Research matters

News from the Harvard Medical School research community.
Research matters
By Harward Medical International
Tue 16 Oct 2007 02:50 PM

News from the Harvard Medical School research community.

Oncology

AMD is the leading cause of irreversible visual impairment and blindness among persons aged 60 and older.

Multi-centre study nets new lung tumour-suppressor gene Collaborating scientists in Boston and North Carolina have found that a particular gene can block key steps of the lung cancer process in mice.

The researchers report in the journal Nature that LKB1 is not only a 'tumour-suppressor' gene for non-small cell lung cancer in mice, it also may be more powerful than other, better-known suppressors. The study was published on the journal's Web site on Aug. 5 and later in a print version.

If further research shows LKB1 has a similar effect in human lung cells, it could influence the way non-small cell lung cancer is diagnosed and treated, says the study's senior author, Kwok-Kin Wong, MD, PhD, of Dana-Farber, one of three institutions, along with Massachusetts General Hospital and the University of North Carolina School of Medicine, leading the work.

If tumours with LKB1 mutations are found to be especially fast-growing, for example, patients with such tumours might be candidates for more aggressive therapy.

People born with defective versions of LKB1 often develop Peutz-Jeghers syndrome, which is marked by intestinal growths and an increased risk for certain cancers. Non-inherited mutations of the gene have been found in some lung cancers. This suggested that LKB1 normally thwarts tumours from forming. Mutated versions may be unable to act as a brake on cancer.

To find out, the investigators ran a series of experiments in mice with a defective form of a gene called Kras, which drives the formation and growth of lung cancer. They tracked the development of lung cancer in animals with mutated LKB1 and compared it to the experience of animals with abnormalities in either of two well-known tumour-suppressor genes.

They found that while Kras "co-operated" with the mutated tumour-suppressor genes to produce lung cancer, it cooperated even more strongly with mutated LKB1.

"The LKB1-deficient tumours grew more rapidly and spread more frequently than the others, and comprised all three types of non-small cell lung cancer - squamous cell carcinoma, large-cell carcinoma, and adenocarcinoma - rather than just one or two," Wong says.

"This suggests that LKB1 plays a role at major stages of the tumours' development: initiation, differentiation of normal lung cells into cancer cells, and metastasis."

An examination of human non-small-cell lung tissue suggests LKB1 mutations play a role there as well. Of 144 samples analysed, 34 percent of the lung adenocarcinomas and 19 percent of the squamous cell carcinomas contained abnormal versions of the gene, researchers report.

"We were surprised at how significant a role LKB1 mutations play in non-small cell lung cancer development in mice," say Wong, who is also an assistant professor of medicine at Harvard Medical School.

"This suggests there may be additional lung tumour-suppressor genes yet to be discovered. We're currently examining whether these results apply to human lung cancers as well and, if so, how such information can improve treatment."

Cardiology

Diabetes significantly increases the risk of death following acute coronary syndromes.

Nearly 65 percent of individuals with diabetes die from cardiovascular disease in the United States, yet the independent effect of diabetes on mortality following acute coronary syndromes is not clear.

Researchers from the TIMI Study Group in Brigham and Women's Hospital's (BWH) cardiovascular division studied the influence of diabetes on death rates among individuals who experienced acute coronary syndromes (ACS), such as an acute heart attack, 30 days and one-year following such events.

The researchers found that after 30 days the risk of death for diabetics experiencing acute coronary syndromes (which covers the full spectrum from unstable angina through mild or severe heart attack) was two times greater compared to non-diabetic individuals experiencing the same type of coronary event. The findings appeared in the August 15, 2007 issue of the Journal of the American Medical Association.

To analyse the effect of diabetes on individuals who experienced ACS the researchers pooled participants from 11 independent clinical trials, spanning nine years, from the BWH-based Thrombolysis in Myocardial Infarction (TIMI) Study Group.

The analysis group was comprised of more than 62,000 individuals, more than 10,000 of whom were diabetic, from 55 countries and more than 900 clinical sites.

"Despite the numerous advances that have been made in coronary care treatment, they are not enough to off-set the very serious increased risk of death faced by diabetics experiencing acute coronary syndromes," said Elliott Antman, M.D., director of the Samuel L. Levine Cardiac Unit at BWH and senior author of the study. "Collaboration between medical organizations, health care groups and industry will be crucial to halt the epidemic of diabetes-related heart disease."
"We found that at one year diabetics who had a less-severe type of heart attack (non-STEMI) were at virtually the same risk of dying compared with a non-diabetic who had suffered a more severe type of heart attack (STEMI)," Antman continued.

Those in the study with diabetes who experienced ACS were older, more often women, had higher body mass index and were more likely to have a history of high blood pressure, high cholesterol levels, past heart attack, coronary bypass surgery and heart failure compared with the non-diabetics in the study. Additionally, of the 55 countries and 900 clinical sites pooled for this study, there was a higher prevalence of diabetes in the North American sites compared with the other regions around the world.

Diabetes

Research identifies sirtuin protein instrumental in fat production and metabolism.

There was a higher prevalence of diabetes in the North American sites compared with the other regions around the world.

A new Joslin Diabetes Centre-led study has identified a protein found in fat cells that may play a major role in how fat is produced and stored, offering a new target for treatments to prevent obesity and reduce the risk for type 2 diabetes. This research appeared in the August 2007 issue of Cell Metabolism.

The study examined the role of a protein called Sirt2, a member of the sirtuin family of seven cellular proteins. These proteins have recently been shown to be important in the control of aging and metabolism. Previous studies have focused on one member of this family, Sirt1, which is activated by high doses of resveratrol, a substance found in red grapes, which can prevent diabetes from developing and also prolong life.

This finding generated tremendous attention, leading biotechnology and pharmaceutical companies to begin developing drugs and supplements to harness this effect. Joslin researchers have focused on other sirtuin proteins to find out what role they might play in fat and glucose metabolism and fat development.

This led to the discovery that Sirt2 is the most abundant of the sirtuins in fat cells, expressed in quantities five to ten times higher than other sirtuin proteins. "We wanted to find out what would happen to the behavior of fat cells - in terms of metabolism or growth - if we changed the levels of Sirt2," said lead investigator C. Ronald Kahn, M.D., an internationally recognized researcher who is head of the Joslin section on Obesity and Hormone Action and the Mary K. Iacocca Professor of Medicine at Harvard Medical School.

When a person gains weight, cells in connective tissue known as pre-adipocytes differentiate and fill with fat and form adipocytes, which are able to store fat as a potential energy source when food is not available. However, too much fat storage leads to obesity and obesity-related diseases, including type 2 diabetes.

Using genetically altered cells from mice, the Joslin researchers were able to manipulate Sirt2 levels in adipocytes. They found that increasing Sirt2 levels in the cell would block the cell's ability to undergo differentiation and store fat, while reducing Sirt2 would promote adiopogenesis, or fat production.

They then went on to pinpoint exactly how Sirt2 produced these effects by interacting with and modifying one of the key transcription factors, or molecular switches, regulating fat differentiation and function, a molecule called FoxO1. FoxO1 is also an important target of insulin action in fat where it helps control the aging process.

Thus, when Sirt2 levels in pre-adipocytes are low, more fat cells develop, while when Sirt2 levels are high, this process is blocked. "So, to reduce the amount of fat in the body and help people stay thin, we need to find an activator of Sirt2," said Kahn.

The discovery of Sirt2's role in fat production gives researchers a new avenue to pursue in preventing and treating obesity. "Since most of the diabetes epidemic is driven by obesity, Sirt2 may also play a role in preventing type 2 diabetes from developing and in treating people who have already developed the disease," said Kahn.

This is an important goal since more than 60 percent of Americans are now overweight or obese, and obesity is a major factor driving the current epidemic of type 2 diabetes, which now affects more than 20 million people in the US alone.

The next step in the research process will be to create an animal model to validate the results. Once they are confirmed, biotechnology companies can try to develop drugs that would activate Sirt2 in fat cells and provide another tool for combating obesity and diabetes.
Ophthalmology

Researchers outline surgical technique for implantable telescope for severe age-related macular degeneration.

Results suggest that people treated for locally advanced colon cancer can actively improve their odds of survival by their dietary choices.

Recent studies have explored the use of an implantable prosthetic device -- an implantable miniature telescope -- for end-stage age-related macular degeneration.

While the device has not yet been approved by the Food and Drug Administration, physicians have described a recommended surgical technique to ensure proper product placement while minimizing damage to the eye. Their technique was published in the August issue of the Archives of Ophthalmology.

AMD is the leading cause of irreversible visual impairment and blindness among persons aged 60 and older. With the elderly population steadily growing, the burden related to this loss of visual function will increase.

"At the very end stages of this disease, vision is very poor and quality of life is compromised," said Lead Author Kathryn Colby, M.D., Ph.D., director of the Joint Clinical Research Center at the Massachusetts Eye and Ear Infirmary. "An implantable miniature telescope can improve the vision and quality of life for patients, but surgeons must be very careful in implanting it."

The implantable telescope has completed two years of follow-up in a pivotal multi center trial. In this phase 2/3 clinical trial, 206 patients received the telescope prosthesis implant.

One-year outcomes showed that 67 percent of eyes with the implant achieved a three line or greater improvement in best-corrected distance visual acuity, as indicated by reading an eye chart, compared with 13 percent of the fellow eyes in control patients. Meaningful improvements in quality of life measurements were also shown.

Surgical implantation of this device is challenging, the authors wrote. It is critical that surgeons not view this first-of-a-kind device as simply a larger intraocular lens, like that used to replace the lens in cataract surgeries. The paper describes the recommended surgical technique, based upon the results of the clinical trial and will be a useful resource for ophthalmic surgeons when the device is approved for use.

Oncology

‘Western' diet linked to increased risk of colon cancer recurrence

Colon cancer patients who eat a diet high in red meat, fatty products, refined grains, and desserts - a so-called "Western" diet - may be increasing their chance of disease relapse and early death, report researchers at Dana-Farber Cancer Institute.

The study, published in the Aug. 15 issue of the Journal of the American Medical Association, involved 1,009 patients with stage III colon cancer that has been treated with both surgery and chemotherapy.

Stage III colon cancer is characterized as being localized to the large bowel area with cancer cells in the lymph nodes near the tumor. The investigators found that those who most closely followed a Western diet were three-and-a-half times more likely to have colon cancer recur than those whose diets were least Western-like.

"We know from previous research that diet and lifestyle influence people's risk of developing colon cancer," says the study's lead author, Jeffrey Meyerhardt, MD, MPH, of Dana-Farber.

"This is the first large observation study to focus on the role of diet in recurrence of the disease. Our results suggest that people treated for locally advanced colon cancer can actively improve their odds of survival by their dietary choices."

The participants, who were enrolled in a large, phase III clinical trial sponsored by the National Cancer Institute of follow-up ("adjuvant") chemotherapy, had their tumors surgically removed within the two months prior to enrolling in the study. They reported their dietary intake on specially designed questionnaires at two different time points - during the period they were receiving chemotherapy and six months after the completion of chemotherapy.

Meyerhardt and his colleagues identified two major dietary trends within the group: A "prudent" pattern characterized by high intakes of fruits and vegetables, poultry, and fish, and a "Western" pattern characterized by high amounts of red and processed meats, sweets and desserts, French fries, and refined grains. Participants didn't fall neatly into one category or the other, but were scored in each by how closely they matched the Western and prudent models.

The survival benefit for those whose diets least resembled the Western pattern held true even after researchers controlled for factors such as gender, age, body mass, degree of cancer spread to lymph nodes, and physical activity level.

Investigators do not know why such a diet is associated with a poorer outcome, but speculate that it may be related to increased insulin levels and insulin-like growth factors. Insulin and related growth factors have been linked to the formation and growth of some types of tumours.

In contrast to the negative effect of a Western diet, researchers found that following a prudent-pattern diet did not significantly influence cancer recurrence or mortality.

"The message is that patients in this category can improve their prospects by avoiding certain foods," comments Meyerhardt, who is also an assistant professor of medicine at Harvard Medical School. Meyerhardt adds that more research is needed to better understand what components of diet are most responsible for the study findings, and why.

Research Matters brings together selected research being conducted at Harvard Medical School's 18 affiliated institutions. For more information, visit the Harvard Medical School website at www.hms.harvard.edu.

This article is provided courtesy of Harvard Medical International.© 2007 President and Fellows of Harvard College.

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