functioned normally, but when researchers knocked out function of either SBP-1 or MDT-15, the worms lost their ability to properly store fat, lay eggs, and move normally.

“The striking effects of the RNAi knock downs in C. elegans suggest that the ARC105/SREBP pathway may play a key role in lipid production in humans,” said Laurie Tompkins, PhD, of the National Institute of General Medical Sciences, which partially supported the research.

“This work highlights the value of model organisms in helping us understand cellular processes that impact human health.”

The research team also showed that removal of ARC105 in human cells by RNAi also negatively affects the same key SREBP target gene as identified in C. elegans.

This suggests that the molecular switch is evolutionarily conserved (and therefore likely physiologically important).

Exhaustive biochemical detective work performed by the Näär group together with the group of Gerhard Wagner, PhD, HMS professor in the Department of Biological Chemistry and Molecular Pharmacology, identified exactly how SREBP and ARC105 interact.

They found a flexible tail on the SREBP molecule that fits into a specific groove on a region of ARC105 called KIX.

The researchers analysed the amino acid sequence of the ARC105 protein, testing many different sections using NMR spectroscopy to eventually find the KIX area that specifically binds to SREBP.

This specific interaction between SREBP and ARC105 might be a target for small molecule drugs, according to Dr Wagner.

“While RNAi completely knocks out a protein including its other functions, perhaps not related to fat metabolism, a small molecule is a more subtle tool that could eliminate one protein-to-protein interaction,” says Dr Wagner.

Finding a molecule that attaches to and inhibits the flexible tail of SREBP is unlikely, but a search for inhibitors to fit the grooved KIX site looks much more promising.

The team is already initiating high-throughput screening at Harvard Medical School’s Institute of Chemistry and Cell Biology to identify small molecule inhibitors of the KIX site.

“Of course there are numerous hurdles that would need to be overcome before finding specific and effective treatments based on these findings,” says Dr Näär.

If small molecules that specifically interfere with the interaction of SREBPs and ARC105 could be identified, careful studies in human cells and in mice would be needed to verify the specificity and efficacy in repressing cholesterol and fat production.

“Unforeseen side effects of such small molecules in mouse studies or in human clinical trials could also emerge, prohibiting further follow-up,” concludes Dr Näär.

“If human tumours respond in the same way that animal models have, rapamycin may normalise and diminish the tumour vasculature, and these findings are clinically relevant today.”/pullquote>

“ARC105 rmay provide a potential molecular Achilles heel that could be targeted by drugs”

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