Research matters

News from the Harvard Medical School research community.
Research matters
By Harvard Medical International
Sun 01 Jul 2007 12:00 AM

Oncology

New mouse model closely mimics human cancers

A team led by Dana-Farber Cancer Institute scientists has developed a more human-like mouse model of cancer they say will aid the search for cancer-causing genes and improve the predictive value of laboratory drug testing.

Ronald A. DePinho, MD, of Dana-Farber has created mice that form tumours that are more genetically complex and unstable - and therefore a better stand-in for human cancers - than those of conventional genetically engineered mouse models of cancer. To characterise these mouse tumours, DePinho collaborated with Lynda Chin, MD, also at Dana-Farber, to perform high-resolution array-CGH profiling, a genome-scanning technology that can define regions of DNA abnormalities. The report was published online and in the print version of the journal Nature.

The scientists, working with a large dataset generated by the Chin laboratory during the past several years, compared the patterns of these chromosomal changes in the mice with patterns observed in more than 400 human tumour specimens, including melanoma, lung, colon, and pancreatic cancers, and multiple myeloma.

The comparisons showed that genetic instability in the mouse cancer cells caused DNA alterations that in many cases were identical to such changes in human tumours.

This match up, said the researchers, suggested that the new mouse model may be useful in guiding the search for genes that are important for cancer growth.

To that end, it may facilitate research associated with the National Institutes of Health-funded Human Cancer Genome Atlas Project, which involves sifting the entire human DNA and identifying the immensely complicated, interacting molecular changes that initiate and maintain tumours. "We found a rather striking overlap of genetic alterations in the mouse and human cancers, which should greatly help us sort out genetic events that drive cancers from those that are simply irrelevant ‘passenger' events," DePinho said.

Indeed, using the new ‘instability' model of cancer in collaboration with Michael Stratton, PhD, and Andy Futreal, PhD, at the Wellcome Trust Sanger Institute in England, the team discovered a pair of gene mutations involved in a type of human blood cancer.

Stratton, Futreal, Chin, and DePinho are co-senior authors of the report.

As part of the ongoing Cancer Genome Project at the Sanger Institute, its researchers analysed human cancer cell lines and clinical samples to identify the new mutated genes. These studies have uncovered an unexpectedly large number of genetic alterations present in the typical human cancer genome, presenting challenges in the identification of truly causative events. DePinho said that the overlap in patterns of genetic abnormalities found in both mouse and human tumours shows that cancer mechanisms in the two species are more alike than had been thought.

Futreal, co-director of the Cancer Genome Project at the Sanger Institute, said that such mouse models and cross-species genomic comparisons will be of "real importance" in facilitating the identification of new human cancer genes and understanding their role in the formation of tumours, "as well as a potential avenue to explore new therapeutic strategies."

Conventional mouse models are made by transferring a cancer-causing oncogene into a mouse embryo. "You plug it into the mouse, and lo and behold, it gets cancer," explained Richard Maser, PhD, of Dana-Farber, one of the study's lead authors. "But that's rigging the game - it's not identical to the process by which tumours normally arise," he said. These tumours lack some key characteristics of human tumours, such as genomic instability - pieces of chromosomes breaking apart and reattaching, which result in widespread abnormalities like missing genes or extra copies of genes some of which are essential to the tumours' formation.

In the current study, the scientists used gene knockouts to create mice whose cells lacked crucial molecules whose role is to guard the genome from instability and chaos in the DNA. As a result, the mice developed T-cell acute lymphoblastic leukemia/lymphoma, or T-ALL, and the cancer cells exhibited "rampant genome instability" leading to a complex pattern of mutations, chromosomal rearrangements, gene amplifications and gene deletions similar to those in human solid tumours.

The mouse model's close resemblance to human T-ALL enabled the scientists to rapidly and efficiently identify two genes, FBXW7 and PTEN, to be commonly deleted or mutated in this type of human cancer.

Diabetes

Low-glycemic diet works better than low-fat diet for people with high insulin secretion

Diets that seek to stabilise blood sugar after eating -- called low-glycemic-load diets -- are effective for long-term weight loss, and much more effective than low-fat diets in people who secrete large amounts of insulin, reported a study in the May 16 issue of JAMA.

The findings, from a careful study of 73 obese young adults, demonstrate that hormonal differences - specifically, how much insulin the body makes - help explain whether a diet is successful.

"A major question in the field of obesity is, why can some people do well on conventional weight-loss diets, while others on the very same diets do very poorly?" says David Ludwig, MD, PhD, of Children's Hospital Boston, the study's senior investigator.

"The usual answer is motivation and compliance - that people just don't stick to their diets. But our findings show that biology determines why some people do well on one weight-loss diet and not on another."

Low-glycemic-load diets limit rapidly-digested carbohydrates that sharply raise blood sugar and insulin levels (such as white bread, refined breakfast cereals and concentrated sugars) in favour of carbohydrates that raise blood sugar more slowly (such as whole grains, most fruits, vegetables, nuts and legumes).

In a study published in The Lancet in 2004, Ludwig and colleagues found that rats whose insulin levels were highest 30 minutes after receiving a dose of oral glucose (sugar) gained the most weight when fed high-glycemic-load diets. They hypothesised that people who make a lot of insulin are similarly sensitive to the effects of glycemic load, and might be more responsive to a low-glycemic load diet.

Study participants were randomised to either a low-fat diet or a low-glycemic-load diet. All underwent initial testing to measure their insulin response. The diets involved no calorie restrictions or portion-weighing; instead, dieters received counselling encouraging them to eat until satisfied, changing only the kinds of foods they ate. Every six months, they received unannounced phone calls asking what they ate the day before; based on their responses, the two groups seemed to be adhering similarly to their diets. Protein and fibre consumption, physical activity and satisfaction with the diet were similar for the two groups.

During the first six months, high insulin secretors (those in the top half of insulin secretion) lost 2.2 lbs/month on the low-glycemic-load diet, versus 0.9 lbs/month on the low fat diet. At 18 months, total weight loss was 12.8 lbs in the low-glycemic-load group, but only 2.6 lbs in the low-fat group.

Those on the low-glycemic-load diet also had a significantly greater decrease in body-fat percentage, and did not regain weight between six to 18 months -- a time when regain virtually always occurs.

Among dieters in the bottom half of insulin secretion, weight loss and changes in body fat did not differ significantly between the low-glycemic-load and low-fat diets.

"These findings can allow clinicians to individualise the treatment of obesity by first giving patients an oral glucose tolerance test," says Ludwig, director of the Optimal Weight for Life clinic at Children's Hospital Boston and author of the new book Ending the Food Fight: Guide Your Child to a Healthy Weight in a Fast Food/Fake Food World. "People who make a lot of insulin may do especially well on diets that reduce glycemic load. They tend to do very poorly on low-fat diets, which are generally high in carbohydrates and raise insulin levels even further, which in turn causes weight gain."

Regardless of insulin secretion, the low-glycemic-load diet had advantageous effects on components of the metabolic syndrome, a condition closely related to diabetes and heart disease: high-density lipoprotein (HDL) or "good" cholesterol increased and triglycerides decreased. Patients on the low-fat diet did not have these improvements, but they did have reductions in low-density lipoprotein (LDL) or "bad" cholesterol.

Cardiology

Future parents' lifestyle choices affect babies' risk of heart defects

Prospective parents can take positive lifestyle steps to increase the chance that their babies will be born with a healthy heart, according to a new American Heart Association scientific statement.

The "Non-inherited Risk Factors and Congenital Cardiovascular Defects: Current Knowledge" statement was published in Circulation: Journal of the American Heart Association.

"Lifestyle choices that prospective mothers make may reduce the risk of giving birth to a baby with heart defects," said Kathy Jenkins, MD, MPH, lead writer of the non-inherited risks statement and senior associate in Cardiology at Children's Hospital Boston.

"This statement highlights the need to think about prevention of heart defects in babies before conception and very early in pregnancy," said Catherine Webb, MD, MS, senior author of the statement, paediatric cardiologist at Children's Memorial Hospital in Chicago and professor of paediatrics at Northwestern University Feinberg School of Medicine.
"Paying attention to parental lifestyle issues and the association with congenital heart disease is a good start. However, congenital heart disease may still occur in children despite excellent prenatal care and the very best efforts on the parents' part. It is very important to continue to learn much more about prevention of congenital heart disease through ongoing research studies."

The American Heart Association's Congenital Cardiac Defects Committee of the Council on Cardiovascular Disease in the Young examined the latest knowledge reflected in medical/scientific literature, which shed light on modifiable risk factors for congenital heart defects.

"This is a new way of thinking and a positive vision of how prospective mothers can influence and protect a child from being born with a heart defect," Jenkins said.

The committee had four key recommendations based on the literature review. These lifestyle recommendations range from three months before pregnancy through the first trimester of pregnancy. The first and most important recommendation is to talk to your doctor. Good preconception and prenatal care is important to the birth of a heart-healthy baby.

Prospective mothers should be checked for diabetes, rubella (German or three-day measles) and influenza. Women of child-bearing age need to be immunised against rubella. Otherwise, rubella infection early in gestation carries the risk of congenital rubella syndrome in offspring. Diabetes needs to be diagnosed and controlled.

"A second recommendation is for women to take a daily multivitamin containing 400 micrograms (mcg) of folic acid or a folic acid supplement," said Jenkins, who is also associate professor of paediatrics at Harvard Medical School in Boston, Mass.

Folic acid is critical to the normal growth and development of the foetus and appears to have a protective effect against the development of heart defects. Data suggest intake of folic acid is particularly important prior to conception.

Third, parents should review medication use -- even over-the-counter medications -- with their doctor. The last recommendation centres on what the prospective mother should avoid, such as contact with people who have the flu or other fever-related illnesses.

Any fever-related illness during the first trimester of pregnancy may carry a two-fold higher risk of offspring with heart defects.

Congenital heart defects, both simple and severe, are structural problems with the heart present at birth. They result when a mishap occurs during heart development soon after conception and often before the woman is aware she is pregnant. The American Heart Association estimates that out of 1,000 births, nine babies will have some form of congenital heart disorder. Congenital cardiovascular defects are the most common birth defects.

Mental health

First report from large-scale study establishes healthy brain and behavioural development norms for 6- to 18-year-olds

Yes, there are gender differences in cognitive function, but they're more limited than previously thought. And yes, income does affect cognitive performance -- but less than expected when only healthy children are considered. And while basic cognitive skills steadily improve in middle childhood, they then seem to level off -- questioning the idea of a burst of brain development in adolescence.

These findings, published online on May 18 in the Journal of the International Neuropsychological Society, are the first data to emerge from the National Institutes of Health (NIH) MRI Study of Normal Brain Development, a large, population-based study that began in 1999 and is documenting structural brain development and behaviour from birth to young adulthood.

The analysis, led by Deborah P. Waber, PhD in the Department of Psychiatry at Children's Hospital Boston, focused on cognition and behaviour in healthy 6- to 18-year-olds enrolled at Children's and five other metropolitan areas across the United States.

Population-based sampling techniques used U.S. Census data to ensure demographic diversity. A rigorous screening process eliminated children with medical, neurological or psychiatric disorders, familial risk factors for such disorders, or prenatal exposure to toxic substances, providing a glimpse of how a healthy brain develops.

"This report -- and many others that will follow -- provides a comprehensive set of benchmark values that clinicians and scientists studying brain development can reference for many years to come," said NIH Director Elias A. Zerhouni, MD.

From an initial sample of more than 35,000 target families, the researchers were able to enroll approximately 450 children, of whom 385 were 6 years or older.

Once enrolled, the children underwent MRI scans of the brain and completed a battery of behavioural and cognitive tests to ascertain their overall IQ, verbal ability, mental processing speed, spatial ability, memory, fine motor dexterity, psychosocial function, reading and calculation ability, and other measures of cognitive function. Most have returned two more times so that their development can be tracked. Overall, this healthy group performed better than previously reported norms.

However, analysis of the first wave of data also found that:

• Sex predicted few aspects of cognitive function, with gender effects less prevalent than in previous studies. Boys performed better on perceptual analysis, and girls were better on processing speed and motor dexterity. Girls showed a slight advantage on verbal learning, but by adolescence, this advantage had disappeared.

• Income predicted IQ and academic achievement. Lower income was associated with lower IQ scores (mean IQs were 105, 110, and 115 for low-, middle- and high-income children respectively). Lower-income children were more likely to be excluded from the study because of medical or developmental conditions; the healthy low-income children who qualified performed, on average, better than previously reported population averages. "We were pleasantly surprised by how well the lower-income children did when we focused on those who were healthy," says Waber. Although income did not predict performance on basic cognitive tasks, such as memory or reading individual words, lower-income children did score lower on tests like reading comprehension and calculation. The authors suggest that such tasks, which require more reasoning and integration of cognitive abilities, are more vulnerable to the effects of poverty-related factors than are more basic skills.

• Age predicted performance on every measure of cognitive function. Performance climbed steeply from age 6, but levelled off overall for most tests between 10 and 12 years of age, then improved more slowly or not at all during adolescence. Waber cautions, however, that these data are "snapshots" at a single point in time, averaging the performance of a whole population. "We don't know whether everyone's performance improves more slowly in adolescence, or whether some children continue to improve while others do not, or whether our standard tests can measure what really changes in adolescence," she notes. "As we follow these children over time, we will have a better understanding of what happens in adolescence."

"In the past, studies of structural brain development and often studies of cognitive development were performed on samples of convenience that weren't necessarily representative of the overall population," Waber adds. "This study provides information on a much more diverse and representative sample, and a much larger one than previously available."

Neurology

BWH sleep research finds light pulses can adjust the brain's clock for a longer day, sufficient for adaptation to the 24.65 hour day found on Mars

Researchers from Brigham and Women's Hospital's (BWH) Division of Sleep Medicine and colleagues, have found that by giving individuals two 45 minute exposures to bright light pulses in the evening they could entrain (synchronise) a persons circadian system to function properly in days longer than the usual 24 hour light/dark cycle.

The study was conducted for NASA's National Space Biomedical Research Institute and the findings can be applied to the planned year-and-a-half visit to Mars, where the Martian day is 24.65 hours long. Without the ability to reset the internal clock to endure the longer day, an individual would feel as if they were in a perpetual state of jet lag. The findings appeared in the May 15, 2007 issue of the Proceedings of the National Academy of Sciences.

The study involved 12 healthy participants between 22 to 33 years of age who had maintained a regular 8 hour sleep and 16 hour wakeful schedule at home for at least three weeks before the start of the study. Participants stayed in individual rooms free from external time cues for a 65 day span with scheduled exposure to light, opportunities to sleep, eat and take showers based on a standard 24 hour pattern.

As a first step, the researchers determined the intrinsic period of each subject's inner brain clock. They found that individual differences in this fundamental property of the internal brain clock determined the timing of the release from the pineal gland of the sleep-promoting hormone melatonin, which has implications for understanding biological differences in the timing of preferred sleep times (for example, morning and evening types). Next, the participants began a 30 day period of longer-than-24 hour days in one of three light/dark conditions including using modulated light exposure.

Scenario number one was exposure to dim light (25 lux), room lighting (100 lux) and a modulated light exposure of dim light (25 lux) for the first 10 hours of the waking day, followed by room light of 100 lux for the remainder of the waking day and two 45 minute exposures to bright light pulses of approximately 9500 lux (equivalent to full daylight).

The researchers found that participants exposed to the modulated light exposure, which included the two evening bright light pulses, were able to synchronise their sleep/wake cycles to a longer than 24 hour day. Dr. Charles Czeisler, Chief of the Division of Sleep Medicine at Brigham and Women's Hospital, Baldino Professor of Sleep Medicine at Harvard School of Medicine and Senior Author of the study commented, "The results have powerful implications for the treatment of circadian rhythm sleep disorders, including shift work disorder and advanced sleep phase disorder. With human long-duration missions planned to the Moon and Mars, the results of our research should enable astronauts to synchronise their circadian pacemaker, or internal clock, to the 24.65 hour long day found on Mars. Without being able to synchronise their internal circadian clock they would be in a constant state of jet lag, which could lead to sharp decreases in the level of performance, jeopardising the health and safety of the crews."

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

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