Most clear genetic link yet to obesity

Scientists have identified the most clear genetic link yet to obesity in the general population as part of a major study of diseases funded by the Wellcome Trust, the UK's largest medical research charity. People with two copies of a particular gene variant have a 70% higher risk of being obese than...

Scientists have identified the most clear genetic link yet to obesity in the general population as part of a major study of diseases funded by the Wellcome Trust, the UK's largest medical research charity. People with two copies of a particular gene variant have a 70% higher risk of being obese than those with no copies.

Obesity is a major cause of disease, associated with an increased risk of type 2 diabetes, heart disease and cancer. It is typically measured using body mass index (BMI). As a result of reduced physical activity and increased food consumption, the prevalence of obesity is increasing worldwide. According to the 2001 Health Survey for England, over a fifth of males and a similar proportion of females aged 16 and over in England were classified as obese. Half of men and a third of women were classified as overweight.

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Scientists from the Peninsula Medical School, Exeter, and the University of Oxford first identified a genetic link to obesity through a genome-wide study of 2,000 people with type 2 diabetes and 3,000 controls. This study was part of the Wellcome Trust Case Control Consortium, one of the biggest projects ever undertaken to identify the genetic variations that may predispose people to or protect them from major diseases. Through this genome-wide study, the researchers identified a strong association between an increase in BMI and a variation, or "allele", of the gene FTO. Their findings are published online today in the journal Science.

The researchers then tested a further 37,000 samples for this gene from Bristol, Dundee and Exeter as well as a number of other regions in the UK and Finland.

The study found that people carrying one copy of the FTO allele have a 30% increased risk of being obese compared to a person with no copies. However, a person carrying two copies of the allele has a 70% increased risk of being obese, being on average 3kg heavier than a similar person with no copies. Amongst white Europeans, approximately one in six people carry both copies of the allele.

"As a nation, we are eating more but doing less exercise, and so the average weight is increasing, but within the population some people seem to put on more weight than others," explains Professor Andrew Hattersley from the Peninsula Medical School. "Our findings suggest a possible answer to someone who might ask 'I eat the same and do as much exercise as my friend next door, so why am I fatter?' There is clearly a component to obesity that is genetic."

The researchers currently do not know why people with copies of the FTO allele have an increased BMI and rates of obesity.

"Even though we have yet to fully understand the role played by the FTO gene in obesity, our findings are a source of great excitement," says Professor Mark McCarthy from the University of Oxford. "By identifying this genetic link, it should be possible to improve our understanding of why some people are more obese, with all the associated implications such as increased risk of diabetes and heart disease. New scientific insights will hopefully pave the way for us to explore novel ways of treating this condition."

The findings were welcomed by Dr Mark Walport, Director of the Wellcome Trust.

"This is an exciting piece of work that illustrates why it was so important to sequence the human genome," says Dr Walport. "Obesity is one of the most challenging problems for public health in the UK. The discovery of a gene that influences the development of obesity in the general population provides a new tool for understanding how some people appear to gain weight more easily than others. This discovery, along with further results expected from the Wellcome Trust Case Control Consortium later this year, will open up a wealth of new avenues to understand and treat common diseases."

The FTO gene was first discovered whilst studying the DNA of a cohort of patients with type 2 diabetes. The risk of developing type 2 diabetes increases significantly for obese people. Through its effect on BMI, having one copy of the FTO allele increases the risk of developing type 2 diabetes by 25%, having two by 50%.

"We welcome this result, which holds promise for tackling rising levels of obesity and the associated risk of developing type 2 diabetes," says Professor Simon Howell, Chair of Diabetes UK, which funded the original collection of samples from people with diabetes. "The discovery has been possible not only because of exemplary team work of scientists from a large number of institutions but also because of the cooperation of the 5,000 diabetes patients and 37,000 people without diabetes who gave blood samples for the study."

Source: Wellcome Trust

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Commonly used herbal supplement, triphala, has cancer-fighting properties

A new study from the University of Pittsburgh Cancer Institute suggests that a commonly used herbal supplement, triphala, has cancer-fighting properties that prevent or slow the growth of pancreatic cancer tumors implanted in mice. The study found that an extract of triphala, the dried and powdered ...

A new study from the University of Pittsburgh Cancer Institute suggests that a commonly used herbal supplement, triphala, has cancer-fighting properties that prevent or slow the growth of pancreatic cancer tumors implanted in mice. The study found that an extract of triphala, the dried and powdered fruits of three plants, caused pancreatic cancer cells to die through a process called apoptosis %26#8211; the body%26#8217;s normal method of disposing of damaged, unwanted or unneeded cells. This process often is faulty in cancer cells. Results of the study, abstract number LB-142, are being presented in a late-breaking session at the annual meeting of the American Association for Cancer Research, April 14-18, at the Los Angeles Convention Center.

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Triphala, one of the most popular herbal preparations in the world, is used for the treatment of intestinal-related disorders. It is typically taken with water and thought to promote appetite and digestion and to increase the number of red blood cells.

"We discovered that triphala fed orally to mice with human pancreatic tumors was an extremely effective inhibitor of the cancer process, inducing apoptosis in cancer cells," said Sanjay K. Srivastava, Ph.D., lead investigator and assistant professor, department of pharmacology, University of Pittsburgh School of Medicine. "Triphala triggered the cancerous cells to die off and significantly reduced the size of the tumors without causing any toxic side effects."

Dr. Srivastava and colleagues fed mice grafted with human pancreatic tumors 1 to 2 milligrams of triphala for five days a week and then compared tumor size and levels of apoptotic proteins in the tumors to a control group of mice that received normal saline only. They found that the mice that received triphala had increased levels of proteins associated with apoptosis and significantly smaller tumor sizes when compared to the control group. Triphala-treated tumors were half the size of tumors in untreated mice. Further testing revealed that triphala activated tumor-suppressor genes, resulting in the generation of proteins that support apoptosis, but did not negatively affect normal pancreatic cells.

"Our results demonstrate that triphala has strong anticancer properties given its ability to induce apoptosis in pancreatic cancer cells without damaging normal pancreatic cells," said Dr. Srivastava. "With follow-up studies, we hope to demonstrate its potential use as a novel agent for the prevention and treatment of pancreatic cancer," said Dr. Srivastava.

Source: University of Pittsburgh

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Managing inflammation may help control cancer

Can reducing inflammation keep cancer at bay? Two novel studies presented at the 2007 Annual Meeting of the American Association for Cancer Research that examine use of common anti-inflammatory agents suggest this might be the case. One large study found that women who regularly use aspirin develope...

Can reducing inflammation keep cancer at bay? Two novel studies presented at the 2007 Annual Meeting of the American Association for Cancer Research that examine use of common anti-inflammatory agents suggest this might be the case. One large study found that women who regularly use aspirin developed fewer cancers than women who did not, while another, conducted in mice and now being confirmed in an analysis of breast cancer patient records, discovered a link between asthma and an increased risk of cancer metastasis to the lungs.

Both studies offer hope that managing inflammation can help control cancer.

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Association of aspirin and non-aspirin NSAIDs with cancer incidence and mortality in a large prospective cohort study: Abstract 3400

Regular aspirin use was associated with lower cancer incidence and cancer mortality, but non-aspirin non-steroidal anti-inflammatory drug (NSAID) use was not, according to one of the largest studies ever conducted to look at the impact of these agents on overall cancer risk. Aspirin was also associated with a lower risk of dying from coronary heart disease, while NSAIDs were not.

Among 22,507 cancer-free postmenopausal women who participated in the Iowa Women%26#8217;s Health Study and provided information on aspirin and NSAID use, those who said they regularly used aspirin had a 16 percent reduced risk of developing cancer more than a decade later, as well as a 13 percent reduced risk of dying from cancer over this same time period, compared to women who did not use aspirin. But there was no statistically significant impact on cancer incidence or mortality among women who used non-aspirin NSAIDs, compared to those who did not, say researchers from the Mayo Clinic, in Rochester, Minnesota.

The researchers also looked at whether smoking status had any impact on the potential preventive effects of aspirin and found that while these agents were associated with lower cancer incidence and mortality among former and never smokers, the same apparent benefits were not seen among active smokers.

These study results do not mean, however, that women should throw away their NSAIDs or pick up a bottle of aspirin, says the study%26#8217;s lead author, Aditya Bardia, M.D., M.P.H. "This is just one study," he says. "However, it does provide provocative evidence that regular aspirin use may play a role in preventing the most common chronic diseases in western countries, namely cancer and heart disease."

The different impact of aspirin compared to other NSAIDs was somewhat surprising, the researchers say. "While chemically different, these agents share at least one similar mechanism of action so you might have expected them to have comparable effects," says Jon Ebbert, M.D., the senior author on the study.

Specifically, aspirin and other NSAIDs reduce inflammation through inhibition of cyclooxygenase (COX) enzymes. These enzymes are responsible for the formation of prostaglandins, which can drive inflammation and possibly stimulate cancer development in a number of organ sites, Dr. Ebbert said.

Previous studies have evaluated whether aspirin or other NSAIDs prevent specific cancers, such as breast cancer. "But this study is unique because we were able to evaluate comprehensive endpoints such as total cancer incidence and cancer mortality, which are more clinically relevant outcomes for patients," Dr. Bardia said.

While the researchers note that one of the weaknesses of this study was that the women were given only a single survey of aspirin and non-aspirin NSAID use, it also had many strengths including the prospective cohort study design, relatively long follow-up (up to 12 years) on a large number of participants, during which time many developed (3,487) and died (1,193) from cancer. The authors were also able to adjust the results for a large number of lifestyle factors, and found little evidence that these other factors could explain the aspirin and cancer associations observed in this study.

Chronic allergen provocation results in a significant increase in the rates of lung metastasis that is dependent on induced pulmonary inflammation: Abstract 2553

An intriguing study, conducted in mice and supported by an ongoing examination of breast cancer patient records, suggests a link between the pulmonary inflammation seen in asthma and increased risk of lung metastasis.

The study, conducted by researchers at Mayo Clinic Arizona, suggests that breast cancer patients who have asthma could reduce their risk of cancer spread by using readily available inhaler medications.

"A link between pulmonary inflammation and lung metastasis would not only have significant effects on patient diagnosis and care, but will also immediately affect the way breast cancer patients are treated," said Anna Taranova, M.D., a senior research fellow in the laboratory of James Lee, Ph.D. at Mayo. "Those with asthma might be able to reduce their risk of lung metastasis, and increase their survival, with aggressive corticosteroid treatment."

Furthermore, the findings could prove to be relevant to asthma patients diagnosed with other cancers that metastasize to the lungs, according to Dr. Taranova.

"We suspect that the relationship between lung inflammation and metastasis will not be limited to breast cancer patients," Dr. Taranova said.

The researchers say these results, along with findings from their other recent research, offer a biological link: activation of cells that line blood vessels is required both for the movement of pro-inflammatory white blood cells into lung tissue (as occurs in asthma) and for the movement of circulating cancer cells from the blood into lung tissue.

In this study, mice were exposed to an aerosolized allergen commonly used in mouse asthma studies and then were injected with melanoma cells. Three other groups of mice were also studied: control mice; mice that received the human corticosteroid allergy and asthma therapeutic agent budesonide after exposure to the allergen; and mice treated with an antibody to eliminate CD4+ T cells before exposure to allergen. (CD4+ T cells orchestrate immune responses to allergens and are largely responsible for the lung inflammation that occurs in asthma.) Metastasis was continually assessed in all groups.

The researchers found that allergen-induced pulmonary inflammation was associated with an almost 400 percent increase in lung metastasis in the mice. But in mice treated with either an antibody to deplete CD4+ T-cells or budesonide to reduce their allergic lung inflammation, the rate of metastasis fell to that seen in mice that were not exposed to allergen. "The treatments wiped out the increases in the rate of metastasis induced by allergic inflammation, reducing the observed rates of metastasis to those found in mice that never experienced the allergen," Dr. Taranova said.

The researchers are now working with epidemiologists at Mayo Clinic Rochester to determine if breast cancer patients with lung metastasis had higher than normal rates of asthma. To date, they have found "productive and provocative results," Dr. Taranova says: over 20 percent of women with breast cancer who developed lung metastasis also appear to have had a previous diagnosis of asthma. The typical frequency of asthma occurrence in U.S. women is, at most, eight percent, she said.

"Our long term goal is to continue this detailed retrospective study of breast cancer patients, eventually translating these studies into a multi-center prospective examination of cancer patients," Dr. Taranova said. "We want to define the specific parameters that link lung metastasis and pulmonary disease."

The researchers say that many questions need to be answered, including whether asthmatics who regularly use anti-inflammatory corticosteroids experience a side benefit of reduced risk for lung metastasis, and whether people who have allergies, but not asthma, are at the same risk.

Dr. Taranova believes these findings are surprising, as the researchers originally suspected that patients with asthma would have limited lung metastasis. "However, as in most things in science, we have learned much more from studies disproving our flawed hypotheses than from studies confirming our preconceived ideas," she said.

Source: American Association for Cancer Research

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Multiple sclerosis drug reduces vision loss in patients with relapsing MS

A drug that slows disability and reduces relapse rates in multiple sclerosis (MS) has been found to also reduce vision loss in patients with relapsing MS. Vision loss is one of the most common and debilitating symptoms of MS. The findings are published in the April 17, 2007, issue of Neurology, the ...

A drug that slows disability and reduces relapse rates in multiple sclerosis (MS) has been found to also reduce vision loss in patients with relapsing MS. Vision loss is one of the most common and debilitating symptoms of MS. The findings are published in the April 17, 2007, issue of Neurology%26#174;, the scientific journal of the American Academy of Neurology.

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The analyses were performed on data from the AFFIRM and SENTINEL studies, which involved 2,138 men and women with relapsing multiple sclerosis from clinics in Europe, North American, Australia, and New Zealand. More than half of the people received the drug natalizumab every four weeks for two years. The rest of the group received placebo. Researchers used eye charts of low contrast letters to test the vision of the participants every 12 weeks.

The study found vision loss, defined as a worsening in score by two rows of letters on the eye chart, was reduced by as much as 47 percent among people taking natalizumab compared to those taking placebo.

"Not only does natalizumab prevent the worsening of vision loss in people with relapsing MS, we also found the drug was associated with significant reductions in the likelihood of sustained vision loss," said study author Laura J. Balcer, MD, MSCE, with the University of Pennsylvania School of Medicine in Philadelphia, PA, and member of the American Academy of Neurology. "Specifically, this drug may have implications for preventing further sustained vision loss due to inflammatory demyelination of nerve fibers that connect to the eye, which is common in MS."

However, Balcer said the potential benefits of natalizumab treatment must be weighed with the drug's potential risks or complications, including the rare, often lethal brain disease progressive multifocal leukoencephalopathy (PML), of which three confirmed cases have been reported.

In addition, data from AFFIRM and SENTINEL studies showed that low-contrast letter acuity eye chart testing is effective for assessing visual outcomes in future MS clinical trials, which have not typically included visual testing components despite vision loss being a main disability of MS.

Source: American Academy of Neurology

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Promising results for brain tumor vaccine

A vaccine for treating a recurrent cancer of the central nervous system that occurs primarily in the brain has shown promise in preliminary data from a clinical trial at the University of California, San Francisco.Known as a glioma, this cancerous tumor is always fatal. Findings from a group of 12 s...

A vaccine for treating a recurrent cancer of the central nervous system that occurs primarily in the brain has shown promise in preliminary data from a clinical trial at the University of California, San Francisco.

Known as a glioma, this cancerous tumor is always fatal. Findings from a group of 12 study patients showed that vitespen vaccination (trademarked as Oncophage) was effective in stimulating the patient%26#8217;s immune system to attack the tumor cells, a function that is known medically as tumor-specific immune response. All the patients had recurrent, high-grade glioma, and all showed the immune response. The vaccine is made from the patient%26#8217;s own tumor.

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The clinical trial was conducted by the UCSF Brain Tumor Research Center. Results were presented today (April 16) at the 75th annual meeting of the American Association of Neurological Surgeons in Washington, DC.

%26#8220;In this trial, we have observed a correlation between immune response as a result of vitespen vaccination and potential clinical benefit,%26#8221; said Andrew T. Parsa, MD, PhD, assistant professor in the Department of Neurological Surgery at UCSF and recipient of the 2007 Young Investigator Award at AANS. %26#8220;We are encouraged by the prolonged improvement in overall survival rates, although this phase 1/2 study is not designed to primarily evaluate efficacy. The patients in this trial represent the most challenging patient population to treat.%26#8221;

Of the 12 patients being treated, eight can currently be evaluated for overall survival, while four are still receiving treatment. Seven out of the eight patients have exceeded the historical median benchmark of 6.5 months survival from time of recurrence. The investigators will continue to follow the patients for overall survival. Based on these results, a larger, multi-center phase 2 study is planned for late 2007.

Derived from each individual%26#8217;s tumor, vitespen contains the %26#8220;fingerprint%26#8221; of the patient%26#8217;s particular cancer and is designed to reprogram the body%26#8217;s immune system to target only cancer cells bearing this fingerprint. The vaccine is intended to leave healthy tissue unaffected and limit the debilitating side effects typically associated with traditional cancer treatments such as chemotherapy and radiation therapy. Vitespen has been granted fast-track and orphan drug designations from the Food and Drug Administration for both metastatic melanoma (skin cancer) and renal cell carcinoma (kidney cancer).

Reviewing the presentation at AANS, Henry Brem, MD, director of neurosurgery at the Johns Hopkins Medical Institutions, noted, %26#8220;This is an encouraging study of a therapeutic cancer vaccine that targets multiple tumor antigens, supported by rigorous immuno-monitoring. A larger phase 2 trial is certainly warranted to evaluate efficacy.%26#8221; Brem is a developer of the first approved local therapy for glioma.

The UCSF clinical trial is a phase1/2 study designed to establish the feasibility, safety and preliminary efficacy of vaccination in patients with recurrent, high-grade glioma. The trial involves two groups of six patients, both of whom receive a minimum of four injections. The first group receives biweekly vaccinations and the second receives weekly vaccinations. Patients are monitored for immune response before, during and after treatment.

The UCSF investigators will continue to follow patients for progression-free survival and overall survival. According to investigators, no adverse events or toxicity identified were considered attributable to the vaccine.

Cheryl Canagelo, a 52-year-old woman from Oakley, Calif., came to UCSF for a second opinion after undergoing radiation and chemotherapy elsewhere for treatment of a glioma. At UCSF she learned that part of the tumor was still present, and she enrolled in the vitespen vaccine trial.

Once the chemotherapy was out of her system, Parsa performed surgery, just four days before Christmas. He removed all but a very small amount of tumor that was near an area that could affect her speech. The removed tissue was sent to Antigenics, the Massachusetts biotech company that produces the vaccine from the patient%26#8217;s tumor tissue. Altogether, Canagelo has now received seven injections of vaccine.

%26#8220;My most recent MRI showed that there is no tumor,%26#8221; Canagelo said. %26#8220;I haven%26#8217;t had any side effects from the treatment, and I%26#8217;m getting stronger every day. I would urge patients to seek out second opinions and investigate clinical trials. I can tell you I am so glad I did.%26#8221;

%26#8220;Our goal is to change the management of recurrent glioma from a life threatening disease, in which survival rates are typically 25 to 26 weeks, into a chronic disease with extended survival and improved quality of life for patients,%26#8221; Parsa said. %26#8220;Although our survival data are encouraging, a larger phase 2 study will be required to determine the benefit of vitespen for patients with recurrent glioma. The consistent, tumor specific immune response seen in these patients suggests that in the right patient population, the vaccine could have a significant impact.%26#8221;

Source: University of California, San Francisco

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Designed molecule could lead to first drug treatment for Alzheimer's disease

A molecule designed by a Purdue University researcher could lead to the first drug treatment for Alzheimer's disease."There are many people suffering, and no effective treatment is available to them," said Arun Ghosh, the Purdue professor who designed the molecule. "There is an urgent need for a dru...

A molecule designed by a Purdue University researcher could lead to the first drug treatment for Alzheimer's disease.

"There are many people suffering, and no effective treatment is available to them," said Arun Ghosh, the Purdue professor who designed the molecule. "There is an urgent need for a drug to treat this devastating disease, and the scientific community has been working on this problem for many years."

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Image: Shown is an image of the X-ray crystal structure of the molecule bound to memapsin 2, the enzyme responsible for amyloid plaque deposits in the human brain. The bond disables the enzyme and prevents the plaques that cause Alzheimer's disease.

The National Institute on Aging estimates that as many as 4.5 million Americans suffer from Alzheimer's disease, which leads to dementia by affecting parts of the brain that control thought, memory and language.

The new molecule prevents the first step in a chain of events that leads to amyloid plaque formation in the brain. The material at various stages of plaque formation is made up of fibrous clumps of toxic proteins that cause the devastating symptoms of Alzheimer's disease, said Ghosh, who has a dual appointment in the chemistry and medicinal chemistry and molecular pharmacology departments.

"Interdisciplinary research and the tools available today allowed us to build a molecule that is both highly potent and highly selective, meaning it does not affect other enzymes important to brain function," he said.

Jordan Tang, head of the Protein Studies Research Program at the Oklahoma Medical Research Foundation, is one of the discoverers of the critical enzyme and target for intervention, Ghosh said.

Tang discovered a key enzyme called memapsin 2, or beta-secretase, that is involved in the development of Alzheimer's disease. The action of this enzyme on a special protein, called the amyloid precursor protein, leads to the formation of plaques in the brain. The development of an inhibitor compound targeting memapsin 2 could block this reaction, thus preventing the disease. Utilizing Tang's information about the enzyme, Ghosh designed the first memapsin 2 inhibitor.

"This is the most exciting target today for Alzheimer's disease intervention," said Tang, who holds the J.G. Puterbaugh Chair in Medical Research at the Oklahoma Medical Research Foundation. "These interactions happen at a very early stage in the disease, and if we could block them, we could prevent many of the harmful steps that follow and drastically reduce the impact. In our most recent tests, a single dose of the designed compound reduced the beta-amyloid level by 30 percent."

As a therapeutic target, memapsin 2 has an additional advantage because it belongs to a class of enzymes called aspartyl proteases. Researchers already have successfully created drugs to block proteases for the treatment of other diseases. One of these successful drugs was developed from a molecule designed by Ghosh for treatment of drug-resistant HIV, which was approved by the Food and Drug Administration last year. The principles used in the development of these drugs can be carried over and used in the design of new drugs, Tang said.

Ghosh's team achieved a breakthrough in Alzheimer's disease research when they were the first to use a method called X-ray crystallography to map the structure of Ghosh's designed inhibitor bound to the enzyme. This revealed information necessary to move the research forward and develop molecules that could be used in drugs.

"The moment we had the crystal structure, we knew exactly how the inhibitor worked, the interactions of the molecular bonds and what properties were most important," Ghosh said. "This allowed us to quickly build inhibitor molecules and bypass the usual lengthy process of trial and error in molecule design. Within a year we had developed modified inhibitors that were much smaller and more druglike in character."

Ghosh's most recent research findings and the collaborative research results with Tang will be published in the May 3 issue of the Journal of Medicinal Chemistry and are posted on the journal's Web site. Purdue postdoctoral fellow Nagaswamy Kumaragurubaran and graduate students Sarang S. Kulkarni and Xiaoming Xu co-authored the paper. In addition, Lin Hong, Wanpin Chang, Vajira Weerasena, Robert Turner, Gerald Koelsch and Geoffrey Bilcer from the Oklahoma Medical Research Foundation and Athenagen Inc. co-authored the paper. The National Institutes of Health National Institute on Aging funded this research.

"We began this work in 2000 and prepared and examined several hundred molecules, we now have one with great clinical potential," Ghosh said.

Research into memapsin 2 faced a setback when memapsin 1, an enzyme very similar in structure, was discovered. Unlike memapsin 2, memapsin1 is involved in many important biological processes and its inhibition would cause serious adverse side effects, Ghosh said.

"Unfortunately, all of our early designed compounds that were potent against memapsin 2 also inhibited memapsin 1," he said. "Selective inhibition of memapsin 2, or building selectivity, became very important. The scientific community was faced with a formidable challenge."

Ghosh's team developed a novel structure-based design strategy to systematically understand where and how to target memapsin 2 specifically.

"According to our studies, inhibition of memapsin 2 does not cause toxic side effects," Tang said. "This is extremely encouraging because it allows for intervention very early in the stages of the disease, and it is a type of enzyme with which we are very familiar. There is a precedence of great success in this type of work."

Ghosh and Tang founded the biopharmaceutical company Zapaq, located in Oklahoma City, which now has merged with CoMentis. San Francisco-based CoMentis has used the research results of Ghosh and Tang to begin to develop pharmaceuticals. A drug from the memapsin 2 inhibitor could go into the first phase of clinical trials this year and begin the lengthy trial process necessary before the FDA approves a drug to be available on the market.

Alzheimer's disease usually begins after age 60, and the risk increases with age. According to the National Institute on Aging, about 5 percent of men and women ages 65-74 have Alzheimer's disease, and nearly half of those 85 and older may have the disease.

Source: Purdue University

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New imaging technique will help researchers learn more about molecular mechanisms of multiple sclerosis

Researchers have developed a way to use three types of microscopic imaging techniques simultaneously to analyze living tissue and learn more about the molecular mechanisms of multiple sclerosis, information that could help lead to earlier detection and new treatments.The combined imaging method is e...

Researchers have developed a way to use three types of microscopic imaging techniques simultaneously to analyze living tissue and learn more about the molecular mechanisms of multiple sclerosis, information that could help lead to earlier detection and new treatments.

The combined imaging method is enabling the researchers to study how multiple sclerosis causes an overproduction of "astroglial filaments," which form bundles between critical nerve fibers and interfere with proper spinal cord functioning. The technique also promises to yield new information about how the disease degrades the myelin sheath, which insulates nerve fibers and enables them to properly conduct impulses in the spinal cord, brain and in the "peripheral nervous system" throughout the body, said Ji-Xin Cheng, an assistant professor in Purdue University's Weldon School of Biomedical Engineering and Department of Chemistry.

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The three imaging techniques - called sum frequency generation, two-photon-excitation fluorescence and coherent anti-Stokes Raman scattering - ordinarily are used alone. Purdue researchers have developed a way to combine all three methods in the same platform, promising to reveal new details about the spinal cord and myelin sheath, Cheng said.

"Combining these three methods allows us to conduct more specific and precise molecular analyses," he said. "Ultimately, this work paves the way toward studying the degradation of the myelin sheath as a result of multiple sclerosis and analyzing living tissue to study the mechanisms of disease."

Multiple sclerosis affects more than 350,000 people in the United States and 2 million worldwide.

Findings will be detailed in a paper appearing in May in the Biophysical Journal and is currently online. The paper was authored by biomedical engineering doctoral student Yan Fu and postdoctoral research associate Haifeng Wang; Riyi Shi, an associate professor of basic medical science in Purdue's School of Veterinary Medicine and also an associate professor of biomedical engineering; and Cheng.

Shi, a member of Purdue's Center for Paralysis Research, specializes in spinal cord and brain trauma and chronic neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and multiple sclerosis.

"We are using a unique and powerful combination of technologies to uncover the mechanisms of multiple sclerosis," Shi said. "We hope to one day establish an effective intervention to not only slow down, but even possibly reverse the development of this disease, which will potentially have profound economic and social impacts on this nation and the world."

Because the imaging techniques work without using dyes to "label" cells and structures, they can be used to study living tissues, representing a major advantage over conventional microscopic imaging technologies.

Raman microscopy, an imaging technique invented more than three decades ago, cannot be used effectively to study living tissue because the extremely weak "Raman scattering" signals require hours to yield an image, whereas coherent anti-Stokes Raman scattering, or CARS, overcomes this limitation, Cheng said.

"CARS microscopy permits label-free imaging of specific molecules with a speed of one frame per second or even faster," he said.

CARS imaging takes advantage of the fact that molecules vibrate at specific frequencies. In a CARS microscope, two laser beams are overlapped to produce a single beam having a new frequency representing the difference between the original two beams. This new frequency then drives specific molecules to vibrate together "in phase," amplifying the Raman signals from those molecules.

"It's like pushing someone on a swing," Cheng said. "If you push in synch with the upswing, the swing will go higher. That's the same as being in phase."

Sum frequency generation imaging does just the opposite, adding the frequencies of the two original beams, producing a new signal with a frequency that is the sum of the original beams.

The third imaging technique, two-photon excitation fluorescence, provides higher contrast and brighter images than conventional fluorescent imaging methods. Photons are the individual particles that make up light. In two-photon excitation fluorescence, two photons are used to illuminate a target.

The researchers have used the imaging methods to observe living spinal tissue extracted from guinea pigs. The technique of extracting the tissue and then keeping it alive long enough to analyze was developed in Shi's lab.

Conventional microscopic imaging techniques require samples to be labeled with dyes, killing the tissues in the process. Being able to analyze living tissue could allow researchers to determine the molecular mechanisms responsible for multiple sclerosis and other conditions, Cheng said.

The myelin sheath is made of molecules called lipids, which consist of a head and tail segment. The new findings show that images can reveal whether the orientation of the chemical bonds in these lipid molecules is "scrambled," when the myelin sheath is unhealthy and degraded from disease, Cheng said.

"We can see the myelin sheath with CARS, and that's great, but it's not enough," Cheng said. "We also want to study other molecules and see the interactions between cells."

Researchers simultaneously took images of astroglial filaments, critical components of structures called astrocyte processes, which provide structural support for the nerve fibers in a spinal column. The sum frequency generation imaging reveals details about the astroglial filaments.

Two-photon excitation fluorescence reveals information about the influx of calcium into cells, which causes damage to nerve fibers.

"So, having all three of these imaging methods in the same platform enables us to study many elements of the disease process simultaneously in the same tissue samples," Cheng said.

Researchers hope one day to use the combined approach to design a "minimally invasive" system for diagnosing patients in the hospital or doctor's office, he said.

"There are two directions of this research," Cheng said. "One is to study the mechanisms of disease, and that should form the foundation for designing new treatments. The other is to keep pushing the technology to make it less and less invasive, which will help in the early detection of multiple sclerosis."

The astroglial filaments also are involved in producing scar tissues following trauma injuries to the central nervous system, so a better understanding of their workings could lead to new treatments for repairing damage caused in accidents.

Source: Purdue University

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Stem cells induce development of protective effect in area hit by stroke

This is the impressive result of a study carried out by a group of researchers coordinated by Dr. Maria Grazia De Simoni of the Mario Negri Institute in Milan, Italy in cooperation with the Istituto Neurologico Besta (Milan) and the University of Lausanne. The study appears in the April 18th issue o...

This is the impressive result of a study carried out by a group of researchers coordinated by Dr. Maria Grazia De Simoni of the Mario Negri Institute in Milan, Italy in cooperation with the Istituto Neurologico Besta (Milan) and the University of Lausanne. The study appears in the April 18th issue of the international, peer-reviewed, open-access online journal of the Public Library of Science, PLoS ONE.

Stroke is the first cause of permanent invalidity and the third cause of death in industrialized countries.

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Despite the recent advancements in the management of ischemic patients (early diagnosis, thrombolysis, stroke units and rehabilitation centers), stroke still represents a major and unresolved medical issue.

"Stroke causes the death of many nervous cells that, in theory, could be substituted by stem cells. A few studies have shown that these cells can be effective, although various issues about their use and the mechanisms of their protective action remained unsolved," says Maria Grazia De Simoni.

"Our research has underlined a possible mechanism of action. Once introduced in the area of the brain hit by a stroke, stem cells induce the development of a protective effect in this same area," explains De Simoni. "Therefore, it is not necessary, as proposed in past studies, for stem cells to turn into neurons in order to protect the brain from ischemic injury and restore brain functions. Their presence in brain tissue is sufficient to induce a protective reaction."

Various cells are involved in this reaction, among which the microglia, which has always been thought to have a toxic and inflammatory role. "Instead, we suggest that the microglia also has a protective function,%26#8221; says De Simoni. %26#8220;Moreover our research shows that these cells survive in brain tissue only for a few days and then they are eliminated. This is very important given the possibility that stem cells may turn into cancer cells."

Source: Public Library of Science

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Real-time MRI helps guide surgical robot

Surgery is about to change with the introduction of a new surgical robotic system at the University of Calgary/Calgary Health Region. NeuroArm aims to revolutionize neurosurgery and other branches of operative medicine by liberating them from the constraints of the human hand.The world's first MRI-c...

Surgery is about to change with the introduction of a new surgical robotic system at the University of Calgary/Calgary Health Region. NeuroArm aims to revolutionize neurosurgery and other branches of operative medicine by liberating them from the constraints of the human hand.

The world's first MRI-compatible surgical robot, unveiled today, is the creation of neurosurgeon Dr. Garnette Sutherland and his team. Dr. Sutherland has spent the last six years leading a team of Canadian scientists, in cooperation with MacDonald, Dettwiler and Associates Ltd. (MDA), to design a machine "that represents a milestone in medical technology."

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"Many of our microsurgical techniques evolved in the 1960s, and have pushed surgeons to the limits of their precision, accuracy, dexterity and stamina," says Dr. Sutherland, professor of neurosurgery, University of Calgary Faculty of Medicine and the Calgary Health Region. "NeuroArm dramatically enhances the spatial resolution at which surgeons operate, and shifts surgery from the organ towards the cell level."

Designed to be controlled by a surgeon from a computer workstation, neuroArm operates in conjunction with real-time MR imaging, providing surgeons unprecedented detail and control, enabling them to manipulate tools at a microscopic scale. Advanced surgical testing of neuroArm is currently underway, followed by the first patient, anticipated for this summer.

"The launch of neuroArm places the U of C and the Calgary Health Region at the forefront of the emerging field of biomedical engineering, and establishes Canada's leadership role in image-guided robotic surgery," says U of C President Harvey Weingarten, PhD.

"The Calgary Health Region considers the introduction of the neuroArm an historic moment in our ability to provide unprecedented care and safety to patients in Alberta," says the Calgary Health Region's Chief Executive Officer and President Jack Davis. "We are extremely proud to be a partner in neuroArm and to have worked with such a dedicated team of individuals and funding partners."

NeuroArm, one of the most advanced robotic systems ever developed, was designed and built in collaboration with MDA, known for creating Canadarm and Canadarm2. Bringing neuroArm to life required a unique partnership between medicine, engineering, physics, and education; some of Calgary's most visionary philanthropists; the high-tech sector, and numerous government agencies and research funding organizations. "This unprecedented collaboration is a direct result of Calgary's optimistic and entrepreneurial community spirit," says Dr. Sutherland. "It's no accident a project like this is coming out of Calgary. Our community believes in innovation and supporting challenging projects."

"This is truly a flagship program for the University of Calgary and all the partner agencies involved," says Weingarten. "Visioning and building neuroArm required unprecedented collaboration between numerous government departments, funding agencies and the private sector. Making this a reality will have impacts and benefits we can't even anticipate as Calgary and Canada become known as world leaders in the field of robotic surgery."

The project began in 2001 when the namesakes of the Seaman Family MR Research Centre, Calgary philanthropists, oilpatch pioneers and brothers Doc, B.J. and Don Seaman provided $2 million to begin planning neuroArm. Their contribution was a natural extension of their support for the research centre that began with the development of the world's first intraoperative MRI scanner based on a movable high-field magnet.

"As engineers, the technology involved in neuroArm intrigued us from the start. We really understood the challenges and appreciated the brilliance that had to go into it," Doc Seaman says. The family realized that a project like neuroArm would place Calgary on the leading-edge of surgery worldwide.

"The best surgeons in the world can work within an eighth of an inch. NeuroArm makes it possible for surgeons to work accurately within the width of a hair," Doc Seaman says. "This will put us on the world stage and will help attract more top people in medicine and surgery, which will benefit the university and the community as a whole."

"This is a shining example of Canadian science making breakthroughs that will improve quality of life for people in Canada and around the globe," says President and CEO of the Canada Foundation for Innovation Dr. Eliot Phillipson. "This world-class project will further develop Canada's international reputation as a place where outstanding research is being conducted."

"Our mission is to be a leader in health and a partner in care. Patient care and safety are always our number one priority," says Davis. "We are thrilled that the neuroArm will improve recovery and wait times for patients, and most of all, improve their quality of life following surgery so they can get back to daily life activities."

The Seaman family's donation, combined with funding from Western Economic Diversification Canada, allowed for detailed planning and design of the project. That set the stage for substantial support from the Canada Foundation for Innovation, the National Research Council of Canada, Alberta Advanced Education and Technology, Alberta Heritage Foundation for Medical Research and additional philanthropists to build the one-of-a-kind machine and create a comprehensive medical robotics program.

A global search for robotics expertise led Sutherland to MDA, a perfect fit for neuroArm because of the company's background in creating specialized space robots, used aboard NASA space shuttles and the International Space Station.

"NeuroArm is a great fit for us, allowing us to apply our world-renowned space solutions to medical applications that will benefit patients here on Earth," says Bruce Mack, vice-president of development programs of MDA's Brampton operations. "The combination of our remote operation and sensory information expertise, coupled with our manipulation technologies, will enable improved decision making and performance in the operating theatre."

Developing neuroArm required an international collaboration of health professionals, physicists, electrical, software, optical and mechanical engineers to build a robot capable of operating safely in a surgical suite and within the strong magnetic field of the intraoperative MRI environment.

"Building a robot is complex to begin with. Adding the constraints of operating in a sterile operating room, within an MRI machine and alongside the other people involved in surgery makes it a very complex environment," says the project's robotics engineer Alex Greer. By acquiring first-hand knowledge of the demands in the operating room, Greer and Paul McBeth, the first U of C neuroArm robotics engineer, acted as the bridge between the physicians, scientists and engineers involved in the project.

"Doctors and engineers are good at what they do but they speak different languages," Greer says. "Translating surgical requirements into technical terms can be a challenge." When the project began, engineers from MDA traveled to Calgary and worked with surgeons for several weeks to define the requirements necessary for the successful design of neuroArm.

Sutherland's team is developing specialized training programs in partnership with the Calgary Health Region, and U of C's faculties of medicine and education to train surgeons in the use of neuroArm. Many other surgical disciplines have and continue to participate in applying neuroArm to various types of surgical procedures.

"We're not just building a robot, we're building a medical robotics program," Dr. Sutherland says. "We want the neuroArm technology to be translated into the global community, i.e. hospitals around the world," he says. "To accomplish this, we will need our students and young professionals because they're the powerhouse when it comes to embracing new technology and applying it to clinical care."

Source: University of Calgary

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Sleep not only strengthens content of memories but also the particular order in which they were experienced

We have usually quite strong memories of past events like an exciting holiday or a jolly birthday party. However it is not clear how the brain keeps track of the temporal sequence in such memories: did Paul spill a glass of wine before or after Mary left the party?
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Previous findings from a r...

We have usually quite strong memories of past events like an exciting holiday or a jolly birthday party. However it is not clear how the brain keeps track of the temporal sequence in such memories: did Paul spill a glass of wine before or after Mary left the party?

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Previous findings from a research group headed by Jan Born at the University of L%26#252;beck have confirmed the widely held view that long-term memories are formed particularly during sleep, and that this process relies on the brain replaying recently encoded experiences during the night. The same research group now provides evidence that sleep not only strengthens the content of a memory but also the particular order in which they were experienced, probably by a replay of the experiences in "forward" direction.

Students were asked to learn triplets of words presented one after the other. Afterwards they slept, whereas in a control condition no sleep was allowed. Later, recall was tested by presenting one word and asking which one came before and which one came after during learning. Sleep was found to enhance word recall, but only when the students were asked to reproduce the learned words in forward direction.

This finding shows that sleep associated consolidation of memories enforces the temporal structure of the memorized episode that otherwise might be blurred to a timeless puzzle of experiences.

Source: Public Library of Science

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Cancer-suppressing gene successfully delivered into tumors

A cancer-suppressing gene has been successfully delivered into the tumors of stage 4 lung cancer patients via an intravenously administered lipid nanoparticle in a phase I clinical trial at The University of Texas M. D. Anderson Cancer Center. The gene, FUS1, also was found to be active in the metas...

A cancer-suppressing gene has been successfully delivered into the tumors of stage 4 lung cancer patients via an intravenously administered lipid nanoparticle in a phase I clinical trial at The University of Texas M. D. Anderson Cancer Center. The gene, FUS1, also was found to be active in the metastatic non-small cell lung cancer tumors.

"We've treated 13 patients in this first-in-human study and we've seen an exciting proof of concept with no significant drug-related toxicity," says principal investigator Charles Lu, M.D., associate professor in M. D. Anderson's Department of Thoracic, Head and Neck Medical Oncology.

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Blinded analysis of pretreatment and post-treatment biopsies of three patients' tumors show that expression of FUS1 was absent from pretreatment samples while a high level of FUS1 was expressed in tumors after treatment. FUS1 can induce apoptosis - programmed cell death - in cancer cells but is frequently lost when normal cells become cancerous.

Lu presented a poster on the study on April 17 at the late-breaking abstract session of the American Association for Cancer Research annual meeting in Los Angeles.

Other attempts at gene therapy have employed an adenovirus to deliver the therapeutic gene. "Here we are using a non-viral, non-infectious delivery system," Lu says.

The only clinically significant side effect so has been fever, but Lu says premedication with a steroid and diphenhydramine has eliminated that so far.

Previous gene therapy clinical trials also involved direct injection into tumors. "This is the first time anyone has shown that a gene can be injected and then be taken up and expressed in cancer cells at distant sites," said Jack Roth, M.D., professor of the M. D. Anderson Department of Thoracic and Cardiovascular Surgery and a pioneer in the field of gene therapy.

FUS1 can induce apoptosis - programmed cell death - in cancer cells but is absent in those cells. The FUS1 nanoparticle formulation was developed and tested in Roth's lab. It advanced to phase I clinical trial after a promising test on human non-small cell lung cancer in a mouse model.

FUS1 was discovered by a research team led by Roth at M. D. Anderson and by John Minna, M.D., of the Department of Internal Medicine and Pharmacology, Hamon Center for Therapeutic Oncology Research, at The University of Texas Southwestern Medical Center at Dallas. Roth and Minna are the co-principal investigators of a National Cancer Institute Specialized Program of Research Excellence in Lung Cancer.

"As a clinician, I am very cautious about saying that we have shown clinical activity at this point. We have some encouraging data. The number of patients is too small to draw any definite conclusions, however," Lu said.

Three patients of eight who received two or more doses experienced stable disease for three to seven months. Median survival time for all patients is 14.6 months, which Lu notes compares favorably to a seven-month median survival time for patients receiving second line therapy.

All patients on the trial had been treated with front line cisplatin combination chemotherapy, which failed to halt their disease. The clinical trial continues. No maximum tolerated dose has been established, Lu says.

The nanoparticle delivery system consists of a plasmid gene expression cassette loaded with DNA that encodes the FUS1 protein. This is wrapped tightly in a form of cholesterol to protect it from the body's defense mechanisms. The nanoparticles accumulate mainly in the lungs, particularly in the tumors, where the genes repeatedly express FUS1 tumor-suppressing proteins.

Lung cancer is the leading cause of cancer death in the United States, causing 160,000 deaths annually. About 80 percent of lung cancer is of the non-small cell type.

Source: University of Texas

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Chinese herbs may help protect breast cancer patient's bone marrow and immune system

Using Chinese herbs either alone or in conjunction with chemotherapy may help protect a breast cancer patient's bone marrow and immune system, as well as improving the woman's overall quality of life.Sixty per cent of women undergoing chemotherapy for breast cancer experience a range of significant ...

Using Chinese herbs either alone or in conjunction with chemotherapy may help protect a breast cancer patient's bone marrow and immune system, as well as improving the woman's overall quality of life.

Sixty per cent of women undergoing chemotherapy for breast cancer experience a range of significant short term side effects. These include nausea, vomiting and fatigue, as well as inflammation of the gut lining, decreased numbers of red and white blood cells and decreased numbers of blood platelets.

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Chinese medicinal herbs include mixtures of herbal compounds or extracts from herbs, and they are prescribed to counteract the side effects of chemotherapy. This Cochrane Systematic Review set out to see if there is conventional evidence indicating that these medicines are safe and whether there is evidence that the medicines are effective.

The researchers identified seven randomised studies involving 542 patients with breast cancer. By analysing these data, the researchers concluded that there was no evidence that the Chinese medicinal herbal treatment caused harm, and some evidence that it might reduce side effects.

"Further trials are needed before the effects of traditional Chinese medicines for people with breast cancer can be evaluated with any real confidence," says Assistant Professor Jing Li, who works at the Chinese Cochrane Centre in Chengdu, China.

Source: John Wiley %26amp; Sons, Inc.

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Chemicals in vegetables may help prevent cancer

Chemicals in cruciferous vegetables, such as broccoli, watercress, cabbage and cauliflower, appear to not only stop human prostate cancer cells from growing in mice but also may cut off the formation of blood vessels that "feed" tumors, says a University of Pittsburgh Cancer Institute study. The stu...

Chemicals in cruciferous vegetables, such as broccoli, watercress, cabbage and cauliflower, appear to not only stop human prostate cancer cells from growing in mice but also may cut off the formation of blood vessels that "feed" tumors, says a University of Pittsburgh Cancer Institute study. The study, abstract number 4200, is being presented today at the annual meeting of the American Association for Cancer Research, April 14-18, at the Los Angeles Convention Center.

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"The contribution of diet and nutrition to cancer risk, prevention and treatment has been a major focus of research in recent years because certain nutrients in vegetables and dietary agents appear to protect the body against diseases such as cancer," said Shivendra Singh, Ph.D., lead investigator and professor of pharmacology and urology at the University of Pittsburgh School of Medicine. "From epidemiologic data, we know that increased consumption of vegetables reduces the risk for certain types of cancer, but now we are beginning to understand the mechanisms by which certain vegetables like broccoli may help our bodies fight cancer and other diseases."

Dr. Singh%26#8217;s study is based on phytochemicals, called isothiocyanates (ITCs), found in several cruciferous vegetables and generated when vegetables are either cut or chewed. His laboratory has found that phenethyl-ITC, or PEITC, is highly effective in suppressing the growth of human prostate cancer cells at concentrations achievable through dietary intake.

The current study follows previous research in which Dr. Singh%26#8217;s laboratory found that mice grafted with human prostate tumors that received a small amount of PEITC daily for 31 days had significantly reduced tumor size when compared to a control group of mice. Now the researchers have shown that treating cells in culture with PEITC inhibits angiogenesis, a process that plays an important role in the growth and spread of cancer by forming new blood vessels that pass oxygen and nutrients to tumor cells.

"Angiogenesis is a major issue in cancer metastases," said Dr. Singh. "Our results provide promising preliminary evidence that constituents of many edible cruciferous vegetables may slow down, or even halt, this process."

Source: University of Pittsburgh

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Is cancer just a fundamental consequence of the way we are made?

Cancer is a natural consequence of human evolution. Our genes have not developed to give us long and happy lives. They are optimized to copy themselves into the next generation - irrespective of our personal desires. According to Jarle Breivik, an associate professor at the University of Oslo, Norwa...

Cancer is a natural consequence of human evolution. Our genes have not developed to give us long and happy lives. They are optimized to copy themselves into the next generation - irrespective of our personal desires. According to Jarle Breivik, an associate professor at the University of Oslo, Norway, we are therefore unlikely to find a final solution to cancer.

Doing research at the Institute of Basic Medical Sciences, Breivik explores the connection between cancer development and Darwinian evolution. In a recent interview with Scientific American, and the research magazine Apollon, published by the University of Oslo, he concludes that %26#8220;Cancer is a fundamental consequence of the way we are made. We are temporary colonies made by our genes to propagate themselves to the next generation. The ultimate solution to cancer is that we would have to start reproducing ourselves in a different way.%26#8221;

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Image: Figure 1- The costs and benefits of DNA repair may be illustrated as alterative strategies on a race track. The green car always stops for repairs when a problem is indicated, whereas the red car ignores all warning lights. The green car may have the better strategy under ordinary conditions (A) because it always has a faultless engine, whereas the red car accumulates errors. Fore the same reason, it may also seem rational that harsher environments favour the repair strategy of the green car. Paradoxically, however, the answer may be exactly the opposite. Imagining your body as a war zone where tobacco smoke, an unhealthy diet and excessive sunbathing attack the genes with heavy ammunition (mutagen in figure B.) Damages appear faster than can be removed, and the green car gets trapped in the check point. To stop for repairs is thus a fatal strategy, and it is better to keep on going despite accumulating errors. The model thus explains why mutagenic environments favour the rise of genetically unstable cancer cells within our body

Genes that repair genes

As a medical student at the Norwegian Radium Hospital, Breivik discovered a curious phenomenon. He found that cancer cells that developed in the upper colon had other types of mutations than those found in tumours closer to the rectum. This finding was confirmed by other researchers and could be traced to mutations in particular DNA repair genes. Such genes have evolved to prevent mutations in other genes and play a vital role in defending the organism from cancer. But why do cells in the upper region of the intestine lose a different type of repair mechanism than those further down?

Breivik was determined to find an explanation. After several years of data mining and theoretical modelling, he was able to demonstrate a connection between loss of DNA repair and harmful environmental factors in the intestines. Curiously however, the cancer cells appeared to have lost the repair mechanisms that would protect them from DNA damage in their particular environment. Breivik thus proposed the following hypothesis: Although DNA repair is favourable to the organism; it may not be favourable to the individual cell. The theory was developed in several science papers, including an invited Commentary in the Proceedings of the National Academy of Sciences USA, and may be illustrated as the effect of alternative strategies in a car race (figure 1).

Image: Figure 2- Multicellular organisms, like humans, implies a division between the somatic cells that make up the body and the germ cells that are sent on to the next generation. The genes that developed through the germ line have been selected for their ability to build functional and reproducing organisms. Branching off to the somatic linage, however, the new mutants are favoured for their ability to reproduce within the body. The aging cells thus relentlessly proceed towards breakdown of growth regulatory mechanisms, and cancer can be understood as a natural consequence of evolutionary dynamics.

%26#8220;Deciding when to stop for repairs and when to keep on going is a difficult challenge. Making repairs assures an optimized vehicle, but it also consumes valuable time and resources. At first thought, it may seem obvious that a damaging environment calls for more repair. Paradoxically, however, the effect may be exactly the opposite. Imagine that you are racing through a war zone with constant bombardment. Stopping for repair can then be a fatal strategy, and it is better to keep on going with flat tires and a screaming engine than to stop for repairs,%26#8221; says Breivik.

This illustration thus explains why genetically unstable cancer cells are favoured in hostile environments%26#8212;such as in the lungs of a heavy smoker. The model may also be described mathematically and has been experimentally confirmed in cell cultures and animal models by leading research groups in the field.

%26#8220;Cells exposed to particular carcinogens die if they have the relevant repair mechanism, while genetically unstable cancer cells continued to grow,%26#8221; Breivik explains.

Evolution within

This research shows how the environment influences the selection of genes inside of the body and is identical to the principle that Darwin found to explain the origin of species.

%26#8220;The body is not a static system. Our cells are in a constant state of development, and new genetic variants arise every day. Many of these mutants are removed by the immune system but, sooner or later, a cell will break through the defences and develop into a tumour of wild-growing renegades.%26#8221;

Cancer development is an evolutionary process within the multicellular organism, but it is also related to the general process of evolution through the generations. Life begins when our parent%26#8217;s genes are united in the zygote. These genes have been selected through millions of generations for their ability to create a functional organism, but few days after fertilization the genes split up in two different directions. Some end up in the germ cells (sperm and ova) that will bring them to the next generation, while the rest end up in the somatic cells that make up our body. The somatic cells are initially programmed to cooperate, but as we age and new mutations arise, the evolutionary process will favour cells that break ranks and propagate freely within the body. Thus, according to Breivik, the division between germ cells and somatic cells represents the Darwinian explanation to cancer (figure 2).

Time bombs

Natural selection favours genes for their ability to replicate in their given environment. Through the course of evolution, they have thereby developed increasingly more complex mechanism for self-replication, first as single celled organisms and later as cells that cooperate in complex colonies.

%26#8220;This is where humans belong. We are cell colonies developed for propagating our genes from one generation to the next. As soon as our children can take care of themselves, we are irrelevant to the genes. Caring grandparents may be good to have, but dozens of enduring ancestors will not increase a gene%26#8217;s chance for survival%26#8212;on the contrary, they may represent a waste of valuable recourses. The entire human genome is therefore probably developed to give us a limited lifespan,%26#8221; says Breivik.

He believes that many of our genes are constructed such that they protect against cancer in the first part of our lives, but that they are programmed for destruction as we get older.

%26#8220;We see that DNA repair genes, which protect us from cancer in early life, contain unstable DNA sequences that increase their probability for breakdown as time passes. These sequences are ticking time bombs in our genome and represent a paradox if we consider what is best for the organism. If we take the perspective of the genes%26#8217;, on the other hand, the phenomenon is quite logical,%26#8221; says Breivik. He is currently studying the molecular and evolutionary mechanisms that lead to such unstable repair genes.

The next step in evolution

Despite important advances in therapy, all statistics show that the cancer incidence will continue to rise.

%26#8220;The better we get at treating cancer, the older we become and the more cancer there will be in the population. Additionally, better therapy for children and young people implies that more cancer genes are passed on to the next generation. From what we know about evolutionary dynamics, I believe it%26#8217;s impossible to find a therapeutic solution to cancer. The basic problem is that we are trapped in a body that the genes have made to be disposable. A solution will therefore be something much more radical than a new drug,%26#8221; says Breivik.

He argues that cancer therapy is an attempt to counteract the natural decay of the body. If we think about it, however, it is not really the body we care about. After all, most people are more than happy to trade in a defect organ for a new one.

%26#8220;It's the mind, our thoughts and consciousness that we desperately want to preserve. If we look at technological developments as a whole, that may be exactly what%26#8217;s happening. The ongoing revolution in information and biotechnology may be interpreted as the mind%26#8217;s liberation from the genes. It%26#8217;s difficult to imagine the alternative, but if I could see a thousand years into the future, I would be very surprised if earth is still dominated by two-legged creatures with a limited life span,%26#8221; says Jarle Breivik.

Source: University of Oslo

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Studies indicate that nanoparticles could damage DNA and lead to cancer

Tissue studies indicate that nanoparticles, engineered materials about a billionth of a meter in size, could damage DNA and lead to cancer, according to research presented at the 2007 Annual Meeting of the American Association for Cancer Research.Nanoparticles are small enough to penetrate cell memb...

Tissue studies indicate that nanoparticles, engineered materials about a billionth of a meter in size, could damage DNA and lead to cancer, according to research presented at the 2007 Annual Meeting of the American Association for Cancer Research.

Nanoparticles are small enough to penetrate cell membranes and defenses, yet they are large enough to cause trouble by interfering with normal cell processes, researchers at the University of Massachusetts say. Such nanoparticles are currently in use in electronics, cosmetics, and chemical manufacturing, among others industries. Because of their extremely small size, they can be difficult to isolate from the larger environment, as they are much too small for removal by conventional filtering techniques.

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When nanoparticles find their way into cancer cells, they can wreak havoc, according to Sara Pacheco, an undergraduate researcher at the University of Massachusetts. Yet very little is known about how they behave in the environment or how they interact with and affect humans.

"Unfortunately, only a very small portion of research on nanoparticles is focused on health and safety risks, or on threats to the environment," Pacheco said. "I am concerned because so many new nanoparticles are being developed and there is little regulation on their manufacture, use and disposal."

Pacheco and her colleagues looked at how two different types of nanoparticles could cause DNA damage in the MCF-7 line of breast cancer cells.

She and her team examined the genotoxicity of silica and C60 fullerene nanoparticle suspensions using the alkaline single-cell gel electrophoresis assay (Comet assay) to quantify breaks in single and double stranded DNA. The team chose these particular nanoparticle types because they are commonly used commercially %26#8211; in electronics, textiles and sporting goods %26#8211; and easy to work with in the laboratory setting.

"We observed both dose-dependent and time-dependent increases in DNA damage in breast cancer cells exposed to either aqueous colloidal silica or C60 fullerenes," Pacheco said. "The DNA damage could potentially lead to mutations and ultimately increase the risk of cancer."

One problem is that, while it%26#8217;s clear that some nanoparticles can be more toxic than others, there%26#8217;s not enough data as yet to determine the most dangerous types.

"A lot is unknown about nanoparticle function, but clearly both size and composition are important," Pacheco said. "Several studies have shown that smaller particles are more likely to enter cells and cause more toxicity."

According to Pacheco, what makes matters worse is the fact that so far, aside from preventing their release, there are no known ways to prevent the harmful effects of environmental nanoparticles.

"It is important to know whether the nanoparticles are entering the cell and causing DNA damage directly or if they are acting on the membrane and inducing a cascade of events resulting in DNA damage," Pacheco said. "Once we understand the mechanisms by which nanoparticles induce their toxicity, we will be better able to prevent or mitigate their harmful effects."

In the meantime, the experimental team suggests that great caution should be taken in handling such nanoparticle suspensions and that any uncontrolled release should be avoided.

"Until we understand which types of nanoparticles are harmless and which have the potential to be harmful, I think it is prudent to limit their introduction into the environment," recommended Pacheco.

Source: American Association for Cancer Research

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Personalized medicine - Gene research helps create more effective therapies for individual cancers

Genetic and epigenetic variations ensure that no two people are exactly alike, and the same holds true for any two cancers. Now, researchers have the tools and the knowledge to help predict how individuals will respond to cancer therapies, enabling them to create more effective therapies for individ...

Genetic and epigenetic variations ensure that no two people are exactly alike, and the same holds true for any two cancers. Now, researchers have the tools and the knowledge to help predict how individuals will respond to cancer therapies, enabling them to create more effective therapies for individual cancers %26#8211; personalized medicine. At the 2007 Annual Meeting of the American Association for Cancer Research, researchers present new biomarkers %26#8211; and techniques for determining biomarkers %26#8211; that could determine how an individual might respond to drug or radiation therapy.

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Molecular predictors of drug response in breast cancer: Abstract 4963

Researchers at Lawrence Berkeley National Laboratory have identified gene expression signatures that could serve as biomarkers to predict how individuals will respond to the breast cancer drugs lapatinib and CI-1040. Their findings could help in individualizing treatments for women, and their methodologies could aid in identifying similar biomarkers for responses to other drugs and for other types of cancer.

"Individuals respond differently to different therapeutics because there are substantial differences in the spectrum of genetic, biological and epigenetic characteristics between breast cancers, although some recurrent abnormality patterns are emerging that define breast cancer subtypes" said Joe W. Gray, Ph.D., staff scientist and director of the Life Sciences Division at Lawrence Berkeley National Laboratory. "We need better ways to identify how we can best tailor existing therapies to individuals and how to target experimental agents."

Gray and his colleagues have developed a system to evaluate drug response comprised of a panel of 50 breast cancer cell lines. Each of these cell lines represents a single variant among the different genomic abnormalities found among breast cancers. They measured molecular profiles of each cell line and used these to identify subsets of cell lines that represent the subtypes observed in analyses of primary tumors.

By correlating the responses of these cells to targeted therapeutic drugs, the researchers were able to identify the molecular characteristics of cells that were most sensitive to the drugs. They tested their approach by analyzing responses of the cell line panel to lapatinib, a duel inhibitor of EGFR and ErbB2 and CI-1040, a MEK enzyme inhibitor. These studies defined molecular signatures that predicted individual responses among the cell lines to the drugs. For Lapatinib, the strongest correlate of response was amplification and over expression of ErBB2, consistent with clinical experience. For CI-1040, changes in the MEK pathway were most strongly associated with response. Predictors based on combinations of molecular correlates of response were able to quantitatively predict individual cell line responses.

"The concordance of our markers of response to lapatinib with those observed clinically suggests that the molecular markers identified in the cell line collection can be used to guide the use and testing of other approved and experimental drugs," Gray said. "This is important since it is logistically and financially impossible to test all of the experimental medicines in each cancer subtype. This %26#8216;systems%26#8217; approach suggests a way to prioritize drugs for use in patients and for initial clinical tests."

According to Gray, a large of number of emerging therapeutic agents should be prioritized for testing in the subtypes of breast cancer along with other cancers and their subtypes. When therapies are ineffective, they may produce harmful side effects and decrease a patient%26#8217;s quality of life.

KRAS mutation in colorectal cancer is a predictive factor of response and progression free survival in patients treated with Cetuximab: Abstract 5671

Mutations in the KRAS oncogene could predict a lack of response to the drug cetuximab in patients with colorectal tumors. For those with the mutations, the drug is likely to be inefficient and possibly harmful, according to researchers at France%26#8217;s Institut National de la Sante et de la Recherche Medicale (INSERM).

"Because a variety of different effective agents may now be available for any given type of cancer, deciding which treatment regimen is likely to be the most effective and the least toxic is more complicated than ever," said Pierre Laurent-Puig, M.D., PhD, a professor of Oncology at University of Paris-Decartes. "Characterizing the factors that are predictive of toxicity and efficacy could lead to significant improvement in both the quality of treatment and outcomes."

Cetuximab, an antibody that attacks the ability of cells to respond to the epidermal growth factor, has been previously shown to be effective in treating metastatic colorectal cancer.

Dr. Laurent-Puig and his colleagues studied 114 patients who had been given cetuximab in combination with another drug, irinotecan.

According to the researchers, approximately 30 percent of patients may have a poor response to the drug. Almost none of the patients who responded to the drug had an activating KRAS mutation, as compared to 35 percent of the patients with stable disease or 55 percent of the patients with progressive disease.

According to Dr. Laurent-Puig, this might be due to the cascade of molecular interactions that occur after epidermal growth factor meets its receptor, EGFR. The KRAS enzyme is a key component to these molecular actions, but mutations in the KRAS gene could allow the enzyme to function whether or not it receives the commanding signal from EGFR. Therefore, the inhibition of EGF receptor by cetuximab will not block the molecular signals that are activated farther down the cascade.

The researchers also determined that KRAS mutations are independent of another predictive marker of cetuximab response, skin toxicity, which appears through a variety of forms including rashes, eczema and fissures. Skin toxicity also indicates a poor response to cetuximab. The study indicated that median survival is 15.6 months for patients with skin toxicity and without a KRAS mutation; whereas the survival is only 5.6 months for patients with the mutation, but no skin toxicity.

Dr. Laurent-Puig and colleagues are continuing to investigate the molecular biomarkers associated with cetuximab, including in tumors without the KRAS mutation that do not respond to the drug.

Recombinant peptides as biomarkers for cancer response to tyrosine kinase inhibitors combined with radiation: Abstract 4657

A new method for determining biomarkers could allow physicians to personalize lung or brain cancer therapy and lower the risk of unnecessary radiation treatments. Researchers at Vanderbilt University are using a biomarker library of peptides to determine whether or not tyrosine kinase inhibitor therapy, combined with radiation therapy, is indeed effective against lung or brain cancer.

"It is difficult to assess the response of cancer in the brain or lung to treatment, since those neoplasms are difficult to access safely," said Roberto Diaz, M.D., Ph.D., a resident in Radiation Oncology at the Vanderbilt-Ingram Cancer Center. "With the proper biomarkers physicians may be able to tell if a patient is not responding to the therapy and alter their treatment strategy accordingly."

The researchers screened lung and brain tumors to determine which peptides %26#8211; or protein fragments %26#8211; were active in the tissue environment surrounding the tumors. This phage displayed library %26#8211; called so after the bacteriophage viruses used to capture protein fragments %26#8211; was then isolated and tested.

With the library, Dr. Diaz and his colleagues could select peptides that bind to tumors that are affected by a combination of radiation and tyrosine kinase inhibitor therapy, but not to tumors that do not respond to therapy. Ultimately, they uncovered 44 peptides that serve as biomarkers for response to therapy. According to Dr. Diaz, the physiological role of the 44 peptides might also point toward new cancer therapies.

"This study provides us with a starting point for understanding how tumors physiologically respond to therapy and a non-invasive technique for monitoring that response," Dr. Diaz said.

Cellular pharmacogenomic to discover genetic determinants of Tykerb response: Abstract 5684

A new high-throughput genetic analysis technique can reveal gene markers %26#8211; by the dozens %26#8211; that determine how a patient might respond to certain cancer drugs, according to scientists at the Translational Genomics Research Institute (TGen). The TGen researchers have found 164 genes that are involved in regulating the sensitivity of squamous cell head and neck cancer cells to lapatinib, a cancer drug that was recently approved for use in metastatic breast cancer under the name Tykerb.

The study, a collaboration with GlaxoSmithKline, evaluated 7,000 genetic targets in human head and neck cancer cells to discover specific genes that might shade an individual%26#8217;s response to Tykerb.

"Our goal is to apply advanced cellular genomic strategies to assist clinical drug development by finding gene states that predict a patient%26#8217;s response to a specific drug, and which combination of drugs produce the most favorable response." said Spyro Mousses, Ph.D., director of the Pharmaceutical Genomics Division at TGen. "In this study, we were able to discover new candidate gene states that may be useful in determining a patient%26#8217;s sensitivity or resistance to Tykerb, and the results have revealed several sensitizing drug targets that reveal a set of candidate combination drugs that are predicted to be synergistic with Tykerb."

Tykerb is an enzyme inhibitor that effectively blocks two cell receptors, ERBB2 and EGFR, from receiving molecular signals. By blocking these signals, Tykerb could effectively shut down the growth of solid tumors, such as those found in breast, lung and head and neck cancer. However, molecular mechanisms within the cell, largely determined by genetics, could determine how effective cancer drugs are for a particular recipient, Mousses said.

To search for target genes that regulate Tykerb response, Mousses and his colleagues performed a genome-scale scan of two cancer cell lines using high-throughput RNAi, "interfering" RNA strands that bind to and knock out one gene individually, across the genome. It is a systematic and highly efficient technique that uses high-speed mechanization to quickly evaluate how specific genes might affect the cell%26#8217;s sensitivity to an agent, Tykerb in this case.

The TGen researchers are currently in the process of refining their genetic "hits" and learning more about how cancer specific variations in these sensitizing genes might further affect Tykerb response. While their findings are still at a preliminary stage, Mousses and his colleagues believe their studies will provide important insights into how to predict oncology drug response and much needed genomic intelligence to support commercial drug development.

Source: American Association for Cancer Research

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Scientists learning more about cancer-initiating properties of stem cells

Recent discoveries about the role of stem cells in cancer have altered the landscape of cancer research. With each new study, scientists are learning more about cancer-initiating properties of stem cells at organ sites and throughout the body. Increasingly, stem cells are examined as the causeand po...

Recent discoveries about the role of stem cells in cancer have altered the landscape of cancer research. With each new study, scientists are learning more about cancer-initiating properties of stem cells at organ sites and throughout the body. Increasingly, stem cells are examined as the cause %26#8211; and potential target of treatment %26#8211; for many, if not all, cancers. At the 2007 Annual Meeting of the American Association for Cancer Research, researchers present new discoveries about stem cells in leukemia, breast and colon cancer that add to the growing evidence that perhaps cancer is, fundamentally, a stem cell problem.

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PTEN and HER2 regulate self-renewal and invasion of human mammary stem cells: Abstract 1287

Two genes associated with aggressive breast cancer are linked to a key property of mammary stem cell function, according to researchers at the University of Michigan. The genes, PTEN and HER2, both are involved in the biochemical pathways that mediate stem cell self-renewal, a defining property of stem cells.

According to the researchers, understanding the pathways that regulate stem cell self-renewal is important in developing therapeutics that target the tumor stem cell pool. These genes might also become targets of interest in the treatment of tumors resistant to the drug Herceptin.

"We now believe that our results show further evidence that breast cancer arises from signaling errors in the biochemical pathways that control mammary stem cell self-renewal" said Hasan Korkaya, D.V.M., Ph.D., a research fellow at the University of Michigan%26#8217;s Comprehensive Cancer Center. "Since only stem cells have the ability to self-renew, deregulation of either PTEN or HER2 expands the stem cell populations with self-renewing ability."

According to Korkaya, cells with deregulated %26#8211; or increased %26#8211; self-renewing ability will then initiate and maintain tumors that are resistant to current therapies.

The two genes appear to influence stem cell self-renewal by controlling two different arms of the pathway, says Korkaya. In breast cancer, the loss of PTEN is linked to nearly a quarter of all cases, while the overproduction of HER2 is associated with nearly 40 percent of all cases. Patients with a combined defect of PTEN loss and HER2 amplification represent worse prognosis than either defect alone.

To replicate this clinical phenomenon and study the link between stem cell self-renewal and tumorigenesis, the researchers altered the expression of the two genes in a line of human breast carcinoma cells. In experimental settings, their results confirmed this clinical data that either defect increases stem cell population by three to five times. Furthermore, Korkaya observed an additive effect and an approximate 10-fold increase in stem cell population when they created a cell line with deleted PTEN and HER2 overexpression. Another property of aggressive tumors is metastasis; the team also found that these cells had increased invasive capacity in a matrigel invasion assay.

"In general, tumors are heterogeneous including stem and non-stem cell populations in a given malignancy," Korkaya said. "If the stem cells acquired mutations in their self-renewing pathways, they will then begin reproducing at an accelerated rate, leading to a particularly aggressive form of cancer."

The researchers believe further studies will identify new biomarkers that will enable physicians to clinically screen patients for mammary stem cells and provide specific treatments designed to target these cells.

Local Radiotherapy Might Contribute to Leukemia Risk in Breast Cancer by Recruitment of Hematopoietic Stem Cells: Abstract 5050

Radiation therapy affects not only the cancer mass, but also the surrounding tissues, including the bone marrow. Signals from the cells in the bone marrow damaged by cancer radiotherapy could be involved in the development of secondary acute myeloma by drawing hematopoietic stem cells, the blood-producing cells of the bone marrow, from distant sites into the irradiated bone marrow, according to researchers from the Ontario Cancer Institute. Their findings suggest that local radiotherapy leads to leukemia, even though radiotherapy directly affects only a small fraction of the bone marrow.

While often effective in treating breast cancer, localized radiation therapy increases the risk of developing secondary cancer, which most frequently manifests in the form of acute myeloid leukemia. In breast cancer, less than 10 percent of bone marrow is exposed to radiation therapy, yet a much higher percentage of hematopoietic stem cells could be affected.

To understand this effect, the researchers labeled and tracked the movement of hematopoietic stem cells in an animal model. Following local radiation therapy, they found that more than four times more hematopoietic stem cells accumulated in the irradiated bone marrow, compared to the non-irradiated bone marrow. Through molecular screening, they found that cells in the area were creating an overabundance of three protein signals known to recruit hematopoietic stem cells: SDF1, MMP2 and MMP9.

"Cells within the bone marrow send out these chemical signals as a sort of call for help, which recruits a large number of hematopoietic stem cells into the affected areas, supposedly to replace damaged cells," said Carlo Bastianutto, Ph.D., a scientific associate at the Ontario Cancer Institute. "In effect, this becomes a trap for this specific population of stem cells, drawing them into the bone marrow present in the radiation field and getting them exposed to the following radiation cycles. This story might repeat at every cycle of radiation therapy, therefore increasing the chance of producing a leukemic stem cell."

According to the OCI researchers, the recruiting signal might be stopped by chemical blockers, which was shown to inhibit the signals experimentally. "Conceivably, it could be possible to inhibit these chemical signals, and this could reduce the risk of secondary acute myeloid leukemia, but much more research needs to be done," Bastianutto said.

The researchers believe this model could help prevent acute myeloid leukemia in patients with malignancies other than breast cancer.

Prospective identification of highly tumorigenic colon adenocarcinoma cells enriched for stem-like properties: Abstract 1288

Colon cancer could join the growing list of stem cell-related cancers with the discovery of a population of highly tumorigenic primary human colon tumor cells, according to researchers from Biogen Idec.

"Such stem cells could be responsible for the perpetuation of colon cancer and its relapse following successful therapy," said Peter Chu, Ph.D., researcher at Biogen Idec. "Our goal is to improve cancer survival rates by identifying these cancer stem cells in order to pave the way for therapeutics to prevent the relapse or metastasis of cancer."

To identify potential cancer stem cells, also known as cancer-initiating cells, the researchers screened a population of human colon cancer cells for molecular markers that differentiated some cells from others. They found a certain subset of cells produced an exceptional amount of CD44 cell surface receptor protein, a well-studied protein involved in many forms of cancer.

According to Chu, to be identified as cancer stem cells, they had to be highly tumorigenic, creating new tumors quickly and from very few starting cells; had to be self-renewing, possessing a capacity to regenerate; and they had to produce tumors similar to the tumor of origin. "These CD44-producing cells fit the bill, although there is evidence to believe that CD44 overexpression is not the sole marker for colon cancer stem cells," said Chu.

Chu and his colleagues discovered that as few as 10 cells producing high amounts of CD44 were capable of creating tumors in an animal model. In contrast, other tumor cells were 10 to 50 times less tumorigenic. The fact that they were tumorigenic at all, the researchers say, indicates that CD44 alone is unlikely to be the sole indicator of stem cell-ness among the tumor cell population. However, according to Chu, the discovery that high CD44 producing cells have cancer stem cell properties provides an entry point into further research into cancer-causing stem cells.

BRCA1 regulates human mammary stem cell self-renewal and differentiation: Abstract 5700

Mutations in the well-known breast cancer susceptibility gene BRCA1 have a role in the propagation of aggressive stem cell-driven cancer. The findings, according to researchers at the University of Michigan, offer further evidence that breast cancer treatment strategies require a stronger focus on the stem cells that drive the disease.

"Our lab previously identified the presence of mammary stem cells and, since BRCA1 is such a strong predictor of breast cancer, we were interested in the involvement of the gene in stem cells," said Suling Liu, Ph.D., a researcher at the University of Michigan%26#8217;s Comprehensive Cancer Center. "If mammary stem cells are, indeed, the driving force of breast cancer, then we need to know more about their function if we hope to create more effective therapies."

To investigate the role of the gene in stem cells, the team engineered a lentivirus to carry small interfering RNA segments that, in effect, silence the BRCA1 gene. They then observed how a population of mammary stem cells functioned without the ability to produce BRCA1. When BRCA1 was inhibited, the number of stem cells was increased by 75 percent. These new cells, in turn, produced three times the normal amount of a stem cell marker protein ALDH1.

In an animal model of the disease, the knockdown of the BRCA1 gene increased the number of stem cells, which then propagated in the fatty tissues of the breast.

These studies suggest that loss of BRCA1 function leads to a block in cell differentiation, expanding the stem cell pool. Since BRCA1 also regulates DNA repair, this may then produce genetically unstable stem cells which in turn generate tumors in these women.

According to Liu, the loss of a single BRCA1 gene can lead to stem cell propagation. The researchers believe their findings might lead to better BRCA1 screening in women with a family history of breast cancer.

Source: American Association for Cancer Research

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