Research

Medical News Release

• Cancer News, Published: 2009 Dec 10

Turmeric, Pepper Spice Out "breast Cancer"

Compounds that have the potential to prevent breast cancer, by limiting the growth of stem cells, exist in spices like turmeric and pepper. These are a small number of cells that fuel a tumor's growth, according to researchers at the University of Michigan.

The researchers found that when the dietary compounds curcumin, which is derived from the Indian spice turmeric, and piperine, derived from black peppers, were applied to breast cells in culture, they decreased the number of stem cells without affecting normal differentiated cells.

"If we can limit the number of stem cells, we can limit the number of cells with potential to form tumors," said lead author Dr. Madhuri Kakarala.

Cancer stem cells are the small number of cells within a tumor that fuel the tumor's growth.

Current chemotherapies do not work against these cells, which is why cancer recurs and spreads.

According to researchers, eliminating the cancer stem cells is key to controlling cancer.

In addition, decreasing the number of normal stem cells - unspecialised cells that can give rise to any type of cell in that organ - can decrease the risk of cancer.

In the current study, a solution of curcumin and piperine was applied to the cell cultures at the equivalent of about 20 times the potency of what could be consumed through diet.

The compounds are available at this potency in a capsule form that could be taken by mouth.

The researchers applied a series of tests to the cells, looking at markers for breast stem cells and the effects of curcumin and piperine, both alone and combined, on the stem cell levels.

They found that piperine enhanced the effects of curcumin, and that the compounds interrupted the self-renewal process that is the hallmark of cancer-initiating stem cells.

Besides, the compounds had no affect on cell differentiation, which is the normal process of cell development.

"This shows that these compounds are not toxic to normal breast tissue. Women at high risk of breast cancer right now can choose to take the drugs tamoxifen or raloxifene for prevention, but most women won't take these drugs because there is too much toxicity. The concept that dietary compounds can help is attractive, and curcumin and piperine appear to have very low toxicity," said Kakarala.

The study is the first to suggest these dietary compounds could prevent cancer by targeting stem cells.

It has been published online in the journal Breast Cancer Research and Treatment.

• Cancer News, Published: 2009 Oct 23

Way to Protect Healthy Cells from Radiation Damage Discovered by Pitt/NIH Team

Researchers at the University of Pittsburgh School of Medicine and the National Cancer Institute (NCI), part of the National Institutes of Health have found a way to not only protect healthy tissue from the toxic effects of radiation treatment, but also increase tumor death. The findings appear today in Science Translational Medicine.

More than half of all cancer patients are treated at least in part with radiation, said study co-author Jeff S. Isenberg, M.D., M.P.H., associate professor, Division of Pulmonary, Allergy, and Critical Care Medicine, Pitt School of Medicine. But the same radiation that kills cancer cells can also destroy healthy ones, causing side effects such as nausea and vomiting, skin sores and rashes, and weakness and fatigue. Long-term radiation exposure can lead to the scarring and death of normal tissue.

He and his NCI colleagues have identified a biochemical signaling pathway that can profoundly influence what happens to both cancerous and healthy cells when they are exposed to radiation. In mouse experiments, they found that blocking a molecule called thrombospondin-1 from binding to its cell surface receptor, called CD47, affords normal tissues nearly complete protection from both standard and very high doses of radiation.

"We almost couldn't believe what we were seeing," Dr. Isenberg said. "This dramatic protective effect occurred in skin, muscle and bone marrow cells, which is very encouraging. Cells that might have died of radiation exposure remained viable and functional when pre-treated with agents that interfere with the thrombospondin-1/CD47 pathway."

There have been concerns that approaches to spare healthy cells will risk inadvertently protecting tumor cells, noted senior author David D. Roberts, Ph.D., of the NCI's Center for Cancer Research. But, he added, "in our experiments, suppression of CD47 robustly delayed the regrowth of tumors in radiation-treated mice."

It's not yet clear why disrupting the CD47 signaling pathway leads to these effects, the researchers said. It's possible that radiation impairs the immune response to tumors even while killing tumor cells, but suppression of CD47 keeps the immune cells safe. Decreasing CD47 levels on tumor cells also could make them more sensitive to attack by the patient's immune system after treatment. Or, suppression of injury to vascular cells might improve blood flow to allow naturally occurring anti-tumor immunity to reach cancer cells more easily.

The researchers are already exploring the signaling pathway's role in several other domains, noted Mark Gladwin, M.D., chief of Pitt's Division of Pulmonary, Allergy, and Critical Care Medicine and director of the Vascular Medicine Institute, where Dr. Isenberg is a principal investigator.

"Dr. Isenberg and his team are examining multiple disease treatment strategies for pulmonary hypertension, wound healing, sickle cell disease and heart attacks, based on the blockade of the thrombospondin-1/CD47 pathway," he said.

• Diet News, Published: 2009 Mar 17

Eating a daily portion of mushrooms could slash the risk of breast cancer by two thirds, new research has found.

The study, carried out in China, also showed that women who combined a mushroom diet with regular consumption of green tea saw an even greater benefit. The risk among women in this group was reduced by almost 90 per cent.

Scientists found that women consuming at least a third of an ounce of fresh mushrooms every day were 64 per cent less likely to develop a tumour.

Dried mushrooms had a slightly less protective effect, reducing the risk by around half.

To reach the conclusion, experts at the University of Western Australia in Perth reviewed the eating habits of more than 2,000 women in China, half of whom had suffered breast cancer.

"Higher intake of mushrooms decreased cancer risk in both pre- and post-menopausal Chinese women," The Daily Express quoted researchers, as saying.

Evidence points that mushrooms act in a similar way to breast cancer drugs called aromatase inhibitors which block the body's production of the cancer-feeding hormone oestrogen.

Dr Julie Sharp, Cancer Research UK's senior science information manager, said: "Both green tea and mushrooms have previously been reported to lower cancer risk. While this study adds to the evidence, more research is needed to confirm these observations and find out if they are relevant to UK women.

"It is important to remember there is no one particular 'super' food that will protect you from cancer. Large scientific studies have proven that the best way to reduce your risk of many cancers is to eat a healthy, balanced diet."

The study has been published in the International Journal of Cancer.

• Cancer News, Published: 2009 Feb 4

Experts Urge People To “Screen the One You Love” for Skin Cancer

While candy, flowers and dinner at a romantic restaurant may seem like great Valentine’s Day gifts, the American Academy of Dermatology (Academy) recommends that people give the gift of life and health this year and “Screen the One You Love” for skin cancer.

Based on current estimates, more than 1 million new cases of skin cancer will be diagnosed in the United States in 2009. Performing regular skin self-examinations is an easy way to detect suspicious moles that could be cancerous, and research shows that involving a partner in the self-examination process can improve the early detection of skin cancer.

In a study published in the Journal of the American Academy of Dermatology, dermatologists found that people who are assisted by a partner in performing skin self-exams are more likely to follow a regular detection routine than those who rely solely on themselves for motivation.

“Since skin cancer is the only cancer you can see on the surface of your skin, it makes sense to ask a partner who regularly sees your skin to assist you in performing a skin exam,” said dermatologist C. William Hanke, MD, MPH, FAAD, president of the Academy. “A partner can help you assess whether a mole seems to be changing or shows any signs that could raise a red flag, and Valentine’s Day is the perfect time for people to start a new tradition by giving each other the gift of a skin examination.”

The Academy’s Body Mole Map is a tool individuals can use to track their moles. The map provides information on how to perform a skin exam, images of the ABCDEs of melanoma and space for people to track their moles to determine any changes over time. The mole map is available at www.melanomamonday.org.


“In my practice, oftentimes patients tell me that their partner urged them to get an unusual-looking mole checked – and in some cases these moles turn out to be skin cancer,” added Dr. Hanke. “Early detection is crucial in the fight against skin cancer, so a partner can be a tremendous ally by helping you examine hard-to-reach spots and encouraging you to see a dermatologist if you notice an unusual lesion or mole.”

One American dies of melanoma almost every hour (every 62 minutes). The five-year survival rate for people whose melanoma is detected and treated before it spreads to the lymph nodes is 99 percent. For more information about skin cancer, please visit the SkinCancerNet section of www.skincarephysicians.com, a Web site developed by dermatologists that provides patients with up-to-date information on the treatment and management of disorders of the skin, hair and nails.

• Cancer News, Published: 2009 Jan 14

Experiments conducted in laboratories have raised US scientists' hopes that herbal supplement can be helpful in fighting prostate cancer.

Dr. Julia Arnold, a staff scientist at the National Center for Complementary and Alternative Medicine (NCCAM) at the National Institutes of Health, has revealed that the current research focused on the preventative effects of dietary isoflavones present in red clover.

She highlighted the fact that DHEA is a natural circulating hormone whose production in the body decreases with age, and which is taken by men as an over-the-counter supplement because it is thought to be effective in reversing aging, or have anabolic effects since it can be metabolized in the body to androgens.

The also said that increased consumption of dietary isoflavones is associated with a decreased risk of prostate cancer, and that red clover (Trifolium pretense) is one source of isoflavones.

During the study, the research team combined DHEA with transforming growth factor beta-1, which increased testosterone production in the stromal cells and prostate specific antigen protein secretion two to four-fold and gene expression up to 50-fold in the cancer cells.

Upon treating the cell cultures with red clover isoflavones, the researcher found that the androgenic effects of DHEA were reversed.

"Something is happening in the prostate tissue microenvironment that is illustrating a potential cancer prevention effect from this supplement," said Arnold.

The researchers said that their study showed that red clover isoflavones might modify androgenic effects in the prostate, but insisted that much more work in the laboratory and clinic was needed to validate such effects.

They are of the opinion that such laboratory manipulations might enable scientists to understand the basic prostate biology as well as learn cellular and molecular mechanisms of over-the-counter supplements and other botanical or herbal agents.

• Cancer News, Published: 2008 Nov 25

A new study conducted by Tel Aviv University researchers suggests that the use of fresh red blood cells in transfusions for cancer patients can improve long-term survival rates, and reducer the incidence of the cancer recurrence.

Reporting their findings in the journal Anesthesiology, the researchers highlight the fact that blood transfusion during certain cancer surgeries is associated with increased cancer recurrence and reduced survival rates, but why this happens is not well understood.

Dr. Shamgar Ben-Eliyahu and his university colleagues say that their study on rats may provide surprising insights that could open doors for important research in humans in the near future.

For their study, the researchers used rat models of leukemia and breast cancer to help determine whether blood transfusion is an independent risk factor for cancer recurrence/progression, and to understand what aspects of the transfusion cause the alleged harmful effects.

"The results of our study clearly indicate that blood transfusion is an independent risk factor for cancer recurrence in the animal models we used," said Dr. Ben-Eliyahu.

"But our study also yielded two surprising findings. First, the storage time of the transfused blood was the critical determinant of harmful effects: fresh blood had no harmful effects. Second, and even more surprising, we found that red blood cells, not white blood cells, caused the effects we observed," the researcher added.

The study's results also contrast the suggestion belief that white blood cells within transfused blood may be responsible for cancer progression, said Dr. Ben-Eliyahu.

He said that there was a co-relation between harmful effects of transfused blood and the amount of time it was stored, with those effects being most significant at nine days storage time or longer.

He added that there seemed to be no difference in harmful effects between transfused blood taken from the same animal or from a different animal.

"The current common approach in cancer patients is to use transfused blood depleted of white blood cells. But we found that removal of white blood cells was ineffective in our setting. Rather, we suggest a different approach: the use of fresh red blood cells for cancer surgeries. For the first time, we have shown in animal models that donor red blood cells, rather than white blood cells or other blood components, can be a critical factor in how blood transfusions affect cancer," he said.

Dr. Ben-Eliyahu said that the findings of their study on mice indicate the need for studies in cancer patients, so that it can be determined whether alterations in blood transfusion practices can indeed improve patient outcomes.

• Cancer News, Published: 2008 Oct 9

Regular Use of Common Painkillers Could Reduce Risk of Breast Cancer

Don’t look upon aspirin and ibuprofen as mere painkillers anymore. For they could be an effective weapon against breast cancer, new study shows.Regular use of aspirin cut the risk by 13%, while ibuprofen lowered it by a fifth.
Both aspirin and ibuprofen are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), and it is their ability to interfere with inflammation in the human body which appears to be the key.
Two body chemicals which help produce inflammation, COX1 and 2, are thought to play roles in the development of cancer by influencing how cells divide and die, the production of new blood vessels that can "feed" tumours, and influence the body's immune responses.
It appears NSAIDS inhibit these chemicals.
Women taking either aspirin or ibuprofen regularly had a 12% lower chance of developing breast cancer compared to those who did not use them at all, while regular ibuprofen use appeared to have the biggest effect.
The research, which looked at information from 2.7 million women, was published in the Journal of the National Cancer Institute.
However, experts warned long-term use of painkillers can have serious side-effects.
Dr Mahyar Etminan, from the University of British Columbia, who led the research, said the results were "encouraging", and could help scientists trying to understand the complex origins of breast cancer.
However, he warned against women adopting painkillers as part of a cancer prevention lifestyle.
"We don't recommend the routine use of NSAIDs for breast cancer prevention until large randomised trials confirm these findings." He said results from a trial of this type would be available next year.
The regular use of painkillers is problematic because, in some people, they can cause serious side-effects, including stomach ulcers, increased risk of stroke, asthma and heart, liver and kidney problems.
The potential benefits of reducing breast cancer risk would have to be balanced against these.
This advice was echoed by Breakthrough Breast Cancer, which urged women worried about breast cancer risk to talk to their GP rather than simply take painkillers.
Head of policy Sarah Rawlings said: "The potential of anti-inflammatory drugs, such as aspirin, to lower the chances of developing breast cancer is very interesting, but as the researchers say, large scale trials are needed to confirm these findings.
"Anti-inflammatory drugs can have potentially very serious side-effects when taken over a long period."

• Men's Health News, Published: 2008 Sept 15

Scientists at Sunnybrook Research Institute (SRI) are developing and commercializing a promising novel therapy for the treatment of prostate cancer that may offer patients a faster and more precise treatment than existing clinical alternatives, with fewer side effects.

The new treatment-magnetic resonance imaging (MRI)-guided transurethral ultrasound-uses heat from focused ultrasound to treat cancer in the prostate gland precisely while sparing the delicate noncancerous tissues around the prostate essential for healthy urinary, bowel and sexual function.

Sunnybrook researchers Dr. Michael Bronskill and Dr. Rajiv Chopra have licensed their innovation and formed Profound Medical Inc., which will develop the technology for clinical use.

Unlike surgical removal of the prostate, the treatment is minimally invasive and could be performed without a lengthy hospital stay. In preclinical studies, treatment takes less than 30 minutes. The therapy, on which clinicians at Sunnybrook will conduct preliminary testing in preparation for a clinical trial, could help limit the number of men living with the common, debilitating and often permanent side effects of surgery and radiation treatments currently used. More of these invasive therapies are being performed now because improved awareness among younger men has converged with better clinical detection tools.

Profound's clinical development is targeted at treatment that reduces the high level of incontinence and impotence associated with current, invasive treatments. The therapy involves two different and naturally incompatible technologies, ultrasound and MRI, which Bronskill and Chopra spent 10 years making compatible. "You have to make an ultrasound heating applicator work inside a magnetic resonance imager, without the two technologies interfering with each other," says Bronskill, who is a professor at the University of Toronto. "The prostate cancer site is a natural for this technology because it's surrounded by structures you want to spare."

Dr. Laurence Klotz, chief of urology at Sunnybrook Health Sciences Centre, and a professor at the University of Toronto, says that a noninvasive therapy for early, localized prostate cancer could improve the quality of life of hundreds of thousands of men. "The key to effective noninvasive treatment is accurate imaging of the target organ and of the effects of the treatment on tissue. In that respect, MR-guided ultrasound has many potential advantages over transrectal ultrasound-guided focused ultrasound, now approved for use in Canada," says Klotz.

The scientists' creation of this clinically viable product was done in a setting committed to commercialization. "At SRI, we are dedicated not only to developing new and better therapies and technologies, but also to getting those discoveries to our patients," says Dr. Michael Julius, vice-president of research at Sunnybrook. Profound Medical Inc. is the third imaging-technology company to be spun out of research at SRI in recent years. The other two are VisualSonics Inc. and Sentinelle Medical Inc.

• Medical Research News, Published: 2008 August 20

Turning up the heat on the red tomato during processing has the potential to give the popular garden staple added disease-fighting power, Ohio State University research suggests.

Scientists have found that lycopene molecules in tomatoes that are combined with fat and subjected to intense heat during processing are restructured in a way that appears to ease their transport into the bloodstream and tissue. The tomato is the primary food source of lycopene, a naturally occurring pigment linked to the prevention of cancer and other chronic diseases.

In its standard structure in the average red tomato, the lycopene molecule is laid out in a linear configuration. That structure seems to hinder the molecule's absorption through intestinal walls and into the blood, said Steven Schwartz, an investigator in Ohio State's Comprehensive Cancer Center and a professor of food science and technology at Ohio State.

Meanwhile, most of the lycopene that is found circulating in human blood is configured in a bent molecular form. This means that either the human body somehow transforms lycopene molecules through reactions that have yet to be identified, or that the bent molecular structures of lycopene are much more likely to be absorbed into the blood and transported to tissue - a necessary step in preventing disease.

Assuming the latter is true, Schwartz and colleagues have devised a way to process red tomatoes - the variety preferred by American consumers - into a sauce that contains bent molecular forms of lycopene. A clinical trial conducted in collaboration with Steven Clinton, a medical oncologist and physician scientist in Ohio State's Comprehensive Cancer Center, showed that people had more lycopene in their blood after eating the specially processed sauce than they did after eating regular red tomato sauce.

Schwartz described the research today (8/20) at the American Chemical Society meeting in Philadelphia.

In the food science world, processing gets a bad rap for its tendency to deplete vegetables of nutrients, change their color and often negatively affect how they taste.

"Instead, here is a case where processing is positive in terms of enhancing absorption of lycopene," said Schwartz.

Lycopene belongs to a family of antioxidants called carotenoids, which give certain fruits and vegetables their distinctive colors. Carotenoids' antioxidant properties are associated with protecting cells and regulating cell growth and death, all of which play a role in multiple disease processes.

In its natural state, lycopene in a red tomato is in what is called an all-trans configuration, characterized by its linear form. The molecular structure of lycopene circulating in human blood is in what is called a cis-isomer configuration, or a bent form. The chemical properties are the same - only the configuration differs.

"What we have found is we can take the red tomato molecular form of lycopene and by processing it and heating it in combination with added oil, we can change the shape of the molecule so it is configured in this bent form," Schwartz said.

Heat is essential to the process, but so is adding some fat, Schwartz said. In previous work, he and colleagues determined that consuming fat and carotenoids simultaneously improved absorption of lycopene and other compounds, but the scientists weren't sure exactly why.

When humans eat fats, or lipids, the body produces tiny droplets of fat called lipid micelles during digestion that are easily taken up through the intestinal wall and absorbed into the bloodstream.

Continuing research has led Schwartz to hypothesize that lycopene in its linear form tends to stack and become crystallized, which lowers, but does not eliminate, its absorption potential. But the bent forms of lycopene are able to more easily find their way into the lipid micelles during digestion, and increasing amounts of the antioxidant in that form are more likely to be transported to the blood along with the fats.

Taking all this into consideration, the researchers processed red tomatoes into two kinds of sauce: a sauce rich in cis-lycopene, the bent configuration, and a sauce containing mostly all-trans-lycopene, the linear form. Both sauces were flavored similarly and initially heated using the same methods. Corn oil was added to both sauces as well. But the sauce designed to produce lycopene in the bent molecular forms was subjected to a second round of heating at 260 degrees Fahrenheit for 40 minutes. The resulting sauce contained nine times more cis-isomers than the regularly processed sauce.

Twelve people participated in a study of the sauces, and all ate both kinds of sauce over the course of the study. After each meal, researchers took samples of participants' blood seven times during the following 9 1/2 hours to measure lycopene levels. The scientists used a special testing method to analyze lycopene levels in the blood associated only with the tomato sauce meal, avoiding any other possible sources of those compounds in the bloodstream.

Research participants had a 55 percent increase in total lycopene absorption after eating the specially processed sauce when compared to their lycopene blood levels after eating the regular sauce. This finding reinforced the expectation that the bent forms of lycopene are more easily absorbed into human blood, Schwartz said.

Details of this study were first published in the British Journal of Nutrition in 2007. Additional clinical trials are ongoing.

Schwartz said most currently available commercial products don't contain the bent forms of lycopene molecules. But he noted that some home cooking practices might be able to produce the same results as the special processing method he and colleagues designed.

"Some people like to cook tomato sauce for prolonged periods, sometimes reheating it day after day, because it tastes better on the second and third day. They add fat by using oil or meat, and that's going to start to induce cis-isomers of lycopene if fat is present and the cooking continues," Schwartz said. "So it's possible people could induce this process and increase lycopene absorption by routine food preparation procedures, as well."

• Miscellaneous News News, Published: 2008 July 21

An elderly man in Britain believes he has beaten cancer by drinking a daily glass of broccoli juice.

Ray Wiseman, a 79 year old grandad was diagnosed with bladder cancer in 2003, at the time his prognosis was not good and Ray was not expected to survive.

However recent scans have revealed that the cancer has stopped spreading and his chances of a recovery have greatly improved.

Mr Wiseman attributes the turn around in his condition to the tumbler of broccoli juice that his wife prepares for him each day.

Mr Wiseman, who lives in Leicestershire, says he knows the daily juice has done him some good and suggests it could do the same for others.

The idea came from his wife Joan who is herself 72, after a friend told her about the healing benefits of green vegetables.

The daily cocktail is a combination of a head of broccoli with some apples and carrots which improve the taste and Joan says her husband's incredible luck is down to the broccoli.

Joan believes their experience could help other cancer sufferers.

Cancer Research UK have asked for the recipe so their scientists can carry out studies into the vegetable's benefits.

Recent research has suggested that broccoli might possibly have cancer-beating properties - scientists at the Institute of Food Research found that men who ate one daily portion had altered patterns of gene activity in their prostates, suggesting that the chemicals in the vegetable might be able to reduce the risk of prostate cancer.

Back in 2006 a report published in the British Journal of Cancer found that natural chemicals in certain vegetables, such as broccoli-cauliflower and cabbage, can enhance DNA repair in cells, which could help stop them becoming cancerous.

Cancer Research UK says a lot of research has focused on broccoli and its healing properties and it should be part of a healthy diet that is high in all fruit and vegetables.

Bladder cancer is the fifth most common form of the disease and affects more men than women.

Broccoli is a member of the cabbage family and is rich in vitamin C and also has properties that boost the human immune systems helping to fight viruses, bacteria and cancer.

Research has found that boiling broccoli can reduce its anti-cancer compounds, while steaming and microwaving do not.

• Medical Research News, Published: 2008 July 9

Using a miniature laboratory-on-a-chip device, a team of investigators at the Massachusetts General Hospital, led by Daniel Haber, M.D., Ph.D., and Mehmet Toner, Ph.D., both members of the MIT-Harvard Center for Cancer Nanotechnology Excellence (CCNE), has developed a method that detects and analyzes the genetic signature of rare tumor cells in the bloodstream.

The results from this analysis allowed the researchers to identify those patients most likely to respond to a specific targeted treatment. This chip-based analysis also allowed the researchers to monitor genetic changes that occur during therapy.

According to Dr. Haber, this chip opens up a new field of studying tumors in real time. "When the device is ready for larger clinical trials, it should give us new options for measuring treatment response, defining prognostic and predictive measures, and studying the biology of blood-borne metastasis, which is the primary method by which cancer spreads and becomes lethal." Dr. Haber and his team published their results in The New England Journal of Medicine.

Circulating tumor cells (CTCs) are living solid-tumor cells found at extremely low levels in the bloodstream. Until the development of the CTC-chip by the Massachusetts Institute of Technology (MIT)-Harvard CCNE team, it was not possible to get information from CTCs that would be useful for clinical decision-making. The current study was designed to determine whether the device could go beyond detecting CTCs to helping analyze the genetic mutations that can make a tumor sensitive to treatment with targeted therapy drugs.

The researchers tested blood samples from patients with non-small-cell lung cancer (NSCLC), the leading cause of cancer death in the United States. In 2004, cancer researchers had discovered that mutations in a protein called epidermal growth factor receptor (EGFR) determine whether NSCLC tumors respond to a group of drugs called tyrosine kinase inhibitors (TKIs), which includes gefitinib (Iressa) and erlotinib (Tarceva). Although the response of sensitive tumors to those drugs can be swift and dramatic, eventually many tumors become resistant to the drugs and resume growing.

The CTC-chip was used to analyze blood samples from 27 patients-23 who had EGFR mutations and 4 who did not-and CTCs were identified in samples from all patients. Genetic analysis of CTCs from mutation-positive tumors detected those mutations 92 percent of the time. In addition to the primary mutation that leads to initial tumor development and TKI sensitivity, the CTC-chip also detected a secondary mutation associated with treatment resistance in some participants, including those whose tumors originally responded to treatment but later resumed growing.

Blood samples were taken at regular intervals during the course of treatment from four patients with mutation-positive tumors. In all of those patients, levels of CTCs dropped sharply after TKI treatment began and began rising when tumors resumed growing. In one patient, adding additional chemotherapy caused CTC levels to drop again as the tumor continued shrinking.

Throughout the course of therapy, the tumors' genetic makeup continued to evolve. Not only did the most common resistance mutation emerge in tumors where it was not initially present, but new activating mutations-the type that causes a tumor to develop in the first place-appeared in seven patients' tumors, indicating that these cancers are more genetically complex than expected and that continuing to monitor tumor genotype throughout the course of treatment may be crucial.

"If tumor genotypes don't remain static during therapy, it's essential to know exactly what you're treating at the time you are treating it," says Haber. "Biopsy samples taken at the time of diagnosis can never tell us about changes emerging during therapy or genotypic differences that may occur in different sites of the original tumor, but the CTC-chip offers the promise of noninvasive continuous monitoring."

This work, which was supported in part by the National Cancer Institute's Alliance for Nanotechnology in Cancer, is detailed in the paper "Detection of Mutations in EGFR in Circulating Lung-Cancer Cells." An abstract of this paper is available through PubMed.

• Medical Research News, Published: 2008 June 2

Chronic inflammation of the intestine or stomach can damage DNA, increasing the risk of cancer, MIT scientists have confirmed. The researchers published evidence of the long-suspected link in the June 2 online issue of the Journal of Clinical Investigation (JCI).

In two studies, the researchers found that chronic inflammation accelerated tumor formation in mice lacking the ability to repair DNA damage.

"It's something that was expected but it was never formally proven," said Lisiane Meira, research scientist in MIT's Center for Environmental Health Sciences (CEHS) and lead author of the paper.

The results of this work suggest that people with decreased ability to repair DNA damage might be more susceptible to developing cancer associated with chronic inflammation such as ulcerative colitis, Meira said.

Inflammation caused by infectious agents such as Helicobacter pylori and Hepatitis C is known to increase the risk of stomach and liver cancers, respectively. Researchers have long known that inflammation produces cytokines (immune response chemicals that encourage cell proliferation and suppress cell death), which can lead to cancer.

In addition, it was suspected that another effect of the inflammation pathway could also induce cancer. During the inflammatory response to infection, immune cells such as macrophages and neutrophils release reactive oxygen and nitrogen species that can damage DNA.

Under normal circumstances, the DNA damage induced during an inflammatory response is repaired by DNA repair systems. But, if the DNA repair system is not functioning properly, that damage can induce mutations that can lead to cancer, according to the new study.

Every individual has variations in the effectiveness of their DNA repair systems, which could help doctors figure out which patients are most susceptible to inflammation-induced cancers.

"That variation could influence the susceptibility of individuals and how they are going to respond to a chronic inflammation response," said Leona Samson, senior author of the study and director of the CEHS.

In the JCI study, the researchers induced colon inflammation in the mice by treating them with a chemical compound that creates a condition similar to human colitis. "Lo and behold, the DNA repair deficient mice were more susceptible" to cancer, said Meira.

To show that this is a general phenomenon, the team did a second study, in collaboration with another CEHS member, James Fox, director of the Division of Comparative Medicine at MIT, and one of his students, Chung-Wei Lee. They showed that mice infected with H. pylori, who also lacked the proper DNA repair mechanisms, were more susceptible to pre-cancerous lesions in the stomach.

This study is related to another recent paper published by Fox, which found that treating H. pylori infection early with antibiotics can prevent cancer development. The new study suggests that if H. pylori goes untreated, patients with poorly functioning DNA repair mechanisms would have a greater risk of developing cancer.

• Medical Studies/Trials, Published: 2008 April 21

Cancer treatment with chemotherapeutic agents is often associated with delayed adverse neurological consequences - an occurrence often referred to as "chemobrain" - that may compromise the quality of life of a proportion of cancer survivors.

Now, research published in the open access Journal of Biology demonstrates that treatment with a single chemotherapeutic agent, 5-fluorouracil (5-FU), by itself is sufficient to cause a syndrome of delayed degeneration in the central nervous system (CNS). 5-FU is a widely used chemotherapeutic agent that is employed, alone or in combination with other agents, in the treatment of cancers of the colon, rectum, breast, stomach, pancreas, ovaries and bladder.

Little is known about the side-effects of chemotherapy on the CNS, despite their obvious clinical importance. Until now researchers have not fully understood the underlying biology, including whether these effects require: exposure to multiple chemotherapeutic agents; chemotherapeutic agents plus the body's own response to cancer; blood-brain barrier damage; or inflammation. Clinicians have also lacked animal models to study this important problem.

Professor Mark Noble and colleagues of the University of Rochester Stem Cell and Regenerative Medicine Institute and the Harvard Medical School, Boston discovered that short-term systemic administration of 5-FU to mice caused both acute CNS damage and a syndrome of progressively worsening delayed damage. This damage was not self-repairing, and instead became worse over time. In addition, Noble and colleagues also demonstrated that treatment with chemotherapy also had delayed effects on the speed with which information is transferred from the ear to the brain.

Myelin sheaths are necessary for normal neuronal function. One key finding of the study was that clinically relevant concentrations of 5-FU were toxic not only for dividing cells of the CNS but also for the cells that produce the insulating myelin sheaths (non-dividing oligodendrocytes). The delayed damage the researchers measured was to the myelinated tracts of the CNS and associated with extensive myelin pathology. The findings regarding the speed of ear-to-brain information transfer may offer a non-invasive means of analyzing myelin damage associated with cancer treatment.

"Multiple clinical reports have identified neurotoxicity as a complication of treatment regimens in which chemotherapeutic agents such as 5-fluorouracil are components," says Noble. "As treatments with chemotherapeutic agents will clearly remain the standard of care for cancer patients for many years to come, the need to better understand such damage is great."

Professor Noble continues "These studies extend the field of stem cell medicine beyond the use of cell transplantation for tissue repair. It is our knowledge of stem cell biology that allows us to begin to understand some of the causes of this syndrome, as well as providing the means of preventing or repairing this damage."

This research provides the first demonstration that delayed CNS damage can be induced by a single chemotherapeutic agent and also generates the first animal model of such damage. These studies further demonstrate that this syndrome differs from that caused by irradiation and thus may represent a new class of delayed CNS degenerative damage.

• Men's Health News, Published: 2007 Dec 13

Extracts from fungi show potential as prostate cancer treatment

A new development in the fight against cancer: Recent research at the University of Haifa found that molecules found in common fungus Ganoderma lucidum aid in suppressing some of the mechanisms involved in the progression of prostate cancer.
The main action of the fungus: disrupting androgen receptor activity and impeding the proliferation of cancerous cells.

Over the past 3-4 decades much scientific research has dealt with the medicinal properties of different fungi. One of the important characteristics of fungi is the ability to fight cancer in a number of ways; however most of the research has been concentrated on how fungi affect the immune system. In this research, conducted by Dr. Ben-Zion Zaidman, under the direction of Prof. Eviatar Nevo and Prof. Solomon Wasser from the Institute of Evolution at the University of Haifa, and Dr. Jamal Mahajna from the Migal Galilee Technology Center, the researchers examined how fungi fight cancer from within cells. "Up to now, research has been based on enhancing the immune system with high-molecular-weight polysaccharides that act through specific receptors in cell membranes. We concentrated our research on low-molecular-weight secondary metabolites that can penetrate the cells and act at the molecular level from within the cell itself," explained Dr. Zaidman.

According to Dr. Zaidman, prostate cancer, one of the most common cancers found among men in the Western World, is controlled by the androgen receptor, especially at the initial stages of development of the disease. Therefore, all of the current medications used to treat prostate cancer work to reduce the production of androgens or to interfere with their function via the androgen receptor.

At the first stage of the research, 201 organic extracts from 68 types of fungi were produced with solvents such as ether, ethyl acetate and ethanol. These solvents are used to select molecules that are small enough to act from within the cells. Of the 201 extracts, 11 were found to deter androgen receptor activity by more than 40%. In further testing, 169 extracts were tested for cancer cell growth inhibition. In this study, 14 extracts were found to be active in inhibiting prostate cancer cells.

From among the active extracts, those from Ganoderma lucidum were found to be the most effective in inhibiting the function of the androgen receptor and controlling vital development of cancerous cells. "The results of this research are particularly interesting from a commercial aspect. Potential possibilities exist to establish research and development of bioactive metabolites from Ganoderma lucidum that could yield an anti-prostate cancer drug," remarked Dr. Zaidman.

• The science journal Nature, Published: 2007 Nov 19

Body's Immune System Can Keep Tumour Dormant

US scientists, studying genetically engineered mice to develop medicine for cancer, have reported this finding. They found that the body's immune system keeps tumors dormant for many years.

It also kills off some cancer cells, but not quickly enough to shrink or destroy the tumour, reported the online edition of Daily Mail.

The finding was described by the medical experts as "startling" and could lead to treatments that would allow patients to live with "neutralised" cancer for the rest of their lives.

Doctors have known for long that cancer can lie dormant in the body for years before suddenly coming back to life. They were however not aware exactly how they could be kept in check.

The findings are a result of a study led by Professor Robert Schreiber at the Washington University School of Medicine and published Monday in the online version of the science journal Nature.

"Thanks to the animal model we have developed, scientists can now reproduce this condition of tumour dormancy in the laboratory and look directly at cancer cells being held in check by the immune system," Schreiber said.

"Further research and clinical validation of this process may also turn established cancer into a chronic condition, similar to other serious diseases that are controlled long-term by taking a medicine," the scientist said.

• Medical Research News, Published: 2007 Oct 31

The next cancer drug might come straight from the grocery store, according to new research published in the November 2007 issue of The FASEB Journal.

In the study, French scientists describe how high and low doses of polyphenols have different effects. Most notably, they found that very high doses of antioxidant polyphenols shut down and prevent cancerous tumors by cutting off the formation of new blood vessels needed for tumor growth. Polyphenols are commonly found in red wine, fruits, vegetables, and green tea.

At relatively low doses, the French researchers found that the same polyphenols play a beneficial role for those with diseased hearts and circulatory systems by facilitating blood vessel growth. The amount of polyphenols necessary for this effect was found to be the equivalent of only one glass of red wine per day or simply sticking to a healthy diet of fruits and vegetables containing polyphenols. This diet is known as the "Mediterranean Diet." This study also adds to a growing body of research showing dose-dependent relationships for many types of commonly used compounds. For instance, research published in the October 2006 issue of The FASEB Journal shows that aspirin, through different mechanisms, also has a dose-dependent relationship for heart disease and cancer.

"When it comes to finding treatments for complex diseases, the answers are sometimes right there waiting to be discovered in unexpected places like the produce aisles and wine racks of the nearest store," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. "But it takes modern science to isolate the pure compound, test it in the lab, and to go on from there to find new agents to fight disease."

According to the authors, the amount of polyphenols necessary to obtain an anti-cancer effect is the equivalent of drinking about a bottle of red wine each day. This amount of daily alcohol consumption obviously is unhealthy, but the research suggests that polyphenols extracted from plants or red wine could be converted into a pill that is highly likely to be safe. Such a pill also would be relatively easy and inexpensive to create and deliver.

"The use of plant polyphenols as therapeutic tools presents important advantages," said Daniel Henrion, senior author of the study, "because they have a good safety profile, a low cost and they can be obtained everywhere on the planet."

• Medical Research News, Published: 2007 Sept 19

Liver cancer marker could yield blood test for early detection

In the face of an emerging liver cancer crisis in Asia, researchers at the Chinese University of Hong Kong have developed a test that could help millions.
Due to widespread hepatitis B virus (HBV) infection, nearly 10 percent of China's population is at high risk for hepatocellular carcinoma (HCC), a liver cancer with low survival rates if not detected and treated early. Researchers report on a new blood screening technique that could make it possible to detect early-stage liver cancer and predict how well a patient will do following treatment. They present their data today at the American Association for Cancer Research's Second International Conference on Molecular Diagnostics in Cancer Therapeutic Development, in Atlanta, Georgia.

According to their report, the Chinese team has detected an altered version of RASSF1A, a tumor suppressing gene, in the blood of HCC patients and in 58 percent of HBV-infected test subjects. Healthy subjects showed no signs of the altered gene. They also found that patients treated for HCC with high blood levels of the gene were more likely to have a relapse of the disease.

"A large portion of the population throughout Hong Kong and China are carriers of hepatitis B, so many people are at risk for hepatocellular carcinoma," said K.C. Allen Chan, MBBS a professor at the Chinese University of Hong Kong. "And we hope that this will form the basis of an effective clinical test for early detection of hepatocellular carcinoma."

Hepatocellular carcinoma is one of the deadliest forms of cancer in China and throughout Asia, according to the researchers. In the West, liver cancer is usually a secondary cancer, caused by the spread of tumor cells from elsewhere in the body. In China, however, liver cancer mainly manifests as HCC, a primary cancer, which has been linked to hepatitis B and C infection and cirrhosis. Noticeable symptoms do not usually appear until the cancer has progressed, so it is rarely caught early, when intervention would be most effective, and survival rates are typically low, said Chan.

Currently, ultrasound and CT scans are the gold standard for detecting HCC. However, they are too expensive to be an effective mass screening tool, the researchers said. About 70 percent of patients exhibit a detectable increase in bloodstream amounts of alphafetoprotein, but a screen for this protein would miss many potential patients. "We need a new biomarker for hepatocellular carcinoma, something that can be used to screen large populations of at-risk people for follow-up studies," Chan said.

RASSF1A is a good candidate, according to Chan. Researchers have known that the DNA of HCC tumor cells lack a functioning copy of RASSF1A. In these cells, RASSF1A is "hypermethylated," meaning the RASSF1A gene has been physically altered by cancer-related processes that added clusters of carbon and hydrogen atoms, called methyl groups, to portions of the DNA within the gene. Hypermethylation is epigenetic - the gene is altered by environmental circumstances and is not inherited. Since the cell's protein making system can't access the gene, hypermethylation effectively knocks out the tumor-suppressing RASSF1A gene, which is then unable to stop cells from becoming cancerous.

While hypermethylated RASSF1A would make a useful biomarker for HCC, methylation-specific PCR - the polymerase chain reaction used to specifically amplify and detect methylated DNA - destroys about 85 to 93 percent of the DNA in a blood sample. Together with the fact that tumoral DNA is only present at very low concentrations in blood during early stages of HCC, this method has not been sensitive enough to detected altered RASSF1A in blood for the purpose of early cancer detection, Chan said.

To compensate, Chan and his colleagues invented a new technique that they call "methylation-sensitive enzyme-mediated real-time PCR," which combines real-time PCR, a technique that enables researchers to simultaneously detect and amplify a given gene, with an enzyme that breaks unmethylated DNA apart. With this new technique, Chan's team was able to separate out the altered methylated DNA, thus developing a more sensitive technique for detecting and quantifying hypermethylated RASSF1A derived from cancer cells in blood.

To test the relationship between altered RASSF1A and HCC - as well as test the new detection technique -- Chan and his colleagues conducted two studies involving HCC patients. In the first, they matched 63 pairs of patients, one with HCC and the other a chronic HBV carrier by age and sex, along with 30 healthy volunteers. They detected hypermethylated RASSF1A in 93 percent of the HCC patients, 58 percent of the HBV carriers and none of the healthy patients. The median RASSF1A levels for the HCC patients were 770 copies per milliliter and 118 copies per milliliter for HBV carriers.

"The respective levels of the gene for HCC patients and HBV carriers, is consistent with what we already know about the progression of the disease," Chan said. "The gene is altered very early in the procession of malignant transformation, and so we can see that the levels of the altered gene increase as the cancer process progresses."

In the second study, the researchers looked at 22 pairs of sex- and age-matched patients who had been enrolled in a HCC surveillance program involving 1018 HBV carriers. For the 22 HBV carriers who subsequently developed HCC, there was a significant increase in circulating RASSF1A levels from the time of enrollment to the time of cancer diagnosis. On the contrary, there was no significant change in RASSF1A levels over the same period for the 22 matched subjects enrolled in the same program who didn't develop HCC.

"As we refine the process of detecting hypermethylated RASSF1A, we hope to have a functioning test for hepatocellular carcinoma," Chan said. "A significant number of people will develop this cancer and it is only through early screening and detection that we can hope to help them."

• Devices/Technology, Published: 2007 Sept 5

Laser technology detects cancer by scanning surface veins

A new technology for cancer detection that eliminates the need for drawing blood has been developed by Purdue University researchers.

Researchers from Purdue's Cancer Center, Department of Chemistry and Weldon School of Biomedical Engineering collaborated with cancer and biotechnology experts from the Mayo Clinic to develop technology to detect tumor cells within the human body. By shining a laser on surface veins, such as those on the wrist and inside the cheek, researchers are able to reveal and count circulating tumor cells.

In addition to being less invasive, the new detection method is able to evaluate a much larger volume of blood than what can be drawn from a patient for analysis, said Philip Low, Purdue's Ralph C. Corley Distinguished Professor of Chemistry.

"In the initial stages of cancer, there are very few circulating tumor cells - cells that indicate the spread of cancer and initiate secondary tumor formation," Low said. "By increasing the volume of blood analyzed, we improve the sensitivity of the test and allow for earlier diagnosis. If there are two cancer cells in every 50 milliliters of blood, odds are the cells would not be found in a 10-milliliter blood sample. However, the cells would be found in the 100 milliliters of blood that flow through large veins each minute."

Optical imaging provides high resolution and chemical specificity for cancer detection, but it usually suffers from limited penetration depth, making it hard to reach tumors inside the body, said Ji-Xin Cheng, an assistant professor of chemistry and biomedical engineering.

"In vivo detection of circulating tumor cells in surface veins provides an excellent way to overcome this problem," Cheng said.

"Circulating tumor cells provide a benchmark for disease progression and precise monitoring of their levels could lead to personalized treatment," Low said. "This technique allows us to quantify the amount of circulating tumor cells present, as opposed to tests that provide a 'positive' or 'negative' result.

"Through such precise monitoring, a physician could evaluate the response to chemotherapy and regularly adjust the dosage so that only the exact amount needed would be administered. This could reduce the time a patient is treated and the serious side effects that occur."

The technique could provide doctors and patients results in a matter of minutes and save the medical industry millions of dollars in testing equipment, said Wei He, a graduate student in the Department of Chemistry and the Department of Biomedical Engineering. He worked on the project with Low and Cheng.

By directly labeling tumor cells while they are in the bloodstream, some of the costs and problems associated with testing drawn blood samples can be avoided, He said.

"One sample can require five to 10 test tubes during the course of sampling, processing and analysis such as handling, labeling and washing," He said. "In addition, large hospitals can have more than 300 cancer patients in one day. Such a large influx can cause delays in sample processing and delays can affect the results of analysis."

A paper detailing the technology and detection technique was published in the July 10 Proceedings of the National Academy of Sciences. In addition to Low, He and Cheng, postdoctoral researcher Haifeng Wang and Lynn C. Hartmann, a professor of oncology and associate director for education of the Mayo Clinic Cancer Center, co-authored the paper.

The technique uses a fluorescent tumor-specific probe that labels tumor cells in circulation. When hit by a laser, which scans across the diameter of the blood vessel 1,000 times per second, the tumor cells glow and become visible. The in vivo flow detection was performed on a two-photon fluorescence microscope in Cheng's lab. The researchers compared several methods and found two-photon fluorescence provides the best signal to background ratio. The technology is able to scan every cell that is pumped through the vessel, He said.

Low's team has developed two labeling agents that attach to different forms of cancer. One label targets ovarian, non-small lung, kidney and endometrial cancer, and the other targets prostate cancer.

These labels would be administered through an injection. The first label has already been tested in humans and has no adverse side effects and could potentially be administered weekly, He said.

Computed tomography, or CT, scans and magnetic resonance imaging, or MRI, are the current methods used to track the spread of cancer. These methods have a limited resolution, and a 1 millimeter tumor could go undetected by CT or MRI. The Purdue-developed technology can achieve single-cell resolution and can detect rare cell populations.

"Our method can detect cancer cells early in disease development and the test can be conducted frequently," Low said. "Discovering the cancer early and knowing whether it has metastasized, or spread, greatly improves a patient's chance for successful treatment."

The laser penetrates to a depth of 100 microns and is able to examine shallow blood vessels near the surface of the skin. Advanced optical technology could be incorporated into the technology platform and enable the method to reach deeper vessels that handle larger volumes of blood, Cheng said.

The Purdue team continues to work with the Mayo Clinic and is planning to initiate a clinical trial to further evaluate the technique. The team also plans to develop labels for additional types of cancer and to downsize the equipment to make the technology portable.

• Medical Research News, Published: 2007 Sept 13

In the September issue of Molecular & Cellular Proteomics, scientists describe a new technique that can detect how proteins undergo changes inside a cell.
The technique promises to improve our understanding of how proteins inside cells work and identify how some proteins are not modified properly in common diseases such as cancer and cardiovascular diseases.

In 2006, Ola Soderberg and colleagues established a technique called in situ proximity ligation assay (in situ PLA) to reveal protein-protein interactions in cells. The technique recognizes a target protein by binding a "probe" consisting of a pair of proteins attached to DNA onto the target protein. Then the DNA is replicated, producing a molecule that can be visualized under a microscope as a fluorescent spot - thus marking the presence of individual molecules in the target protein.

In the new study, Soderberg and colleagues developed a generalized version of the technique in which different probes can identify proteins that have undergone various changes in their structure. The researchers used this technique to detect a protein on the membrane of cells called platelet-derived growth factor receptor beta, which undergoes changes that will promote cell proliferation and movement. The technique is more sensitive and selective than other currently-used techniques, that is, it does not miss as many proteins as the other techniques do and the rate of mix-ups among the detected proteins is lower.

Article: " In Situ Detection of Phosphorylated Platelet-derived Growth Factor Receptor Beta Using a Generalized Proximity Ligation Method," by Malin Jarvius, Janna Paulsson, Irene Weibrecht, Karl-Johan Leuchowius, Ann-Catrin Andersson, Carolina Wahlby, Mats Gullberg, Johan Botling, Tobias Sjoblom, Boyka Markova, Arne Ostman, Ulf Landegren, and Ola Soderberg

The American Society for Biochemistry and Molecular Biology is a nonprofit scientific and educational organization with over 11,900 members in the United States and internationally. Most members teach and conduct research at colleges and universities. Others conduct research in various government laboratories, nonprofit research institutions and industry. The Society's student members attend undergraduate or graduate institutions.

Founded in 1906, the Society is based in Bethesda, Maryland, on the campus of the Federation of American Societies for Experimental Biology. The Society's purpose is to advance the science of biochemistry and molecular biology through publication of the Journal of Biological Chemistry, the Journal of Lipid Research, and Molecular and Cellular Proteomics, organization of scientific meetings, advocacy for funding of basic research and education, support of science education at all levels, and promoting the diversity of individuals entering the scientific work force.

• Cancer News, Published: 2007 August 7

Scientist identified Lung tumor suppressor

 

The gene is found in almost a quarter of all human lung cancers and in mice its mutation results in aggressive tumors that are more likely to spread throughout the body.
The study was conducted by a team of researchers led by Dr. Norman Sharpless at the University of North Carolina at Chapel Hill School of Medicine and Harvard Medical School.
As part of the study researchers developed a mouse model with defects in the LKB1 gene that causes one of the most lethal malignancies in man, a form of lung cancer called squamous cell carcinoma.
The researcher demonstrated that cancer developed at a much faster rate in genetically engineered mice as compared to those with defects in other tumor suppressors commonly mutated in lung cancer.
The study found that these mice exhibited not just one, but all three forms of non-small cell lung cancer, adenocarcinomas, squamous cell carcinomas and large cell carcinomas and they were more likely to metastasize, or spread to other organs.
"Clearly mice with lung cancers harboring LKB1 mutations do much worse than those with other types of cancers; however, we still do not know what this gene does," Nature quoted Sharpless, as saying.
Researchers then analyzed DNA from 144 non-small cell lung cancer patients to study whether the mouse model related to genetic events of human lung cancer.
The study noted defects in LKB1 in 34 percent of human lung adenocarcinomas, 19 percent of squamous cell carcinomas and 10 percent of large cell carcinomas.
Dr. Neil Hayes, co-author of the study explained that by studying cancer progression in patients, specific LKB1 mutations can be identified.
"Based on this study and ones like it we should be able to sort patients into groups based on exactly what genetic lesion is causing their cancer," Hayes said.

• Cancer News, Published: 2007 July 27

Researchers at the University of Michigan have identified a gene linked to the development of an aggressive form of breast cancer. The researchers found that the gene, FOXP3, suppresses tumor growth. FOXP3 is located on the X chromosome, which means a single mutation can effectively silence the gene. This is unusual, as only one other gene linked to cancer has been found on the X chromosome. When one copy of the FOXP3 gene is silenced, the researchers found in studying mice, 90 percent of the mice spontaneously developed cancerous tumors. The researchers also looked at FOXP3 in human breast tissue cells, comparing cancerous and non-cancerous cells. FOXP3 was found to be either deleted or mutated in a substantial portion of the cancer sample: about 80 percent of the cancer tissues studied did not express the gene at all.

In addition, the researchers found FOXP3 to be a repressor of HER-2, a protein that typically marks a more aggressive form of breast cancer. The researchers believe FOXP3 suppresses the HER-2 gene. HER-2 can be activated by many different factors, but the researchers found that when FOXP3 is normal, it keeps HER-2 levels low; when FOXP3 is missing or mutated, HER-2 levels are likely to rise.

The researchers have shown that FOXP3 was reduced or missing in about 80 percent of the more than 600 cases of breast cancer tissue examined. At this point, the researchers do not know if FOXP3 can predict breast cancer risk, like the BRCA1 and BRCA2 genes, both of which are linked to a higher risk of breast cancer.

 

“FOXP3 defects promote cancer development. We do not know whether this is a genetic defect that puts women at higher risk. For treatment, this gene could be quite important, but for diagnosis, it’s too early to tell,” says study author Yang Liu, Ph.D., deNancrede Professor of Surgery at the U-M Medical School and co-director of the cancer immunology program at the U-M Comprehensive Cancer Center. Results of the study appear in the journal Cell.

 

Initially, the researchers were studying FOXP3’s role in autoimmune disease, when they noticed that female mice with one copy of the mutated form of the gene were developing breast cancer. Moreover, the tumors expressed high levels of ErbB2, the mouse equivalent of HER-2. Breast cancer is rare in mice, and ErbB2-positive breast cancer is even more rare.

“FOXP3 is the first X chromosome-linked gene that suppresses breast cancer and represses the HER-2/ErbB2 oncogene. Given the significant role HER-2 plays in breast cancer and the widespread defects we found on FOXP3, it is likely that this gene play an important role in suppressing breast cancer,” says Pan Zheng, M.D., Ph.D., associate professor of surgery and pathology at the U-M Medical School.

• Medical Research News, Published: 2007 July 17

Experts in the United States say that eating the right food with certain medications could improve the effectiveness of drugs and also reduce the cost of treating patients.

The oncologists from the University of Chicago suggest that taking a breast cancer drug with fatty food, rather than on an empty stomach, boosts absorption of the drug and means patients could take lower doses, which would reduce costs.

They found that taking the breast cancer drug lapatinib at the same time as a fatty meal may make it work at least three times as well and when grapefruit juice accompanies the meal the researchers say the pills could be five times more effective than normal by aiding absorption.

The researchers say however that further tests are needed and that patients should not alter how they take their cancer drugs.

They suspect a better understanding of the relationship between common drugs such as statins and for example grapefruit juice could possibly cut down drug costs.

In the past experts have warned of the potential dangers of interactions between food and drugs which can render drugs becoming toxic, or less effective.

Professors Mark Ratain and Ezra Cohen say they have found that taking the breast cancer drug lapatinib (TYKERB) with food, rather than on an empty stomach as suggested on the label, increased the availability of the drug in the body by 167%, meaning the drug could work more effectively; taking it with a meal rich in fat boosted levels by 325%.

The researchers say their findings about the interactions between foods and anti-cancer drugs could be exploited to help decrease costs and increase the benefits from such drugs.

Professor Ratain says by simply changing the timing and taking lapatinib with a meal instead of on an empty stomach only 40% of the drug is needed.

Grapefruit is known to boost absorption of certain drugs and Professor Ratain says drinking grapefruit juice, which is known to increase the rate at which some drugs enter the blood stream could increase these savings even further.

Ratain also suggests that eating such "value meals" at the same time as taking drugs could have other benefits too; a major toxicity associated with lapatinib is diarrhoea, which is thought to be caused by some of the drug being unabsorbed, therefore taking lower doses with food to boost its absorption should help reduce this side-effects.

He says that one 250mg lapatinib pill accompanied by food and a glass of grapefruit juice may yield plasma concentrations comparable to five pills on an empty stomach.

The authors caution against patients experimenting themselves and say more research to assess the effects of drug-combinations on patients.

They are in fact currently conducting a study testing the effect of combining a drug with grapefruit juice.

The Medicines and Healthcare Products Regulatory Agency says any new recommendations about drug dosages need to be backed up by evidence and full testing through clinical trials.

The research is published in the Journal of Clinical Oncology.

• Men's Health News, Published: 2007 July 1

Lifestyle changes and prostate cancer

Up to 73% of men with prostate cancer take nonprescription supplements, and smaller numbers use diet, exercise, or both in the hope of improving their outcome.
Most of these men also receive conventional therapy, but a few depend on lifestyle alone. The appeal of lifestyle therapy is obvious-but does it work. Experts don't know, though research raises hope that it may have a beneficial impact, reports the July 2007 issue of Harvard Men's Health Watch .

All of the 93 men who signed up for the trial had newly diagnosed low- to moderate-grade cancers that were localized to the prostate gland. Half were randomly assigned to a lifestyle program, and half got no advice on lifestyle changes. The program that researchers created included four elements: An ultra-low-fat vegan diet; supplements, including soy, fish oil, vitamins E and C, and selenium; an exercise program of walking 30 minutes six days a week; and stress reduction that included yoga-based stretching, breathing, and meditation for an hour a day.

At the end of a year, a small but significant difference was evident. The average PSA in the intensive lifestyle group fell, whereas the average PSA in the untreated men rose. The participants in the lifestyle group also showed favorable cancer-fighting changes in their blood.

Much more research is needed before lifestyle therapy can be recommended clinically. But, the Harvard Men's Health Watch notes, men with prostate cancer may choose not to wait until science catches up with their disease. And since the lifestyle program studied is good for general health, its elements will make a reasonable addition to any prostate cancer program.

• Medical Condition News, Published: 2007 June 12

In a special publication sent to thousands of oncologists nationwide this month, University of Rochester Medical Center scientists offer an in-depth examination of cancer-related fatigue, with hope that a better understanding of the topic will prompt new research and treatment.

Virtually all cancer patients complain of some degree of persistent fatigue. Coping with this challenging side effect is critical to surviving cancer, especially since many people desire to work, raise children, run a household, or engage in recreation throughout their treatments, said Joseph Roscoe, Ph.D., a co-author and research associate professor of Oncology at the University's James P. Wilmot Cancer Center.

"It used to be that fatigue was viewed as an inevitable part of sickness," said Roscoe, a cancer survivor. "Now we know better, and there's a great deal of ongoing research about what causes fatigue and how it can be managed. For some people, fatigue is so debilitating that they want to stop their cancer treatments, which is why it is particularly important to find ways to address this problem."

During his own bout with cancer fatigue, Roscoe recalled feeling "jet lagged all the time." But rest or sleep does not alleviate cancer fatigue, and it often persists for months. In some studies, patients report more stress from fatigue than from pain, depression or nausea.

Unfortunately, no one has turned up a quick fix. "Exercise is looking very promising and one psychostimulant drug, modafinil, is being studied as a potential new treatment," Roscoe said. "But nothing yet has clearly demonstrated the ability to relieve cancer-related fatigue."

The Oncologist, a peer-reviewed journal, published a body of work from the James P. Wilmot Cancer Center's Behavior Medicine Unit on current knowledge of this condition. Six articles form a special journal supplement, which is intended for use as a physician reference guide.

The following is a snapshot of what is reviewed in the journal:

Scale of the problem. Of the 1.3 million Americans diagnosed with cancer in 2005, 95 percent of the people scheduled to receive chemotherapy or radiation expected to experience fatigue. Studies show the frequency of actual fatigue during chemo ranges from 70 to 100 percent; likewise, 90 percent of patients who receive radiation therapy report fatigue. Also, up to 40 percent of patients report unusual fatigue upon diagnosis, a sign that fatigue is an early symptom of malignancy as well as a consequence of treatment.

Underlying causes. Cancer fatigue disrupts several interrelated systems: physiological, biochemical, psychological. The effect varies among individuals and also during different phases of treatment. It likely involves changes in the endocrine system, circadian rhythms, metabolism, cytokines and seratonin production. Predisposing factors must be understood before researchers can develop useful prevention or treatment strategies.

Measurement of a subjective symptom. More than 20 different assessments are used to diagnose fatigue, from single-question scales to multidimensional measurements of a patient's physical, emotional and cognitive functioning. Most patients can easily rate their fatigue on a scale from 0 to 10, researchers said. However, it is important for physicians to distinguish cancer fatigue from other ailments such as depression, and treat accordingly.

Fatigue and cancer-related sleep disorders. Approximately 25 to 50 percent of all prescriptions that doctors write for cancer patients are for hypnotics. Studies show that sleep disturbances are more severe in the most fatigued patients, suggesting a reciprocal relationship between these two distinct conditions.

Drug remedies. The first step to managing cancer fatigue is to treat conditions that may contribute to it, such as anemia, pain or depression. Studies show that anemia medications alleviate cancer fatigue to some degree. Other classes of drugs called psychostimulants have shown promise in open-label trials. Further research is needed.

Non-drug remedies. A growing body of evidence shows that exercise and support groups help people with cancer fatigue the most. Additional studies into nutrition therapy, yoga, mindfulness stress reduction, and polarity therapy also show promise. Many people with cancer already use non-drug behavioral therapies on their own, researchers said, but it's important that the scientific community continue to fund and study these interventions.

• Medical Studies/Trials, Published: 2007 June 3

Women with breast cancer who receive higher doses of radiation with IMRT each day can reduce their treatment time by two weeks without increasing side effects, according to a study released in the June 1 issue of the International Journal of Radiation Oncology*Biology*Physics, the official journal of the American Society for Therapeutic Radiology and Oncology.

Intensity modulated radiation therapy (IMRT) is a specialized form of radiation therapy that allows the radiation to be more exactly shaped to fit the tumor. With IMRT, the radiation beam can be broken up into many "beamlets," and the intensity of each beamlet can be adjusted individually. In some cases, this may allow doctors to send a higher dose of radiation to the tumor, potentially increasing the chance of a cure.

In this particular study, IMRT was delivered with an additional concurrent "boost," or high-dose radiation to the lumpectomy site where the tumor was removed. The standard boost is typically given after the four to five weeks of conventional radiation therapy and adds another one to two weeks to the treatment time. The boost in this study was given during the four weeks of whole breast irradiation to see if the increased dose would increase side effects. Some women who receive standard radiation therapy for breast cancer develop skin irritation as a side effect from the radiation's effect. This side effect is similar to sunburn and usually heals on its own once treatment ends. Doctors believe that without the use of IMRT, the elevated level of radiation would not be tolerated by the patients.

Seventy-five women were treated in this Phase II study using IMRT for four weeks, as opposed to the traditional six to seven weeks. The women were treated with a slightly higher radiation dose to the entire breast while also delivering the boost to the original lumpectomy site of the breast. Though the dosage of radiation was increased, the daily treatments of radiation were at a well-tolerated level. Doctors graded the skin toxicity of each patient on a scale of Grade 0 (no skin toxicity present) to Grade 9 (severe toxicity). More than half of the women, 65 percent, had Grade 1 skin toxicity at the end of the four week treatment period, with 23 percent of the women reporting a skin toxicity of Grade 2. The other 12 percent had Grade 0 toxicity, meaning they showed no skin irritation. None of the patients had higher than Grade 3 toxicity.

In the short-term follow-up of six weeks, doctors found that the all toxicity levels had returned to normal, including the women who had Grade 2 skin toxicity.

This study demonstrated that in addition to safely increasing the daily dose to the whole breast during the four-week period, it is possible to deliver the "boost" concurrently, eliminating the extra two weeks and possibly sparing the women from more discomfort during the post-operative treatment.

"Earlier studies have proven without a doubt that six to seven weeks of radiation therapy after a lumpectomy cures most early-stage breast cancers. Now, we're working to find ways to make the treatments easier for patients by reducing side effects or shortening the treatment. This study presents a good foundation of knowledge for the potential of IMRT for breast cancer," said Gary Freedman, M.D., lead author of the study and a radiation oncologist at Fox Chase Cancer Center in Philadelphia. "With long-term follow up and further study, we can aim to condense the length of post-operative treatment for these women."

• Medical Research News, Published: 2007 May 24

Scientists have made a breakthrough in understanding how cancers spread in what could lead to new ways of beating the disease.

 
The University of Manchester study used embryonic stem (ES) cells to investigate how some tumours are able to migrate to other parts of the body, which makes the treatment of cancer much more difficult.

Dr Chris Ward, in the University's Faculty of Medical and Human Sciences, studied a crucial change that makes cancer cells able to start moving and spread into other tissues.

Normal cells, as well as early cancer cells, are called epithelial cells because they bind tightly to each other forming stable layers of tissue. However, as a tumour becomes more advanced, some of the cells change to become mesenchymal.

Mesenchymal cells do not bind to each other, forming more disorganised tissues in which the cells can move around. Since this crucial change known as the epithelial-mesenchymal transition, was first observed in the early embryo, Dr Ward theorised that embryonic stem cells might undergo a similar process.

Dr Ward, whose findings are published in the journal Molecular Biology of the Cell, said: "We have shown that ES cells spontaneously change in a manner that is remarkably similar to the epithelial-mesenchymal transition. They lose the proteins that cells use to bind to each other and have other protein alterations that are characteristic of spreading cancer cells.

"Since ES cells can be grown in the laboratory where they keep the characteristics of the cells in the early embryo they can be studied in detail. By studying these ES cells we have already identified a novel component of this transition process. We expect the use of ES cells will lead to the identification of other unknown factors involved in cancer cell spread, hopefully leading to new avenues for cancer therapy."

Previously, it has been quite difficult to study this crucial transition in cancer cells as it only happened to a limited number of cells in a growing tumour. The team's discovery that it happens spontaneously in ES cells means that it can be studied more easily in the laboratory.

"Understanding how cancer cells start to spread is tremendously important for cancer research; tumours that do not spread are rarely, if ever, dangerous," said Dr Ward, who leads the stem cell research group in the School of Dentistry.

"It is the ability of tumours to invade into other tissues and spread around the body that makes them so dangerous. Finding out more about the mechanism that controls the spread of cancer cells will help us find new treatments that can prevent tumours spreading and make them essentially harmless."

The study, which was funded by the Association for International Cancer Research (AICR) and also involved the University's Immunology Group at the Paterson Institute for Cancer Research (PICR), used embryonic stem cells to investigate how the protein E-cadherin stopped cells from migrating during normal growth.

The team found that, as well as helping cells stick together, E-cadherin also blocked the action of another protein known to increase the mobility of cells. This important dual function of E-cadherin opens up the potential for new targets to prevent tumours from spreading.

Derek Napier, Chief Executive of AICR, said: "Dr Ward's work will open the door to a detailed dissection of the process that makes cancers spread around the body.

"Scientific research occasionally makes sudden leaps forward when a new way of investigating something is discovered. We predict that this will lead to a huge growth in our understanding of cancer spread and the development on several new approaches to stopping it."

• Women's Health News, Published: 2007 May 6

Radiation for breast cancer not likely to increase heart attack risk

 

In 1973, two researchers published an article in the journal Lab Investigation saying that radiation to the breast area might damage the capillaries and restrict blood flow to the heart.

Since that time, conflicting reports about the long-term risk of radiation to the heart have been published. According to a study released today in the International Journal of Radiation Oncology* Biology*Physics , the official journal of ASTRO, elderly women who receive radiation therapy for early-stage breast cancer appear to have no increased risk of a heart attack after taking pre-existing cardiac risk factors into account. Interestingly, pre-existing cardiac risk factors such as diabetes, hypertension and hyperlipidemia do not potentiate the effects of radiation on the heart.

Using the Surveillance, Epidemiology and End-Results (SEER) database, researchers conducted a retrospective study of female Medicare recipients aged 65 and older who were diagnosed with breast cancer from 1992 to 2000. Researchers then reviewed the records of more than 48,000 breast cancer patients. Of those women, 19,897 had lumpectomies (42 percent) and 26,534 has mastectomies (55 percent). Of all the patients in the study, 21,502 (45 percent) received radiation therapy and 4,151 (9 percent) received both radiation and chemotherapy. Patients with pre-existing heart disease were less likely to receive radiation.

After adjusting for pre-existing heart problems as well as other health and socioeconomic factors like age, race, marital status, income, rural versus urban living and receipt of chemotherapy, doctors found that women who received radiation were not at an increased risk of having heart attacks. As would be expected, heart attacks were more likely to be found among individuals already at higher risk for heart disease, such as women of increased age, African-American ethnicity and those with more co-morbid conditions.

"Women with breast cancer are naturally concerned about the side effects of their treatments, including radiation therapy. This study provides them and their physicians with some peace of mind knowing that the benefits of radiation appear to outweigh the cardiac risks," said John Doyle, Dr.P.H., the lead author on the study and an Adjunct Assistant Professor of Health Policy and Management and Epidemiology at the Mailman School of Public Health of Columbia University in New York.

• Medical Studies/Trials, Published: 2007 April 30

The American Cancer Society is launching a major new cancer research study that may be the 'last best chance' to do large-scale population research in the United States to discover the genetic and environmental factors that cause and prevent cancer.

The Cancer Prevention Study 3 (CPS-3) aims to enroll a geographically and ethnically diverse group of half a million adults across the United States to help pave the way for the next generation of American Cancer Society research and further advance the understanding of the lifestyle, environmental, and genetic factors that cause or prevent cancer. It is the latest in a series of important large-scale American Cancer Society studies stretching back to the 1950's that have contributed significantly to the understanding of how tobacco, obesity, diet, physical activity, hormone use, air pollution, and other factors affect the risk of cancer and other diseases.

"There are no U.S. studies on the horizon positioned to take advantage of rapidly developing new knowledge and technologies over the coming decades, except CPS-3," said Eugenia E. Calle, PhD, managing director of analytic epidemiology at the American Cancer Society, who is leading the study. "This type of study involves hundreds of thousands of people, with diverse backgrounds, followed for many years, with collection of biological specimens and assessments of dietary, lifestyle and environmental exposures. It also requires active follow-up to discover if and when study participants develop cancer."

Large studies of up to one million participants are being conducted in Europe, the United Kingdom, China, Taiwan, and even Estonia. Unlike the U.S., in many other countries, health care is administered through a national system that gives each citizen a unique identification number linking health care data and all visits to government clinics. In addition, electronic registries of disease can often be linked to study members. "Another important factor is the fact that people in other countries are often willing to be enrolled in a study, historically a serious challenge in the U.S.," said Dr. Calle.

Enrollment in CPS-3 will take place at 64 of the 4,800 Relay For Life, events taking place across the U.S. in 2007, and continue at select Relay events through 2011 (a pilot program enrolled participants at a handful of Relay events in 2006). Relay For Life is a fun-filled overnight event designed to celebrate survivorship and raise money for research and programs of the American Cancer Society. During the event, teams of people gather at schools, fairgrounds, or parks and take turns walking or running laps. Each team tries to keep at least one team member on the track at all times.

CPS-3 will enroll men and women between the ages of 30 and 65 who have never been diagnosed with cancer (important in studies that focus on the causes of cancer), and who are willing to make a long-term commitment to the study. Enrollees spend 20 to 30 minutes at a Relay For Life event, where after consenting to participate they complete a brief study questionnaire, get a simple waist measurement, and provide a small blood sample (similar to a doctor's visit).

For the next 20 or more years, Society researchers will track CPS-3 participants through questionnaires mailed every few years, identifying and studying factors associated with cancer occurrence or prevention in the study cohort.

Researchers will use the data from CPS-3 to build on evidence from a series of American Cancer Society studies that began in the 1950s and involved hundreds of thousands of volunteer participants. The Hammond-Horn study and the first Cancer Prevention Studies (CPS-I and CPS-II) have played a major role in understanding cancer prevention and risk, and have contributed significantly to the scientific literature and to the development of public health guidelines and recommendations. Those studies confirmed the link between cigarette smoking and lung cancer, showed that obesity increases the risk of several cancers, and linked aspirin use to a lower death rate from colon cancer. The current study, CPS-II, began in 1982 and is still ongoing. But changes in lifestyle and in the understanding of cancer in the more than two decades since its launch make it important to begin a new cohort.

"It is not an exaggeration to say the American Cancer Society is the only organization likely to be able to successfully recruit and retain such a large-scale population for cancer research," said Dr. Calle. "We have an excellent record dating back to the 1950's of conducting these types of studies; we can bring together a world-class research department with a unique community-based volunteer structure like Relay For Life; we can reach diverse populations nationwide who have a shared commitment to cancer research and to eliminating this disease; and because we are a non-profit organization with the ability to partner with volunteers, we can conduct the study for much less than would be possible for the government or a private corporation."

"While science can do a lot to explain the biology and genetics of cancer, some of the most valuable information we have is a direct result of the contributions of dedicated individuals over several generations," said Dr. Calle. "We are once again looking to the dedication, compassion, and generosity of Americans to come through and help us provide answers that we know will save lives and improve the outlook for future generations."

• Medical Studies/Trials, Published: 2007 April 12

Cancer occurs more frequently in the prostates of men than in any organ other than the skin. While DNA damage caused by exposure to the sun is likely the cause of many skin cancers, the cause of prostate cancer remains largely unknown.

Research conducted by the group of Marikki Laiho, M.D., Ph.D., a Professor at the University of Helsinki, Finland, in collaboration with Donna Peehl, Ph.D., an Associate Professor (Research) at Stanford University, US, points to absence of critical mechanisms protecting prostate cells from DNA damage as a key contributor to the development of prostate cancer.

Results of the study will be published in the online Early Edition of the Proceedings of the National Academy of Sciences, USA, during the week of April 9-13.

The investigators used primary cultures of normal epithelial cells derived from patients' surgical specimens to examine responses to DNA damage induced by irradiation or chemicals. These cultured cells are the "progenitor" cells in the prostate in which cancer may originate, and therefore provide a realistic experimental model in which to study carcinogenic processes.

After exposure to DNA damaging agents, cells typically mount several types of defensive mechanisms to allow repair of DNA damage prior to cell division. These mechanisms prevent the passage of damaged genetic material to daughter cells, which would contribute to the conversion of those damaged cells to cancer. One of these protective mechanisms is cell cycle checkpoint arrest, which is mediated by a series of molecular events triggered by DNA damage.

Surprisingly, normal prostate cells were unable to enforce cell cycle checkpoint arrest and continued to proliferate following DNA damage. Early events involving cellular recognition of DNA damage were intact, so lack of checkpoint arrest in these cells was not due to inability to recognize DNA damage. Rather, inability to enforce cell cycle arrest was linked to low levels of the protein Wee1A, a tyrosine kinase that phosphorylates and inhibits cyclin dependent kinase 2 (cdk2). In the absence of Wee1A activity, cdk2 remained active and continued to drive the prostate cells to undergo cell division. In conjunction, slower clearance of DNA damage foci suggested persistent DNA damage. When Wee1A protein was restored in these cells, checkpoint control was rescued, showing that Wee1A was indeed critical to this important pathway.

When using cultured cells, there is always a concern that the in vitro environment may alter cellular behavior. To confirm that the observed results were not an artifact of cell culture, the investigators used a novel model system of "tissue slice cultures", developed by Peehl. Cores of fresh tissue were bored from surgical specimens, then were precision-cut to thicknesses of only a few hundred microns. These slices were incubated and retained their structure and function for several days. The value of tissue slice cultures is that all elements of the whole tissue remain intact, permitting realistic experiments that are not feasible to perform directly in humans. The responses to DNA damage of the normal epithelial cells in these tissues were similar to those of the cell cultures, signifying that defensive mechanisms against DNA damage are indeed lacking in the human prostate.

The lack of Wee1A-mediated DNA damage-induced checkpoint enforcement is not the only defective protective mechanism in prostate cells. In 1995, Peehl in collaboration with another investigator at Stanford, Amato Giaccia, Ph.D., reported in Cancer Research that normal prostatic epithelial cells lacked the p53 response to DNA damage. The p53 protein is a major tumor suppressor and lack of p53 function leads to genomic instability and malignancy. The defects in the two checkpoint enforcement pathways, mediated by p53 in one and by Wee1A in the other, are unrelated, since correcting the Wee1A pathway did not restore p53 function in prostate cells.

The use of human cells and tissues in these studies was key to the medical relevance of the findings. The human prostate is almost unique among mammals in having a high incidence of prostate cancer. Rodents, most commonly used in the laboratory to study mechanisms of cancer, do not develop prostate cancer spontaneously. The absence of at least two key checkpoint elements in the DNA damage response pathways may predispose human prostatic epithelial cells to accrual of DNA lesions and provide a mechanistic basis for the high incidence of cancer in the prostate.

Why prostate cells lack these mechanisms is unknown, but discovery of ways to restore these checkpoints controls might protect against prostate cancer.

The study was funded by the Department of Defense Prostate Cancer Research Program, the Academy of Finland, Biocentrum Helsinki, the Finnish Cancer Organizations and the Finnish Cultural Foundation.

• Medical Studies/Trials, Published: 2007 Mar 22

When Susan Wright learned that she had a type of fatal, rapidly growing brain cancer at age 46, her doctors at the University of Florida told her she wouldn't live more than 18 months.

Three years later, Wright is still alive, rides her bike and spends days canoeing on a local river. "I can't do things at the level that I used to, but I'm still here," she said.

Wright and her doctors attribute her survival in part to a new vaccine, developed by a researcher at the Stanford University School of Medicine, to treat her aggressive brain tumor called glioblastoma. Although her doctors in Florida didn't have access to the vaccine, they sent Wright to Duke University where she spent the next year receiving the experimental treatment in a clinical trial.

"I remember that as a time of great health and optimism," she said. However, Wright has not been cured, and has since had a relapse and is on chemotherapy. But even with the relapse, the vaccine has helped Wright lived longer than most glioblastoma patients, who have an average survival rate of less than a year.

Now the vaccine will be tested at Stanford as well as other sites nationwide. Originally developed by Albert Wong, MD, professor of neurosurgery and member of the Stanford Comprehensive Cancer Center, results so far have been promising enough to spur a 20-center trial sponsored by Celldex, the New Jersey-based company developing the therapy. Wong has stock in Celldex and is a consultant for the company.

The vaccine is already attracting interest, and is scheduled to be featured during the March 22 "CBS Evening News" broadcast in a report by anchor Katie Couric.

Stanford expects to begin enrolling patients in the trial in April. For Wong, the start of this trial is the result of a career-long interest in the vaccine and in curing glioblastoma. "When you hear about people being diagnosed with brain cancer and dying several months later, that's usually glioblastoma," he said. Any treatment that improves survival time in people with the disease is a significant improvement, he said.

Only 3 percent of people with glioblastoma survive five years, with the average survival being just under a year. The disease resists treatment with chemotherapy and radiation, and spreads so effectively throughout the brain that a surgeon can no more remove every last cell than a picky eater could remove every bit of cheese from a casserole.

The vaccine arose from a 1992 discovery Wong made while he was a postdoctoral fellow at Johns Hopkins University. He found that in many glioblastomas the cells are dotted with an unusual form of a common protein called epidermal growth factor receptor, or EGFR. Although the gene for that altered protein doesn't contain any mutations, the cells inexplicably chop out several chunks of the normal protein before lodging it on their cell surface. He named this unusual variant EGFRvIII because it was the third variant he had discovered.

Anything that makes a tumor cell look different from the surrounding tissue intrigues researchers hoping to develop cures. In this case, Wong thought he could direct the immune system to attack cells carrying EGFRvIII by administering a vaccine. The activated immune cells resulting from the vaccine would ignore normal versions of EGFR on other noncancerous cells throughout the body, attacking only the cancer.

In later work, Wong realized that other solid tumors - such as those in the lung, prostate and ovary - also sport EGFRvIII. This made him think that a vaccine that attacks the unusual protein might be widely useful in treating these tumors.
In mice, the vaccine worked exactly as Wong had hoped. Based on that success, colleagues at the University of Washington started a small phase-1 trial to test the vaccine in patients with ovarian and prostate cancers that contain EGFRvIII. Each of those patients showed a response to the vaccine, but so far not enough time has elapsed to know whether it prolonged their lives.

Wong's colleagues at Duke University started another small phase-1 trial, this time testing the vaccine in people with glioblastoma. In that trial, 14 patients who got the vaccine lived on average more than 21 months. That's still not considered a cure, but it's a significant improvement over the typical survival rate.

In a follow-up phase-2 trial of 23 patients in which Duke researchers partnered with colleagues at M.D. Anderson Cancer Center, the average survival went up to about 30 months because of some changes in how the doctors delivered the vaccine and in the types of patients selected to receive it. The previous trial had accepted all glioblastoma patients, whereas this one only accepted patients whose tumors made EGFRvIII. That was the trial in which Wright participated. Results from both trials will be published in the next year.

The phase-2 trial opening up at Stanford will include 81 patients-the largest trial of the vaccine to date. Like the previous phase-2 trial, this one will only enroll patients whose tumors produce the altered protein.

For her part, Wright hopes those people experience the same tumor response and good health she felt while on the vaccine. "It's the only treatment I've had where I felt no side effects," Wright said. "It was really a wonderful experience."

• Miscellaneous News, Published: 2007 Mar 25

The Food and Drug Administration (FDA) is re-issuing its warning to consumers not to drink "Jermuk" brand mineral water due to the risk of exposure to arsenic, a toxic substance and a known cause of cancer in humans.
The agency is providing this information again to consumers due to an expansion of the recall initiated by the products' importers and distributors. "Jermuk" water is imported from Armenia and distributed under different labels in California. Five brands of these products have been recalled since March 7.

The latest recall, which was initiated on March 16 by the product's distributor, Andreas Andreasyan DBA Arnaz & Nelli Co., North Hollywood, CA., is for "Jermuk Natural Mineral Water Fortified with Gas from the Spring". This product is additionally labeled as "Produced by Sam-Har Co. Republic of Armenia" and "Exclusive Distributor in USA: Arnaz & Nelli Inc., CA 91605".

Although arsenic is a well known human poison, there is little chance that someone would become seriously ill after consuming the recalled products over a brief period of time (days to weeks). However, it is likely that the person would experience nausea, abdominal pain and possibly vomiting, which are indicators of arsenic toxicity.

FDA has sampled the contents of 500 milliliter (mL) green glass and/or plastic bottles of all of these brands and found they contained 454-674 micrograms of arsenic per liter of water. FDA's standard of quality for bottled water allows no more than 10 micrograms per liter.

The agency is investigating whether other bottle sizes or types of packaging contain similarly tainted products, and will continue working to remove all such bottled water from the market.

There have been no illnesses reported at this time. Consumers who drank this water and have concerns are encouraged to contact their health care provider.

FDA may provide additional updates as more information becomes available.

The following products were recalled on March 7:

"Jermuk Original Sparkling Natural Mineral Water Fortified With Natural Gas From The Spring". The product is in glass bottles and is additionally labeled as "2006 Jermuk Mayr Gortsaran CJSC" and "Imported by: Zetlian Bakery Inc." The importer and distributor is Zetlian Bakery, Inc., Pico Rivera, CA.
"JERMUK,1951, NATURAL MINERAL WATER, JERMUK MAYR GORTSARAN CJSC." The product is in plastic bottles which are additionally labeled as "Imported by: Zetlian Bakery Inc." The importer and distributor is Zetlian Bakery, Inc., Pico Rivera, CA.
"Jermuk Sodium Calcium Bicarbonate and Sulphate Mineral Water". The product is additionally labeled as "Bottled by ARPI Plant, Republic of Armenia" and "Exclusive US importer and distributor: Importers Direct Wholesale Co., Los Angeles, CA". The product is being recalled by Importers Direct Wholesale Company, Los Angeles, CA.
"Jermuk, Natural Mineral Water Sparkling". The product, recalled on March 7 is additionally labeled as "Bottled by Jermuk Group CJSC" and "Sale Agent Kradjian Importing Co. Inc." in Glendale, CA. The product is being recalled by Kradjian Importing Company, Glendale, CA.

• Men's Health News, Published: 2007 Mar 11

After being diagnosed with aggressive prostate cancer, many men are told that their disease is untreatable and that less aggressive treatment is best.

Often this means patients are told to watch and wait -- that is, to do nothing at all. A new study by physician-scientists at NewYork-Presbyterian Hospital/Weill Cornell Medical Center turns conventional wisdom on its head, finding either surgical removal of the prostate (prostatectomy) or radiation treatment more than doubles the life expectancy for these patients when compared with those receiving the conservative approach.

Patients with the most aggressive non-metastatic prostate cancers (Gleason scores 8-10), if treated with prostatectomy or radiation, can expect to live more than 14 years; those treated conservatively will live, on average, less than 7 years. The study appears in the March Journal of Urology.

"Unfortunately, pessimism abounds among many doctors, who believe that aggressive prostate cancers are beyond cure and should only be followed with watchful waiting, forestalling any immediate treatment. This new study points to the fallacy of this outlook, finding surgery and radiation more than double the life expectancy for these patients," says Dr. Ashutosh Tewari, the study's first author and director of robotic prostatectomy and urologic oncology outcomes at NewYork-Presbyterian/Weill Cornell and the Ronald P. Lynch Associate Professor of Urologic Oncology at Weill Cornell Medical College.

The study involved a retrospective statistical analysis of outcomes of 453 cases of clinically localized aggressive prostate (graded Gleason scores 8-10) at the Henry Ford Health System in Detroit.

"Ultimately, randomized clinical trials studying long-term outcomes will be necessary to fully demonstrate the benefits of treatment for these patients," adds Dr. David Nanus, a study co-author and medical director of the Genitourinary Oncology Program at NewYork-Presbyterian/Weill Cornell. He is co-division chief of hematology and medical oncology and the Mark W. Pasmantier Professor of Hematology and Oncology in Medicine at Weill Cornell Medical College.

The study's senior author is Dr. Mani Menon of the Henry Ford Health System in Detroit.

In 2006, roughly 234,000 American men were diagnosed with prostate cancer. The most aggressive prostate cancers often result in early metastasis and death. Left untreated, as many as 85 percent of men die from prostate cancer within 10 years of diagnosis. High-grade cancers are also unique because they can affect younger men and have a relative resistance to radiation.

• Medical Research News, Published: 2007 Feb 22

A microRNA directly regulates a gene implicated in human cancers, researchers from Whitehead Institute and Massachusetts Institute of Technology report in the February 22nd online issue of Science.

MicroRNAs are tiny snippets of RNA that can repress activity of a gene by targeting the gene's messenger RNA (which copies DNA information and starts the process of protein production).

The first microRNA was discovered in 1993, in worms. It took seven years for the second one to be found, also in worms, but then the floodgates burst. Many microRNAs now have been found in diverse plants and animals, including hundreds in humans. Moreover, microRNAs found in mammals regulate over a third of the human genome, as shown in a 2005 study by the lab of Whitehead Member and Howard Hughes Medical Institute Investigator David Bartel and colleagues.

But given the wealth of microRNAs, and the ability of individual microRNAs to target hundreds of genes, researchers have struggled to show the biological impact of a particular microRNA on a particular target in mammals (although such connections have been shown in plants, worms and flies). Several groups have demonstrated that over-expression or under-expression of a microRNA can play a role in certain cancers, but have not clarified the genes responsible.

Looking to find a promising target for an individual microRNA, Christine Mayr, a postdoctoral researcher in the Bartel lab, picked Hmga2, a gene that is defective in a wide range of tumors.

In these tumors, the protein-producing part of the Hmga2 gene is cut short and replaced with DNA from another chromosome. Biologists have mostly focused on the shortened protein as the possible reason that the cells with this DNA swap became tumors. But this DNA swap removes not only the gene's protein-producing regions but also those areas that don't code for protein. And these non-protein-producing regions contain the elements that microRNAs recognize.

It turns out that in the non-protein-producing region, Hmga2 has seven sites that are complementary to the let-7 microRNA, a microRNA expressed in the later stages of animal development. Mayr wondered whether loss of these let-7 binding sites, and therefore loss of regulation by let-7 of Hmga2, might cause over-expression of Hmga2 that in turn would result in tumor formation.

To find out, Mayr created a series of Hmga2 in which various numbers of let-7 sites were destroyed. She found clear evidence that when exposed to let-7, the fewer sites that were intact, the more protein was produced.

Next, she tested whether disrupting let-7's ability to repress Hmga2 would lead toward tumor creation. In a standard in vitro test of cancer-causing genes, colonies of mouse cells that expressed normal or shortened Hmga2 did not grow significantly, while cells in which Hmga2 contained disrupted let-7 sites did. In fact, the more that let-7 sites were damaged, the greater the number of colonies.

Mayr also worked with MIT assistant professor Michael Hemann to inject these cells in mice with a compromised immune system. The scientists found that the mice with cells that expressed the version of Hmga2 with the disrupted let-7 sites developed tumors.

Overall, the results highlight a new mechanism for cancer formation. Hmga2, and perhaps certain other genes that are normally regulated by microRNAs, can help give rise to tumors if a mutation in the gene disrupts the microRNA's ability to regulate it. In addition, the results show that the interaction of one microRNA with one of its target genes can produce a certain trait in mammals. This is important because scientists are only beginning to learn the functions of microRNAs in animals.

"Because hundreds of human genes appear to be regulated by the let-7 microRNA, we were afraid we wouldn't see any difference when we changed only one of these target genes," says David Bartel, who is also an MIT biology professor. "Seeing the difference encourages us to explore the biological importance of other examples of microRNA regulation."

• Medical Research News, Published: 2007 Jan 29

A new testing approach has been shown to be effective in identifying patients at the highest risk of cancer relapse after surgery for bladder cancer, say researchers in the February issue of The Lancet Oncology.

"Bladder cancer recurs in many patients after radical cystectomy [removal of the bladder and surrounding tissues]. Conventional prognostic features such as tumour grade, stage, and lymph-node status are not accurate enough to predict outcomes in patients with bladder cancer", says one of the study's researcher Dr Yair Lotan, from the Texas Southwestern Medical Center, Dallas, TX, USA.

The researchers analysed bladder samples from 226 patients that were removed during surgery for bladder cancer. Using a tissue profiling technique, the authors tested for four different proteins (known as P53, Bcl-2, caspase-3, and survivin) that have been implicated in causing cancer. The researchers found that when expression of all four proteins was altered, patients had a greater risk of developing a recurrence of their bladder cancer, and eventual death from the disease, compared with patients who had no change of expression of these proteins.

"We found that evaluation of combined apoptosis biomarkers [markers of cell death] status can help identify patients at high risk of recurrence and death from bladder cancer after radical cystectomy, independent of conventional prognostic features", says member of the research team, Dr Jose Karam. Lead researcher Professor Shahrokh Shariat continues, "clinical trials are needed to target bladder cancer in patients with a high number of [alterations], as these patients have poor survival rates with current treatments and might benefit the most from experimental therapy".

In a linked Reflection and Reaction commentary, Dr Francisco Real and Dr Nuria Malats state that, "this is the first study in which multiple apoptosis markers have been used together to asess the value in improving accuracy of predicting outcome for patients with bladder cancer".

• Medical Studies/Trials, Published: 2007 Jan 10

DNA methylation and breast cancer

 

A new study using mastectomy tissue shows that precancerous changes can occur in normal-appearing areas of the breast as distant as two inches from a tumor's edge.

The findings, while preliminary, might have important implications for identifying breast-cancer patients at high risk of a second tumor in the same breast.

Researchers looked for - and found - a chemical change called DNA methylation in healthy tissue adjacent to breast tumors.

They measured this chemical change in a gene that often becomes highly methylated in breast cancer. The gene, called RASSF1A, is a tumor-suppressor gene. Tumor-suppressor genes normally protect cells from becoming cancerous, but the gradual silencing of these genes by abnormal methylation is thought to be an early change in cancer development.

In addition, the study identified three other genes that were abnormally methylated in both tumor and normal tissues.

The study, led by researchers at the Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute and at H. Lee Moffitt Cancer Center and Research Institute, is published in a recent issue of the journal Clinical Cancer Research.

"This is evidence that DNA methylation is a very early event in tumor development, and that genes that are methylated might serve as useful markers for early cancer detection and diagnosis," says principal investigator Tim H-M. Huang, professor of molecular virology, immunology and medical genetics with Ohio State's Comprehensive Cancer Center.

"Our study might also help explain why, in the absence of radiation therapy, breast cancer often recurs near the site of the original tumor following a lumpectomy," says first author Pearlly S. Yan, research assistant professor of molecular virology, immunology and medical genetics and a researcher and a researcher in Huang's laboratory. Lumpectomy is a surgical procedure in which only the tumor tissue is removed.

If the findings are verified in more patients, they might lead to a prognostic test that could help doctors estimate a woman's risk of cancer recurring near the surgical site.

Evidence began emerging 10 years ago that the healthy tissue adjacent to breast tumors may show precancerous changes, but the means to study the question comprehensively were not available until recently.

During this study, the researchers measured the degrees of methylation in tissue removed from 47 patients who had undergone mastectomies for a form of breast cancer called invasive ductal carcinoma. This tissue was compared with 69 samples of normal tissue taken up to four centimeters (almost two inches) from the tumor's visible edge and with control tissues removed during breast-reduction surgery.

The study also included two double-mastectomy cases in which both breasts had been removed to prevent cancer recurrence. For these, the researchers also tested tissue from four locations on the breast that had no visible tumor.

The researchers used microdissection techniques to isolate tiny milk ducts in each sample. They then measured methylation levels in the RASSF1A gene in epithelial cells that lined the ducts. These cells were the sources of the initial tumor.

As expected, tumor cells showed the highest methylation levels. But the researchers found significant methylation levels in normal tissue adjacent to the tumors in 29 patients. The degree of methylation was lower than in the tumor cells, but it was 1.75 times higher than in control cells.

"In both double-mastectomy cases, we were surprised to find high methylation levels in the tumor-free breast," says Yan.

In addition, the researchers identified three other genes (called CYP26A1, KCNAB1 and SNCA) that were highly methylated in about one-third to nearly one-half of the breast tumors.

"Again to our surprise, we found that in 70 percent of cases, when these genes were highly methylated in tumor cells, they were also highly methylated in the adjacent normal tissue," says Yan.

"This suggests that the presence of DNA methylation in normal tissue adjacent to tumors is more prevalent that previously thought."

Next, the researchers will study whether the abnormal chemical change in normal tissues adjacent to tumors is associated with local recurrence.

Funding from the National Cancer Institute supported this research.

• Medical Studies/Trials, Published: 2006 Dec 2

Elasticity imaging could alleviate need for biopsies

A noninvasive technique to visualize soft tissue stiffness allows radiologists to accurately distinguish benign from malignant breast lesions.

Using elasticity imaging, researchers correctly identified both cancerous and harmless lesions in nearly all of the cases studied. The findings were presented at the annual meeting of the Radiological Society of North America (RSNA).

"In our work, elasticity imaging has been found to have high specificity," said Richard G. Barr, M.D., Ph.D., professor of radiology at Northeastern Ohio Universities College of Medicine and radiologist at Southwoods X-Ray and MRI in Youngstown. "If our results can be reproduced in a large, multicenter trial, this technique could significantly reduce the number of breast biopsies required."

The American Cancer Society (ACS) estimates that 212,920 women will be diagnosed with breast cancer in the United States this year. Early detection through screening is the best way to combat cancer at its early, most treatable stage. While mammography is the standard breast cancer screening exam, screening with magnetic resonance imaging (MRI) or ultrasound may be more effective for high-risk patients or women with dense breast tissue. MRI and ultrasound depict more breast lesions than mammography but have low specificity, meaning they are less effective at distinguishing benign from malignant lesions, resulting in a high number of invasive biopsies. ACS reports that 80 percent of breast lesions biopsied are found to be benign.

Elasticity Imaging is a diagnostic technique for noninvasive visualization of soft tissue stiffness. Elasticity imaging can detect disease processes involving local inflammatory responses, which can be acute or chronic and associated with fibrosis, hyperplasia, and neoplasia. The noninvasive technique works by gauging how much tissue moves when pushed, and it can detect how soft or stiff an object is. "There are no needles," Dr. Barr explained. "The patient does not notice any difference from a standard ultrasound."

Dr. Barr used a real-time, free-hand, elasticity imaging technique in correlation with a routine ultrasound exam to study 166 lesions identified and scheduled for biopsy in 99 patients. Lesions were measured for the largest length on both the standard ultrasound image and the elasticity image. Lesions where the elasticity image was smaller than the standard image were characterized as benign, and lesions where the elasticity image was larger were characterized as malignant.

Ultrasound-guided biopsies were performed on 80 patients with 123 lesions. Biopsy showed that elasticity imaging correctly identified all 17 malignant lesions and 105 of 106 benign lesions, for a sensitivity of 100 percent and a specificity of 99 percent.

"Our ability to find lesions in the breast has increased significantly over the last 10 years but at the expense of an increased number of biopsies," Dr. Barr said. "This technique could significantly reduce the number of biopsies and increase the confidence of women that a detected lesion is truly benign."

He anticipates that elasticity imaging will also help in detecting cancers, but did not evaluate that capability for this study. Dr. Barr and colleagues are planning to expand their research in an international, multicenter trial beginning in January 2007.

• Medical Science News, Published: 2006 Nov 20

Nanotechnology continues to advance anticancer gene therapy

Given that cancer is a disease in which genetic errors play a major role, it should come as no surprise that many experts envision a time when gene therapy will play an equally important role in the treatment of cancer. But before that day can come, researchers much overcome a major hurdle: safely delivering therapeutic genes and other nucleic acid-based regulatory agents into malignant cells. Enter nanotechnology.
With the ability to sequester a wide variety of molecules and deliver them in a targeted manner to tumors, nanoparticles could prove to be the ideal delivery vehicle for oligonucleotide-based drugs such as anticancer genes, antisense oligodeoxynucleotides, and small interfering RNAs. Recently, for example, a team of investigators led by Huixin He, Ph.D., of Rutgers University, and T.J. Thomas, Ph.D., of the Robert Wood Johnson Medical School, demonstrated that dendrimer-based nanoparticles can deliver antisense oligodeoxynucleotides into breast cancer cells.

The researchers, who reported their work in the journal Nanotechnology, formed the nanoparticles using a biocompatible dendrimer made of poly(propyleneimine) (PPI). This particular type of dendrimer belongs to a family of what are known as amine-terminated polymers, a class of compounds that other investigators have found promote gene uptake by cells. These dendrimers are also relatively easy to modify chemically, affording the option of adding tumor-targeting agents or additional anticancer drugs to the nanoparticle.

In this study, the investigators showed that simply mixing the dendrimer with antisense oligodeoxynucleotides triggered a self-assembly process that generated stable nanoparticles. Electron microscopy revealed that these nanoparticles were toroidal in shape, a finding that implies that the dendrimer and oligodeoxynucleotide first zip together to form a single structure that then wrap around themselves to create the final nanoparticle.

Using an antisense oligodeoxynucleotide that they labeled with a fluorescent dye, the investigators were then able to track uptake of this agent by breast cancer cells. Little, if any, native oligodeoxynucleotide entered breast cancer cells, but oligodeoxynucleotide trapped within the dendrimer nanoparticle accumulated rapidly in the cells. Confocal microscopy revealed that the oligodeoxynucleotide not only entered the cells but built up in the cells' nuclei.

In another recent study, published in the journal Biomaterials, Andreas Bernkop-Schn?Ph.D., and colleagues at the Leopold-Franzens University in Innsbruck, Austria, used the naturally occurring polymer chitosan as the starting material for a gene delivery nanoparticle. The researchers first modified chitosan, a polymer obtained from shrimp and crab shells, with a chemical that added multiple free sulfur-containing thiol groups to each molecule of chitosan. Thiol groups play an important role in stabilizing some proteins by linking to one another - under certain cellular conditions, two thiol groups that come close to each other will react to form a sulfur-sulfur bond. These so-called disulfide bonds can stabilize a protein's three-dimensional structure.

The investigators in this study took advantage of this process to form chitosan-DNA nanoparticles that are stable in blood. Mixing thiol-modified chitosan with DNA triggers a self-assembly process that creates a nanoparticle. As the chitosan chains fold up upon one another, some of the thiol groups come close to other thiol groups. Disulfide bonds form as a result, stabilizing the nanoparticle.

To test this stability, the investigators exposed the nanoparticles to artificial intestinal fluid. Over the course of 10 hours, the nanoparticles released a mere 10 percent of their DNA payload. However, when the investigators added the nanoparticles to a solution that more closely mimics the chemical conditions inside a cell, the nanoparticles started falling apart, releasing nearly all of their DNA payload over the same time period. Under the latter conditions, disulfide bonds break easily, allowing the chitosan chains to drift apart from one another and release any DNA entrapped within them. In a final experiment, the researchers showed that the thiol-modified chitosan-DNA was more effective at getting DNA into cells than unmodified chitosan nanoparticles.

The work with dendrimers, which was funded by the National Cancer Institute, is detailed in a paper titled, "Oligodeoxynucleotide nanostructure formation in the presence of polypropyleneimine dendrimers and their uptake in breast cancer cells." An abstract of this paper is available at the journal's website. View abstract.

The work with chitosan nanoparticles is detailed in a paper titled, "Development and in vitro evaluation of a thiomer-based nanoparticulate gene delivery system." This paper has been published online in advance of print publication. An abstract is available through PubMed. View abstract.

• Medical Studies/Trials, Published: 2006 Nov 13

Link between common lifestyle factors, immune system and cancer

The immune system is fickle, and easily influenced by more than just viruses and bacteria. It can be swayed by the seemingly unexpected, such as by what we eat, for example, and affected by surprising sources.

 

At the American Association for Cancer Research's Frontiers in Cancer Prevention Research meeting, scientists are taking a closer look at the link between increasingly common lifestyle factors, the immune system and cancer, with the ultimate goals of preventing and better understanding cancer development.

A Prospective Study of Periodontal Disease and Pancreatic Cancer

Can diseased gums increase the risk of pancreatic cancer? Epidemiologists at the Harvard School of Public Health in Boston think it could, at least according to the findings of a study analyzing 16 years of health data on more than 52,000 men.

Dominique Michaud, Sc.D., assistant professor of epidemiology in the Harvard School of Public Health in Boston, and colleagues at Dana-Farber Cancer Institute and the University of Puerto Rico wanted to know if inflammation, and specifically, systemic inflammation from periodontal disease, might be related to pancreatic cancer.

According to Michaud, several studies have linked inflammation and cancer, and researchers have found a high risk of developing pancreatic cancer among individuals with pancreatitis, or inflammation of the pancreas. But the ties between periodontal disease and cancer have been more tenuous.

Previous studies have shown associations between tooth loss and cancer, and pancreatic cancer as well. But the validity of such studies was questionable because of confounding factors, including smoking, which contributes to both periodontal disease and cancer. An association with periodontal disease and heart disease has also been examined, with systemic inflammation being a potential mechanism behind the connection. Periodontal disease results in chronic inflammation over many years, both in the mouth and potentially, systemically, as well.

The researchers analyzed the health records of a fairly homogenous group of about 52,000 highly educated, male health professionals between ages 40 and 75 who participated in the Health Professionals Follow-up Study, which was created in 1986 to look at lifestyle factors related to cancer and other chronic diseases. They continue to be followed at present through mailed questionnaires, with a greater than 95 percent follow-up rate, Michaud said.

The researchers recorded 216 cases of pancreatic cancer in the 16 years of follow-up between 1986 and 2002. Men who reported having periodontal disease had a 63 percent higher risk of developing pancreatic cancer compared to those who did not report periodontal disease, after the team adjusted for smoking, diabetes, age, physical activity and diet. Those men who never smoked fared even worse, with a two-fold increase in risk. Men who reported a history of periodontal disease and tooth loss in the last four years showed a more than a 2.5-fold increase in the risk of developing pancreatic cancer compared to those without periodontal disease and recent tooth loss.

In a secondary analysis, the team looked at tooth loss at both the beginning of the study (baseline) and during the follow-up period. While tooth loss at baseline was not associated with a risk of pancreatic cancer, those who lost teeth during follow up showed an increased, albeit lesser, risk for pancreatic cancer. Tooth loss among older individuals is likely due to periodontal disease, Michaud explained, whereas tooth loss at enrollment in the study is more likely to reflect teeth that were lost or removed because of cavities.

"The results confirm our hypothesis that pancreatic cancer is related to periodontal disease, not merely tooth loss," Michaud said.

Other potential mechanisms, she said, include the fact that those with periodontal disease have high amounts of bacteria in the mouth and in the gut, and also tend to have higher amounts of nitrosamines, which have been proposed to increase pancreatic cancer risk.

"The work might provide new insights in understanding the role of systemic inflammation on initiation or promotion of pancreatic cancer," she said. Smoking, she noted, is a risk factor that could be acting as a promoter by causing inflammation.

"Establishing whether periodontal disease increases the risk and understanding the mechanisms behind these associations are important because we know so little about pancreatic cancer."

Pancreatic cancer, the fourth-leading cause of cancer death in this country, takes some 30,000 lives a year.

Diet-Induced Obesity Impairs Both Innate and Adaptive Immune Responses

Obese mice experience a far lower immune response than do normal weight mice to a vaccine typically given to cancer patients, according to studies by National Cancer Institute immunologists.

The diminished immune activity not only may explain the connection between obesity and heightened cancer risk, it also suggests that obesity might reduce the effectiveness of common vaccines, such as flu and tetanus.

According to Connie Rogers, Ph.D., MPH, a research fellow at the Laboratory of Tumor Immunology and Biology at the National Cancer Institute (NCI) in Bethesda, several studies over the years have implicated obesity with diminishing immune function. In the early 1990s, studies showed low antibody levels after vaccination in those who had a high Body Mass Index, or BMI, which is a measure of body fatness.

"We hypothesized that perhaps there are global immune impairments that occur in the face of obesity, and in turn, maybe this is one of several mechanisms that might lead to, or mediate, the relationship between obesity and tumor risk," she said.

Rogers and co-workers at NCI and at the University of Texas compared the immune system function of lean, overweight and obese mice. They created lean mice by slightly restricting their diets and watching carbohydrates. Mice that were given unlimited access to food with a mildly fat content, about 10 percent versus the usual 5 percent to 7 percent fat in their diet, became overweight. Mice that were given unlimited access to a diet made up of about 60 percent in fat, similar to consuming a diet plentiful in fast-foods, became overweight to obese.

"The mice differed in body fat," Rogers noted, "and we wanted to tease out whether it was the weight or body fat that impaired immune function, and if there was a fat threshold in regard to immune function."

The researchers injected mice with a vaccine usually used for cancer patients and which targeted tumor antigens commonly seen in breast, prostate or colon cancers. By stimulating the immune system and measuring a specific response, they could compare the extent of obesity-induced immune function impairment in each animal body type.

"We needed to simulate the immune system and be able to measure a specific response," she said. The study also served "as a tool to probe the immune system and to shed some light on whether obesity might be impacting patients we see who come in for cancer vaccine treatment."

The scientists gave mice a primary vaccination and two booster vaccines to mimic as closely as possible the schedule used in patients. They examined both the broad-based or innate immune responses, and the adaptive immune responses, including T- and B-cell responses to vaccination. While adaptive immune responses require prior exposure to a foreign protein such as a virus or bacterium, innate immunity does not.

"Interestingly, it looks like both innate immune responses such as natural killer cell function and T-cell proliferation to broad-based stimuli were impaired, and importantly, their adaptive immune responses to the vaccine were impaired," Rogers said. The group found that the obese mice failed to develop appropriate antibody levels and "their ability to proliferate in response to the vaccine antigens was impaired." Both are important for generating an adequate immune response to a vaccine.

Neither the lean mice nor the moderately overweight mice showed similar immune system impairments in response to vaccination, suggesting that the response might be a "stepwise decrease" in adaptive immunity, Rogers said.

"I think we now know that this obesity-induced impairment is fairly widespread, and affects many components of the immune system," she said. "The clinical and public health importance of this is that there are probably some significant long-term consequences. We targeted many components of the immune system, and several, such as general response to infection and tumor response to vaccine, for example, could be affected by this obesity-induced impairment in immunity."

"In the long term, we're considering the usual cancer patient who is in his sixties and probably overweight," Rogers said. "But a basic biological question and one with public health significance is that of general immune health of overweight or obese people. That has an impact on long-term health."

Rogers and her team have several questions to explore. "Now that we know about obesity-induced impairments in immune function, we want to know whether these can be reversed by interventions, such as diet and exercise," she said. "Is a person permanently immunologically impaired, or can losing weight, body fat or both, reverse the effects, or is some other mechanism involved?" Such studies involving diet and exercise currently are underway in animals.

A 23-Year Survival Analysis of Prediagnostic BMI and Risk of Lethal Prostate Cancer

A team of Harvard scientists has peered into 23 years of health data on more than 22,000 physicians and concluded that men who are overweight or obese years before being diagnosed with prostate cancer are more likely to die of the disease than those who are of normal weight.

While no studies have definitively shown that obesity and/or higher Body Mass Index, or BMI, which measures body fat, increases the risk of developing prostate cancer, these studies showed that obese men at the time of diagnosis were more likely to have a cancer recurrence.

But according to Jing Ma, M.D., Ph.D., a researcher at the Brigham and Women's Hospital-based Channing Laboratory and associate professor of medicine at Harvard Medical School, few studies have focused on obesity and the risk of dying from prostate cancer.

In fact, she said, there is "considerable debate in the urology and cancer fields regarding whether rising PSA (Prostate Specific Antigen) is a good indicator for whether people will eventually die from prostate cancer or not."

Ma and her co-workers at Brigham and Women's Hospital and at the Harvard School of Public Health examined 23 years of data from the Physician's Health Study, which began in 1982 as a randomized, double-blind trial of aspirin and beta-carotene. More than 22,000 U.S. male physicians were recruited for the trial to study the role of aspirin and beta-carotene in preventing heart disease and cancer.

About 15,000 men provided blood samples at enrollment, along with information on their body weight and height, and their BMI was calculated. Approximately 99 percent of the original participants were tracked through questionnaires for 23 years, including cause of death.

By the end of 2005, 2,367 men had developed prostate cancer, while 265 died of the disease. They found that 39 percent of the participants were overweight and 3.4 percent were obese at the beginning of the study, and that higher BMI was positively associated with the risk of dying from prostate cancer. They also showed that the risk of dying from prostate cancer increased 8 percent for each point increase in BMI.

A person with a BMI of between 25 and 29.9 is considered overweight, whereas someone with a BMI of 30-plus is called obese. The physicians were in relatively good shape compared to the U.S. population in general. U.S. males between 50 and 69 are approximately 40 percent overweight and more than 30 percent are obese.

"It was surprising since it is a moderate association and the BMI was measured in 1982 and was on average eight to 10 years before developing prostate cancer," Ma said. "The beauty of the study is that we could factor out smoking at baseline, and tumor grade and stage didn't affect the trend."

"Some people might think that what they do today has little to do with cancer risk, especially for prostate cancer," Ma said, "and some individuals probably wouldn't believe that obesity has anything to do with prostate cancer. But we have found that if a man develops prostate cancer, being obese could put him at a higher risk of dying from the cancer. There is something many men can do about that."

She and her co-workers are exploring the underlying mechanisms that link being overweight and/or obese to prostate cancer progression. A better understanding of the risk factors that influence the disease's progression, said Ma, is imperative.

Prostate cancer is the most common type of cancer found in American men, other than skin cancer, and the third leading cause of cancer death in men. The American Cancer Society estimates that there will be about 234,460 new cases of prostate cancer in the United States in 2006, with approximately 27,350 deaths from the disease.

• Women's Health News, Published: 2006 Oct 23

The Wall Street Journal on Saturday examined the debate over the risks and efficacy of alternatives to hormone replacement therapy for treatment of menopausal symptoms. Summaries appear below.

"A Safer Prescription for Menopause?": Women take a "litany of drug regimens" -- including antidepressants, osteoporosis drugs, sleep aids and prescription anti-inflammatories -- to handle symptoms of menopause that previously were treated with traditional HRT. According to the Journal, physicians are beginning to worry whether the "shift away from hormones [has] made women safer or ... just subjected them to a whole new set of drug risks." After results from the Women's Health Initiative study showed that women using estrogen and progestin appeared to have a higher risk of breast cancer and heart disease, use of HRT has dropped. According to IMS Health, sales of menopause hormones declined by 33% from 2001 to an estimated $1.9 billion in 2005, and sales of estrogen-progestin combination therapy decreased by 8% in the first half of this year from the year-earlier period. Sales of estrogen therapies dropped by 4%. Shari Lusskin, director of reproductive psychiatry at New York University Medical Center, said, "People are saying, 'If it's hormones we won't take it, but I'll take anything else you'll hand me.'" She added, "But there's no medical treatment that has only benefits and no risks. Patients have to be educated consumers and think carefully about what drugs they're going to take" (Parker-Pope [1], Wall Street Journal, 10/21).

"Treatments: The Debate on Compounded Hormones": A debate is "raging" about what to call hormones that are custom mixed by pharmacists and whether they are any safer than commercial hormone preparations or prescription drug alternatives. The treatments are called "bio-identical hormones" and have the same molecular composition as hormones produced by a woman's body. They often are promoted as "natural" hormones that do not have the same risks as hormones sold by drug companies, the Journal reports. FDA has said that women should assume that all hormone treatments have the same risks and benefits, though commercial hormone products have that warning, while compounded treatments do not. Critics say that the terms "bio-identical" and "natural" are misleading to women who think their bodies will respond differently to the treatments than to commercial hormone drugs, the Journal reports. There is no is published evidence that compounded hormones are safer or more beneficial that tradition HRT, according to the Journal. "The argument is not against the use of compounded hormones," Wulf Utian, executive director of the North American Menopause Society, said, adding, "The argument is that women aren't being informed" (Parker-Pope [2], Wall Street Journal, 10/21).

• Mercury News, Published: 2006 Oct 2

When Andrew Z. Fire applied to Stanford University as a Sunnyvale teenager, he was turned down. Decades later, his biological research became so compelling that Fire was recruited to the Stanford faculty, and on Monday he shared the 2006 Nobel Prize in physiology or medicine.

Fire, 47, a professor of pathology and genetics, and Craig Mello, 45, of the University of Massachusetts Medical School, discovered the mechanism that lets the body turn off genes within a cell.

While it has not yet led to medical treatments, it has opened up a promising area of research that could allow scientists to silence genes that cause afflictions from HIV to cancer, bridging the gulf between the Human Genome Project and the death bed. The two scientists' 1998 discovery quickly turned into a lab tool embraced by thousands of researchers around the world.

``It's an obscure molecule doing an obscure process in an obscure organism,'' said Fire at a news conference Monday. ``I didn't know where it would lead. I had no idea.''

Born at Stanford Hospital, and a graduate of Sunnyvale's Fremont High School and the University of California-Berkeley, Fire did much of his ground-breaking work at the small Carnegie Labs in Baltimore, Md.

Now recognized as one of the nation's star biologists, he was recruited by Stanford University three years ago to find ways to apply his basic research to the fast-moving field of medicine. He is Stanford's 15th Nobelist, and the third from the medical school.

``If we can silence genes that contribute to disease, that is very important,'' said Dr. Phil Pizzo, dean of Stanford's School of Medicine.

Fire said he welcomed the chance to work with the doctors and patients at Stanford. ``It was an attractive place to settle, closer to family,'' he added; Fire is married with two young children, and his parents still live in Sunnyvale.

Bemused by Monday's publicity, the self-effacing Palo Alto resident said the announcement -- delivered in a 1:45 a.m. phone call from Sweden -- wouldn't change his life.

``It's a good chance to say `thank you,' '' to Stanford, the Carnegie Labs and the legions of students and colleagues who made his work possible, he said. ``We came into the field where a lot of work was already done. We put a nice piece in the puzzle.''

Fire and Mello will share the $1.4 million prize.

Scientists have puzzled over how the human body -- with a mere 20,000 to 30,000 genes, no more than a worm possesses -- has achieved such elegance and complexity.

It succeeds, in large part, due to cells' natural ability to turn a gene on at one stage of development and off at another, when the gene is no longer needed.

However, there are times when turning on a gene can trigger diseases such as Parkinson's, diabetes, cancer and ALS, or amyotrophic lateral sclerosis, also known as ``Lou Gehrig's disease.''

Silence is golden, if this deadly mechanism can be turned off.

The field of gene silencing had its origins in flowers. In 1990, a biologist sought to make purple petunias a deeper hue by injecting them with genes for coloration. Instead, surprisingly, the blossoms bloomed white. Rather than bolstering each other, the pigment-producing genes interacted by shutting themselves off.

Scientists later created the same effect, using different traits, in the microscopic roundworm. But no one understood how it worked.

Fire and Mello injected into a cell an RNA molecule that blocked the manufacture of a particular protein, thereby shutting off a gene. Voila! They had discovered a silencer, which came to be known as RNA interference.

``Who would have thought that a plant could tell us something about ourselves?'' Fire said.

RNA -- the chemical cousin of DNA, which carries the genetic instructions within each living cell -- was once thought to act as a lowly messenger of information. It has since gained more respect as a controller of gene activity. In 2002, Science magazine called a string of RNA interference discoveries the breakthrough of the year.

The technique is already being used to better understand the human genome, by selectively silencing the voice of one gene in the cacophony of the tens of thousands that pilot a cell throughout its development and death.

The next goal is to harness this mechanism. Several biotechnology companies have sprung up or altered course to capitalize on the ideas of Fire and Mello.

The road to RNA therapies could be long, because all gene therapy carries unknown risks. RNA molecules are difficult to package into a safe and effective drug. The digestive system breaks them down. And they don't readily diffuse into a cell, because of their large size and chemical properties. Further, they can be toxic.

``There will be ups and downs,'' Fire warned, urging a long-term commitment to the field.

``It will take awhile to see where this fits in with other advances.''

• Medical Science News, Published: 2006 Sept 13

It is estimated that 174,470 new cases of lung cancer will be diagnosed in the United States in 2006. Lung cancer is the major cause of cancer-related mortality in both men and women, with an estimated 162,460 deaths expected to occur in 2006.

Brain tumors account for nearly 90 percent of all primary central nervous system tumors. It is estimated that 18,820 new cases of brain cancer will be diagnosed in the United States this year, and 12,820 patients will die from the disease. Glioblastomas, also called glioblastoma multiforme or grade IV astrocytoma, are often fatal, malignant brain tumors that grow and spread very aggressively, and are the most frequently occurring type of brain cancer. An estimated 20,180 new cases of ovarian cancer and an estimated 15,310 deaths from the disease are expected in the United States in 2006. Often detected late, ovarian cancer causes more deaths than any other cancer of the female reproductive system.

NCI and NHGRI launched TCGA in December 2005 as a collaborative three-year pilot project to test the feasibility of using large-scale genome analysis technologies to determine all of the important genomic changes involved in cancer. When fully operational, TCGA will consist of four integrated components: a Biospecimen Core Resource (BCR); Cancer Genome Characterization Centers; Genome Sequencing Centers; and a Principal Bioinformatics Resource.

Today, the two institutes also announced the biorepositories that will provide biospecimens of the first three cancer types to be studied as part of the TCGA Pilot Project. The source of the lung cancer biospecimens will be the Lung Cancer Tissue Bank of the Cancer and Leukemia Group B (CALGB) clinical trials group, which is housed at the Brigham and Women's Hospital in Boston, Mass. The source of the brain tumor (glioblastoma) biospecimens will be MD Anderson Cancer Center in Houston, Texas. The ovarian cancer biospecimens will be provided by the Gynecologic Oncology Group tissue bank at the Children's Hospital of the Ohio State University in Columbus, Ohio.

NCI and NHGRI also announced today that the International Genomics Consortium, part of the Translational Genomics Research Institute, of Phoenix, Ariz., was selected to establish and manage TCGA's BCR. The BCR will collect, store, process, and distribute biomolecules from cancerous and normal samples to the Cancer Genome Characterization Centers and Genome Sequencing Centers for genomic analysis.

TCGA's Cancer Genome Characterization Centers will analyze samples from the BCR to identify key genomic alterations, such as copy number changes and/or chromosomal rearrangements, some of which are known to contribute to cancer development and/or progression. Selected genes will be sequenced by the Genome Sequencing Centers using high-throughput methods to identify small genomic changes, such as single base mutations and small insertion/deletions. TCGA Cancer Genome Characterization Centers and the Genome Sequencing Centers will be selected in the coming months.

"Cancer is exceedingly complex, and includes more than 200 different diseases. The overall goal of TCGA is to delve more deeply into the genetic origins that lead to this complexity, in order to enable the discovery and development of a new generation of therapies, diagnostics, and preventive strategies for all cancers," noted Acting NCI Director John E. Niederhuber, M.D. "Results from the TCGA Pilot Project may provide the results we need to detect cancer early, in its most treatable stage, and provide new targets for the development of specific therapies."

"The Cancer Genome Atlas will use cutting-edge technologies and knowledge from the Human Genome Project and other genomic studies to assess the range of genomic changes that cause the uncontrolled cell growth that characterizes cancer," explained National Human Genome Research Institute Director Francis S. Collins, M.D., Ph.D. "TCGA will analyze hundreds of tumor specimens with multiple technologies, including the comparison of genome sequences from the cancers with the normal DNA sequence derived from the same patients, in order to identify changes that are specifically associated with cancer."

The three cancers selected for study by TCGA were identified in a process that began in the fall of 2005 with a Request for Information (RFI) from NCI and notification to NCI Cancer Centers. The goal of the RFI was to identify candidate biospecimen collections that employed the highest level of ethical, technical, biologic, pathologic, and bioinformatics standards in the development of their biorepository.

The collections that qualified were evaluated in a three-stage process. The primary criteria addressed minimal requirements for the quality and quantity of the samples and the associated clinical information. Secondary criteria were then applied to effectively rank those tumor collections that met the primary criteria. Site visits to the biorepositories were then conducted by NCI and NHGRI staff. Critical factors for TCGA, such as timing, logistics, and the need for re-consent of patients, were factored into selection of the biorepositories to be considered. Finally, the biorepositories that emerged from this tiered process were further reviewed by an expert panel that included representatives from the surgery, research, pathology, bioethics, and patient advocate communities. The primary, secondary, and additional criteria are described in detail at http://cancergenome.nih.gov/media/qanda.asp.

"The Cancer Genome Atlas Pilot Project is an important opportunity as we survey the potential future of cancer research. We must put aside our specific disease interests and channel our energy into the larger issues that can empower the cancer research enterprise to find new ways to improve outcomes for all cancer patients," said Doug Ulman, cancer survivor, chief mission officer of the Lance Armstrong Foundation, and chair of the NCI Director's Consumer Liaison Group.

Success factors for the TCGA Pilot Project include completion of genomic analysis of the three initial cancer types; identification of specific alterations in genes associated with cancer; and differentiation of cancer subtypes based on genomic changes. In addition, the pilot project will establish a publicly available integrated database that scientists can use to generate new knowledge through research. TCGA data will be made available through public databases supported by NCI's cancer Biomedical Informatics Grid (caBIG) and the National Library of Medicine's National Center for Biotechnology Information (NCBI). TCGA data will be provided in a manner that meets the highest standards for protection and respect of the research participants.

"The Cancer Genome Atlas is a revolutionary project with the potential to provide cancer researchers the information needed to generate new hypotheses that can be tested in the laboratory and the clinic," said NCI Deputy Director Anna D. Barker, Ph.D. "Achieving the long-term goal of TCGA to identify all of the significant genomic changes in all cancers will benefit patients by enabling the discovery and development of the molecular biomarkers needed to develop targeted interventions to prevent and cure cancer."

Data from the TCGA Pilot Project will provide researchers and clinicians with an early glimpse of what promises to become an unprecedented, comprehensive "atlas" of molecular information describing the genomic changes in all types of cancer. TCGA will ultimately enable researchers throughout the world to analyze and employ the data to develop a new generation of targeted diagnostics, therapeutics, and preventives for all cancers, and pave the way for more personalized cancer medicine.

• Medical Studies/Trials, Published: 2006 Sept 04

Individuals with major depression have an exaggerated inflammatory response to psychological stress compared to those who do not suffer from depression, according to a study by researchers at Emory University School of Medicine.

 
Because an overactive inflammatory response may contribute to a number of medical disorders as well as to depression, the findings suggest that increased inflammatory responses to stress in depressed patients may be a link between depression and other diseases, including heart disease, as well as contributing to depression itself.

Results of the study, led by Andrew Miller, MD, and Christine Heim, PhD, of Emory's Department of Psychiatry and Behavioral Sciences, are published in the Sept. 1 issue of the American Journal of Psychiatry.

"Several examples of increased resting inflammation in depressed patients already exist in the literature, but this is the first time anyone has shown evidence to suggest that the inflammatory response to stress may be greater in depressed people," says Dr. Miller.

The study included 28 medically healthy male participants, half of whom were diagnosed with major depression and half of whom were not depressed. The participants were exposed to two moderately stressful situations during a 20-minute time period. Blood was collected every 15 minutes starting immediately before and then up to an hour and a half after the test to check for key indicators of inflammation. The researchers measured levels of a pro-inflammatory cytokine (a regulatory protein secreted by the immune system) called interleukin-6, and the activity of a pro-inflammatory signaling molecule in white blood cells called nuclear factor-kB.

While at rest (before the stress challenge), the depressed patients had increased inflammation relative to the control group. Both the depressed and the healthy groups showed an inflammatory response to the stress challenge, but people who were currently depressed exhibited the greatest increases of interleukin-6 and nuclear factor-kB.

"While inflammation is essential for us to fight bacterial and viral infections, too much inflammation can cause harm," says Dr. Miller. "There's always some collateral damage when the immune system gets fired up, and we now believe that too much inflammation, either at rest or during stress, may predispose people to become depressed or stay depressed." In addition, medical research over the last decade has shown that runaway inflammation may play a role in a number of disorders, including heart disease, cancer, and diabetes, all of which have been associated with depression.

People in the study who suffered from depression also had higher rates of early life stressful experiences. "We have found that this kind of personal life history may make people more likely to develop major depression and is actually common in depressed patients," says Dr. Heim.

It was part of a larger project at the Emory Conte Center for the Neuroscience of Mental Disorders led by Charles B. Nemeroff, MD, PhD, Reunette W. Harris Professor and Chair of Emory's Department of Psychiatry and Behavioral Sciences. The Conte Center is dedicated to understanding the contribution of early life abuse and neglect to the neurobiology of adulthood psychiatric disorders. Ongoing studies by Dr. Miller's team of researchers will attempt to determine how early life experiences contribute to excessive inflammatory stress responses.

"According to the Depression and Bipolar Support Alliance, major depression is the leading cause of disability worldwide and costs the U.S. economy $70 billion annually in medical expenditures, lost productivity, and other expenses," says Thaddeus Pace, PhD, lead author on the paper. "This study is leading us toward finding out what actually causes depression and to identifying what aspects of immune system function are abnormal in depressed people. The goal is to find potential targets within the molecular machinery of the immune system so we can better treat major depression and minimize its consequences on health."

• Medical Science News , Published: 2006 August 21

By combining a compound produced by the plant St. John's wort with polymeric nanoparticles, researchers at the University of Geneva in Switzerland have developed a promising method for treating ovarian tumors using light.

Perhaps more importantly, this nanoscale construct may also enable surgeons to detect the microscopic metastatic tumors that often remain after surgery but lead to cancer recurring years after initial therapy. This work has been published in the International Journal of Pharmaceutics.

Florence Delie, Pharm. D., Ph.D., and her colleagues set out to create a powerful photosensitizer that would kill cancer cells when irradiated with light. Photosensitizers are the active agent in photodynamic therapy, which is used currently to treat or relieve the symptoms of esophageal cancer and non-small cell lung cancer. The Swiss researchers chose the compound hypericin, isolated from St. John's wort, because it can function as both a photosensitizer and a fluorescent marker that they hoped might illuminate microscopic metastatic tumors.

The investigators studied hypericin encapsulation in several polymers before settling on poly(lactic acid) as the nanoparticle material that produced the best photosensitizing properties. Studies with the resulting nanoparticle-hypericin formulation showed that this combination was more effective than hypericin itself at killing ovarian cancer cells. Indeed, the researchers note that their data suggest that the nanoparticles not only improve cellular uptake of the photosensitizer but also deliver more hypericin to therapeutically useful sites within cells.

Following their demonstration that nanoparticle formulations of hypericin have the potential to kill ovarian cancer cells, the researchers then showed that they could detect hypericin inside cells using fluorescence microscopy. This finding suggests that surgeons may be able to use nanoparticle-delivered hypericin to find micrometastatic lesions while performing surgery to remove the primary ovarian tumor.

This work is detailed in a paper titled, "Hypericin-loaded nanoparticles for the photodynamic treatment of ovarian cancer." This paper was published online in advance of print publication. An abstract of this paper is not yet available, but information on this paper is available at the journal's website. View information.

• Medical Condition News, Published: 2006 August 20

The American Society of Clinical Oncology and the National Comprehensive Cancer Network on Tuesday released seven quality guidelines for breast and colorectal cancer care, CQ Today reports.

The guidelines are based on clinical impact, feasibility, potential for improvement, reliability, scientific acceptability and usefulness.

They include post-operative chemotherapy recommendations for people ages 80 and younger; hormonal therapy recommendations for people with tumors one centimeter or larger; and breast radiation therapy recommendations for women ages 70 or younger (CQ Today, 8/17).

According to the guidelines, the recommendations -- three breast cancer-related, two rectal cancer-related, one colon cancer-related and one colorectal cancer-related -- continually will be tested by the organizations and will be updated to reflect the findings of such tests (ASCO/NCCN, "ASCO/NCCN Quality Measures: Breast and Colorectal Cancers," 8/15).

• Medical Research News, Published: 2006 August 3

Researchers from the Pacific Northwest Research Institute (PNRI) and the National Institute of Standards and Technology (NIST) have uncovered a pattern of DNA damage in connective tissues in the human breast that could shed light on the early stages of breast cancer and possibly serve as an early warning of a heightened risk of cancer.

In the United States, breast cancer is the second leading cause of cancer-related death in women. Breast cancer detection and therapy generally target epithelial cells, the primary locus of breast cancers, but in recent years evidence has accumulated that genetic mutations that develop into cancer may occur initially in a deeper layer of breast tissue, called the stroma. Genetic changes in this connective tissue that supports the breast's network of glands and ducts have been reported to precede the malignant conversion of tumor cells, but the actual role of stromal cells in the early stages of breast cancer initiation and progression is not well understood.

In two recent papers, the PNRI/NIST team explored the occurrence of damage to stromal DNA caused by free radicals and other oxidants. NIST researchers used a high-precision chemical analysis technique (liquid chromatography/mass spectrometry with isotope dilution) to identify specific DNA lesions, while the PNRI team used a spectroscopic technique (Fourier transform-infrared spectroscopy) to reveal subtle conformational changes to DNA base and backbone structures. Such alterations to the molecular structure can change or disrupt gene expression.

The team identified a unique oxidation-induced lesion in the DNA of breast epithelium, myoepithelium and stroma and found that the highest concentrations of this lesion tended to occur in women in the 33- to 46-years age group, a bracket that corresponds to a known rise in the incidence of breast cancer. In a second paper, the team studied age-related concentrations of two similar mutagenic DNA lesions and again demonstrated that their occurrence is roughly commensurate with the age at which the incidence of female breast cancer rises. "Collectively," they observe, "the findings reveal that the structural changes in DNA described may potentially disrupt normal reciprocal interactions between the cell types, thus increasing breast cancer risk." The findings suggest that lesions measured in the DNA of the stroma, which is readily obtained, may prove to be convenient and sensitive biomarkers for assessing oxidative DNA damage and for signaling an increased breast cancer risk.

• Medical Research News, Published: 2006 August 3

For years, researchers have struggled to understand how IVIG worked. It's ability to treat autoimmune diseases seemed to bean apparent contradiction.
Intravenous immunoglobulin (IVIG) is a complex mixture of IgG antibodies made from human plasma that contains the pooled antibodies from thousands of people, and is only FDA-approved to treat a few assorted conditions; nonetheless, practitioners have used it off-label with varied success in patients with lupus, arthritis and asthma, among other autoimmune disorders. In the body, the antibodies in plasma act as part of the immune response to identify and deactivate foreign invaders. When they begin attacking the body's own cells, the same protective immunoglobulins (known as IgG antibodies) can cause autoimmune disorders like lupus, arthritis and asthma. And yet, when IVIG is infused into people with those exact autoimmune conditions, it calms inflammation rather than causes it.

Jeffery Ravetch, Theresa and Eugene M. Lang Professor and head of Rockefeller's Laboratory of Molecular Genetics and Immunology, was struck by this inconsistency. "If IgG triggers autoimmune disease, how could it be pathogenic and therapeutic?" he asked. "We call it the IgG paradox." Six years ago he started an investigation into exactly how IVIG worked, and what he's discovered could one day lead to a whole new class of therapeutics. In a paper published today in the journal Science, Ravetch and his colleagues, Falk Nimmerjahn and Yoshi Kaneko explain what makes IVIG effective: A small fraction of the IgG antibodies in the IVIG solution carry a sugar called sialic acid that is required for its protective ability.

IgG antibodies bind to and activate specific immune cells, with different forms or "subclasses" binding to specific receptors (called Fc receptors) on the immune cell's surface. Antibody subclasses have different abilities to induce inflammation in the body by virtue of their selective ability to engage either activating or inhibitory Fc receptors. Earlier work had shown that IVIG infusion changed this ratio of activating and inhibitory receptors on the cells that trigger inflammation, rendering the pro-inflammatory autoantibodies in autoimmune diseases, like lupus and arthritis, less inflammatory. The next logical step then, Ravetch says, was determining how the IgG molecules in IVIG preparation could have an anti-inflammatory effect.

Because a therapeutic, anti-inflammatory response to IVIG requires a concentration of IgG antibodies that's hundreds of times greater than is normally used for antibody therapy for cancer or infection, for example, Ravetch and his colleagues began to look for something that was only present in IVIG in small amounts. That's how they discovered that just the very terminal sialic acid on the Fc portions of the IgG molecule were the root of the anti-inflammatory activity. When the researchers removed the sialic acid, the molecule retained its structure and its half-life, but it lost its protective abilities. "This is a very interesting condition that's set up," Ravetch says. "IgG can shift from a state that is quite inflammatory to a state that is actively anti-inflammatory by just changing a sugar." This switch occurs during a normal immune response to a foreign substance, shifting the IgG antibodies from an anti-inflammatory state to one that is pro-inflammatory and able to efficiently dispose of the foreign challenge.

To test the theory, Ravetch and his colleagues tried enriching IVIG for the IgG molecules that contained sialic acid. They found that just enriching for this IgG species increased IVIG activity by a factor of ten, while removing it wiped out the therapeutic activity altogether. This discovery, Ravetch says, has potentially huge implications, and his lab is now working to generate a recombinant form of IgG that, by virtue of a sialic acid molecule attached in the right place, will be anti-inflammatory and could act as a novel treatment for autoimmune disorders. "We have the opportunity to make a much better form of IVIG that will work 100 times better and be a pure molecule--to build a much better class of therapeutics based on a property that already exists in nature."

• Medical Research News, Published: 2006 July 24

The most aggressive form of breast cancer may originate from breast stem cells that have undergone genetic mishaps.
Victorian Breast Cancer Research Consortium scientists from The Walter and Eliza Hall Institute, using mouse models, have discovered that breast stem cells do not express receptors for the female hormones oestrogen or progesterone. These and other features of the stem cell resemble the aggressive 'basal' subtype of breast cancer. There is increasing evidence that breast cancer is not simply a single disease. Scientists now view breast cancer as a heterogeneous disease, made up of various subtypes. This observation has led to speculation that breast tumours are derived from different cell types that could include the breast stem cell or its descendents that have suffered genetic accidents.
This possibility has generated great interest in understanding the composition of normal breast cells including the stem cell. A question of particular interest is whether the breast stem cell expresses receptors for oestrogen and progesterone and the marker 'Her2', since these help define the subtypes of breast cancer; and also guide current approaches to therapy.
The WEHI team, together with the Eaves group in Vancouver, have found that the breast stem cell in mice is 'triple negative' for oestrogen, progesterone and Her2 receptors but does express certain 'basal cell' markers. These characteristics also define the basal subtype of breast cancer, which is more commonly seen in tumours that develop in women who are carriers of the breast cancer predisposing gene BRCA1.
These findings support previous speculation that breast stem cells, or very early descendents, are the cells from which basal tumours arise. Dr Visvader, who led the team effort with Dr Lindeman at WEHI, said, "This finding made by Marie-Liesse Asselin-Labat in our lab reinforces the need to understand the normal biology of the breast stem cell. Our hope is that this kind of research could in the long-term lead to the identification of new therapeutic targets against breast cancer, particularly the basal subtype." Currently drugs such as Tamoxifen, the aromatase inhibitors or Herceptin are ineffective against basal tumours and chemotherapy is the only option.
Dr Lindeman, who is also an oncologist at the Royal Melbourne Hospital, said that their team's findings will now be extended using excised human breast tissue and tumours. "We are fortunate that the Royal Melbourne Hospital campus is strongly committed to this type of translational research. Our hope is that this will lead to better cancer outcomes from a disease that strikes one in 11 Australian women." The team findings are published in the Journal of the National Cancer Institute.

• Medical Studies/Trials, Published: 2006 July 24

While it is established that nicotine by itself is not carcinogenic, researchers have now shown that nicotine promotes cell proliferation and the progression of tumors already initiated by tobacco carcinogens.
In a study by Srikumar Chellappan and colleagues from the University of South Florida appearing in the Journal of Clinical Investigation, the authors show that the presence of receptors that bind nicotine, known as nicotinic acetylcholine receptors (nAChRs), on bronchial cells as well as lung cancer cells are key to nicotine-induced cell proliferation of lung cancer cells.
nAChRs function mainly in the neuronal system, however recent studies have shown their expression and function in non-neuronal systems as well. In the current study, the authors show that stimulation of human non-small cell lung cancers (NSCLCs) as well as cells lining the air passages of the lung (known as bronchial cells) with a physiological concentration of nicotine leads to robust cell proliferation that is dependent on nAChRs.
Furthermore, nicotine appears to activate the major components of the cell proliferation cycle in a manner very reminiscent of growth factors. Specifically, nicotine stimulation leads to the binding of Raf-1 to Rb, activation of cyclin-dependent kinases, phosphorylation of Rb, and recruitment of E2F1 to proliferative promoters.
Previous studies had shown that interfering with the interaction of Rb and Raf-1 prevented cell growth and tumor growth. In the current study the same appears to be true for nicotine stimulation of cells. A role for the Rb-Raf-1 interaction in the genesis of lung cancer is further supported by the observation that there was more Raf-1 associated with Rb in 8 out of 10 tumor samples examined, compared to the adjacent normal tissues. These observations suggest a role for Rb-Raf-1 interaction in the genesis of lung cancer.
These studies shed new light on the previously unknown mechanisms underlying nicotine-induced cell proliferation in lung cancer cells - namely that functional nAChRs on bronchial cells as well as lung carcinoma cells enable nicotine to promote the growth of established tumors.

• Medical Research News, Published: 2006 July 04

Proteins that regulate sleep and biological timing in the body work much differently than previously thought, meaning drug makers must change their approach to making drugs for sleep disorders and depression and other timing-related illnesses.
The surprise finding is an about-face from previous research, said Daniel Forger, assistant professor of math at the University of Michigan.
Forger and his collaborators from the University of Utah's Huntsman Cancer Institute have written a paper on the topic, which appears in the Proceedings of the National Academy of Science.
Scientists studied two proteins (one called CKIe and another called PERIOD) that help regulate timing in the body, and looked at how those proteins function in cells, said Forger. One of the proteins causes the other protein to degrade, and the body knows what time it is by how much or how little PERIOD protein is present at any one time in the body. The body's clock is called a circadian rhythm.
Drug makers spend billions to develop drugs to help people with sleep disorders, and other disorders impacted by our biological clocks. Drugs to restore a healthy circadian rhythm by manipulating the levels of PERIOD proteins are currently under development.
One such sleep disorder is called Familial Advanced Sleep Phase Syndrome and this is caused by a gene mutation, Forger said. Patients suffering from the disease routinely wake very early, say at 4 a.m. and must go to bed early, at say 7 p.m. said Forger.
If put in a cave with no light, these people should have a shortened day, Forger said. This means that on our time, they would wake the first day at say, 6 a.m. then at 4 a.m. then at 2 a.m. on subsequent days.
"When they have light and dark cycles in the normal world, they pretty much have to live in a 24-hour day," Forger said. "They were able to adjust but the price they have to pay is their body wakes up early, and they have to go to bed earlier than we do."
"The theory was that the mutation caused (more of the PERIOD protein) so you get a short day so you want to get up very early in the morning," Forger said. But, during testing they found the opposite is true: the mutation actually caused the PERIOD to degrade more quickly so that less is present in the body.
The finding wasn't a complete surprise to Forger, who develops math models of the circadian rhythms. Forger's computer models always said that the opposite of the prevailing thinking should be true---that the PERIOD protein should degrade more quickly when the mutation is present.
"I had this prediction for a year or two," Forger said. "Basically, people said this is ridiculous, you're a mathematician, what do you know?"
Then he met David Virshup, M.D., while giving an invited talk at the University of Utah. Virshup's previous research was on the gene involved in circadian rhythms and its role in cancer development. Their experiments had also suggested that genetic mutation caused the protein to degrade more quickly. Virshup suggested they test Forger's simulation.
The researchers took cell cultures and observed that for those with the mutated gene, the protein only took a couple hours to degrade. For the normal gene, it took 8-10 hours.
Next, Virshup said, his team will begin testing ways to regulate the circadian rhythm in mice, a necessary step before new drugs can be developed.
Funding for the study was provided by the National Institutes of health, the Huntsman Cancer Institute and the Sloan Foundation.

• Medical Studies/Trials, Published: 2006 July 04

Exposure to radioactive iodine increases the risk of thyroid cancer in children and adolescents, a study of thyroid cancer prevalence after the Chornobyl accident shows.
The study is published in the July 5 issue of the Journal of the National Cancer Institute.
In 1986, an accident at the Chornobyl nuclear power plant exposed large numbers of people in Belarus, Ukraine, and the Russian Federation to radioactive material high in isotopes of iodine and cesium. Numerous studies have shown that exposure to certain types of radiation increases the incidence of thyroid cancer in children and teens. However, few studies have examined the effects of exposure to radioactive iodines, and only three studies have examined cancer risk from the Chornobyl-related exposures.
Geoffrey R. Howe, Ph.D., of Columbia University in New York, and colleagues screened 13,127 people for thyroid cancer who at the time of the Chornobyl accident were under 18 and lived in highly contaminated areas of Ukraine. The researchers estimated each participant's individual radiation dose using thyroid radioactivity measurements made shortly after the accident and interview data obtained during screening.
The researchers found 45 cases of thyroid cancer in the screened group in comparison with the 11.2 cases expected without the accident. Subjects had a tendency toward lower risk of thyroid cancer with increasing age at the time of the exposure. The authors suggest that exposure to radioactive fallout from the Chornobyl accident increased thyroid cancer in those exposed as children and adolescents.
The authors write, "We estimate that 75% of the thyroid cancer cases would have been avoided in the absence of radiation. With appropriate adjustment for dose, this estimate demonstrates a substantial contribution of radioactive iodines to the excess of thyroid cancer that followed the Chornobyl accident."

• Medical Research News, Published: 2006 June 26

Scientists in the U.S. say they have discovered a way to make the brain reverse the damage it suffers after a stroke, and are optimistic that it will lead to treatment which will exploit the body's ability to heal itself.
Along with heart disease and cancer, strokes are one of the biggest killers and although the death rate has fallen in recent years, the condition still claims many lives.
The researchers found in experiments on rats whose brains had been starved of oxygen to simulate the effects of a stroke, fewer were left paralysed after the treatment, which activated stem cells in their brains.
Professor Ronald McKay and a team from the U.S. National Institute of Neurological Disorders and Stroke examined the adult stem cells in the rats' brains and stimulated a receptor known as "notch", on the stem cells.
The researchers found that it caused reactions that produced new brain cells and say notch is important in all tissues and the beneficial effects may involve responses in cells of the vascular, immune and nervous systems.
The treatment improved the ability of existing cells to survive the lack of oxygen and when rats were given the treatment, many recovered from the loss of movement they suffered with the stroke.
The discovery will raise hopes for new treatments for stroke by using the body's own stem cells to encourage healing and has wide implications for stem cell research.
Other treatments using embryonic stem cells have been restricted because implanted cells come under attack from the body's immune system.
More than 150,000 people in the UK have a stroke every year which equates to one every three minutes.
Although most occur in people over 65, anyone can have a stroke, including children and even babies.
Strokes are more common in men than women and is the third most common cause of death in the UK and is the most common cause of severe disability.
More than 250,000 people live with disabilities caused by stroke; about a third of people who have strokes suffer from some form of disability.
There are two main types of stroke and the most common is an ischaemic stroke, which happens when a clot blocks an artery carrying blood to the brain.
The second type is called a haemorrhagic stroke, which is caused when a blood vessel bursts and causes bleeding into the brain.
Signs of a stroke include facial, arm or leg weakness, speech problems and a partial loss of vision.
A healthy diet, regular exercise, not smoking and ensuring blood pressure is normal, can help prevent a stroke.

• Men's Health News, Published: 2006 June 20

It may be possible to protect the testes of cancer patients against the loss of fertility caused by chemotherapy, a scientist told the 22nd annual conference of the European Society of Human Reproduction and Embryology in Prague, Czech Republic.
Mr. Alon Carmely from Bar-Ilan University, Ramat Gan, Israel, said that his work showed for the first time that the injection of a drug that enhances the immune system could protect the testis from the effects of paclitaxel (Taxol), a widely used chemotherapy drug.
"The effects of chemotherapy treatment on fertility are an important issue for long-term survivors of cancer who may not have started or completed a family at the time of diagnosis", said Mr. Carmely. "AS101 is a Tellurium-based non-toxic immunomodulatory compound developed and synthesised by us. Tellurium is a transition element with similar properties to Selenium, which is also known to have many beneficial effects."
Knowing that AS101 had been shown to have chemoprotective effects in both animal and human studies, he and his team decided to investigate whether it could be used to avoid testicular damage in mice treated with Taxol. "Clinical studies had already shown that AS101 could protect against bone marrow damage and hair loss, and also sensitises the tumour to treatment", he said.
The scientists divided the mice into four groups - Taxol only, AS101 plus Taxol, AS101 only, and a control group. After 30 days they were euthanized and their testes examined and weighed. The researchers found that a single dose of Taxol had induced significant testicular weight loss compared with the control group. An injection of AS101 a day before that of Taxol prevented the Taxol-induced weight loss.
"Tissue analysis of the testes of Taxol-injected mice showed severe atrophy and empty seminiferous tubules, where the sperm-producing cells are contained", said Mr. Carmely. "In contrast, we saw only minimal testicular damage in the group that had previously been injected with AS101, and we could also find mature sperm. Injection of AS101 alone did not alter testicular weight or tissue analysis results.
"These results hold out much promise for fertility preservation in men undergoing cancer treatments", he said. "We now intend to study the mechanism of protection, which is still unclear. Our work suggests that in addition to the direct damage caused by the treatment, significant testicular damage is caused by the immune reaction to it. We hope to begin clinical studies in cancer patients in the next few months."

• Medical Procedure News, Published: 2006 June 13

The subject of changing public advice over the years, mammography and the controversy over its use continue to cause confusion in the minds of many women.
A new book for lay readers entitled "Understanding the Mammography Controversy: Science, Politics, and Breast Cancer Screening" (Praeger Press), by women's health expert Dr. Madelon L. Finkel of Weill Medical College of Cornell University, provides a comprehensive guide to mammography, the mammography controversy and breast health.
The book directly addresses the still-controversial issues, such as deciding when is the "right" time to have a mammogram, what is the "right" age for mammography (the body of evidence indicates a benefit for women aged 50 to 69) and whether mammography is useful at all (it is). While not perfect, mammography is the only population-based breast cancer screening method that has been shown to actually save lives.
"It's no wonder women are confused about mammography. Sensational media stories tout the latest scientific studies, often contradicting previous findings. Above all, women need to separate the facts from the myths in order to make informed decisions about their breast health," says Dr. Finkel, professor of clinical public health and director of the Office of Global Health Education at Weill Cornell Medical College.
This book includes a timeline that details the disagreement within the scientific community and changing public advice on mammography over the years.
"The mammography debate is still not yet settled. While the latest research shows that mammography can save lives, there is still no overall consensus on what age mammogram screening should be recommended, and even whether the benefits of mammogram screening outweigh the risks in the first place," says Dr. Finkel." Each woman must consider her personal risk factors, and in consultation with her doctor, decide when and how frequently mammography should be scheduled."
The book offers readers practical information, including how to give a breast self-exam, how to communicate with one's doctor, a list of support groups and organizations for breast cancer patients, and resources for clinical trials.
"Most women will not develop breast cancer in their lifetime, and for those who do, it's no longer a death sentence. Thanks to public awareness, screening, research and new treatment options, it has become a treatable, chronic illness," says Dr. Finkel.
"Understanding the Mammography Controversy: Science, Politics, and Breast Cancer Screening" received the highest rating from BookList. The book is dedicated to the author's mother, who died of breast cancer.

• Medical Studies/Trials, Published: 2006 June 12

According to a new study supplements of folic acid may help prevent cancer.
Italian researchers enrolled 43 patients with untreated laryngeal leucoplakia and treated them with folic acid (5mg three times a day) and evaluated the progression of leucoplakia every 30 days for six months.
Leucoplakia appears as white patches in the mucus membranes of the mouth or throat, and can contain precancerous cells.
The researchers found that over six months of treatment, 12 patients had complete resolution of their leucoplakia lesions; 19 patients had reduction of 50 percent or more in the size of their lesions and 12 patients had no response.
Folate levels in the blood increased and homocysteine levels decreased significantly.
Excess homocysteine is linked to chronic health problems, such as cancer and cardiovascular disease.
There were no moderate or severe adverse events reported.
Study leader Dr. Giovanni Almadori from Universita Cattolica del Sacro Cuore, Policlinico A. Gemelli in Rome says previous studies have shown that patients diagnosed with head and neck cancer or laryngeal leucoplakia have had lower than normal levels of folate in the blood.
Folate deficiency is the most common vitamin deficiency in the United States; it is a naturally occurring B vitamin found abundantly in fresh vegetables and fruits
It is found in dietary supplements and fortified foods and is important to healthy life because it promotes DNA synthesis and DNA repair.
The researchers say the results suggest that folate is an effective chemopreventive drug with few adverse effects and alone or in combination with other chemopreventive drugs, folate could effectively reduce the risk of cancer progressing.
The team say that laryngeal leucoplakia often recurs in a more advanced form that has a greater chance of progressing to cancer.
They are planning a larger trial to evaluate the effectiveness of folic acid supplements as follow-up treatment after surgery to remove laryngeal leucoplakia in order to prevent the development of head and neck cancer.
The study is published in the July 15, 2006 issue of CANCER.

• Pharmaceutical News, Published: 2006 June 12

The Federal Drug Administration (FDA) in the U.S. has recently given its approval for a new vaccine which protects against the human papillomavirus known as HPV.
HPV is one of a group of viruses found to cause cervical cancer, a life-threatening disease that is expected to strike nearly 10,000 women in America this year.
HPV is the most common sexually transmitted infection in the United States, and is most common in adolescents and young adults; more than half of all sexually active men and women will acquire an HPV infection at some point in their lives.
News of an effective HPV vaccine is welcome but studies have found that the vaccine is most effective for those individuals who have not yet become sexually active i.e young girls.
Experts who identify and diagnose cervical cancer, HPV and other diseases, believe that women who have been sexually active continue to get regular Pap tests and women 30 years of age and older should also have an HPV test, to enhance the chances for identifying precancerous changes.
Critics of the vaccine who say that it will only serve to encourage increased sexual activity among teenagers but have found little support from the Center for Disease Control (CDC) or the FDA.
An FDA advisory committee last month recommended approval of Gardasil for girls and women ages nine to 26.
If Gardasil receives FDA approval, which is likely it also must be examined by CDC's Advisory Committee on Immunization Practices (ACIP) and ACIP's HPV vaccine group has also recommended giving the vaccine to girls ages 11 and 12.
CDC analyst Lauri Markowitz says fear of contracting sexually transmitted infections does not appear to be a primary reason that teens abstain from sex and research shows that teens know little about HPV's link to cervical cancer.
Meanwhile the global health group PATH has launched a five-year program that aims to provide access to HPV vaccines to women in developing countries.
By using a $27.8 million grant from the Bill & Melinda Gates Foundation will conduct research in India, Peru, Uganda and Vietnam, selected because they have committed to cervical cancer prevention programs and efficient childhood vaccination programs.
According to PATH, cervical cancer affects about 490,000 women annually worldwide and leads to more than 270,000 deaths.

• Medical Research News, Published: 2005 October 17

A new study suggests that restoring a gene often silenced in lung cancer causes the cells to self-destruct. The findings could lead to a new strategy for treating the disease.
The research focused on a gene known as WWOX, which is lost or silenced in a large majority of lung cancers, and in cancers of the breast, ovary, prostate, bladder, esophagus and pancreas. The work was led by scientists at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.
The study showed that both in the laboratory and in animal experiments, restoring the missing or silenced WWOX gene can slow or stop the cells' growth.
The research also showed that the reactivated gene is highly effective in stopping the growth of human lung tumors that have been transplanted into mice.
The findings are published online in the Oct. 13 Early Edition of the Proceedings of the National Academy of Sciences.
The American Cancer Society expects more than 172,500 Americans to develop lung cancer in 2005, and more than 163,500 people to die of the disease, making it the most common cause of cancer death in the U.S.
"Our findings show that restoring the WWOX gene in lung-cancer cells that don't express it will kill that lung-cancer cell," says coauthor Kay Huebner, professor of molecular virology, immunology and medical genetics and a researcher with the OSU Comprehensive Cancer Center .
"This suggests that if this gene could be delivered to, or reactivated in, the tumor cells of lung-cancer cases that are deficient in this gene, it should have a therapeutic effect."
WWOX is a tumor suppressor gene. Tumor suppressor genes safeguard the body by triggering the death of cells that have sustained serious DNA damage before the cells become cancerous. The loss or silencing of tumor suppressor genes is a fundamental cause of tumor development.
The WWOX protein is missing in cells making up many lung tumors, and in 62 percent of cases, the gene is turned off by a chemical process known as methylation.
"There is nothing wrong with those genes except that they are silenced by methylation," Huebner says. "Experimental drugs are now being tested that cause demethylation and may reactivate WWOX and other genes."
For this study, Huebner and her colleagues used three different lines of laboratory-grown lung-cancer cells that were missing WWOX protein. The researchers then used a virus engineered to carry working copies of the WWOX gene into the three cell lines.
After five days, the researchers found that cells having an active WWOX gene died off. The cells self-destructed through a natural process known as programmed cell death, or apoptosis. The lung-cancer cells that lacked the WWOX gene, on the other hand, continued growing and increased in number nearly five- or six-fold.
Next, the researchers took some of the lung-cancer cells to which they'd added working copies of the WWOX gene, and they transplanted the cells into mice; a second group of control mice received lung-cancer cells without the WWOX gene.
After 28 days, the mice that received tumor cells with no WWOX gene had developed tumors. Of the mice that received tumor cells with the gene, 60 percent in one group and 80 percent in another group showed no tumors.
"Our study is a proof of principle," Huebner says. "It shows that if the WWOX gene can be delivered into tumor cells, it can kill them.
"We also showed that if a silenced WWOX gene is present and can be turned back on, that too will kill tumor cells," adds first author and postdoctoral researcher Muller Fabbri.
"We don't believe that using WWOX as a therapy will necessarily eradicate tumors, Fabbri says, "but we do believe that this kind of gene therapy might be useful when used in combination with chemotherapy and other therapies."

• Women's Health News, Published: 2006 May 23

According to a large new study women who pile on the kilos as adults increase their risk of all types of breast cancer even if they do not take hormone replacement therapy after menopause.
The study supports a growing body of evidence which has found that weight and breast cancer are inextricably linked and reveals that the greater the weight gain as an adult, the greater the risk for all histological types, tumor stages, and grades of breast cancer, in particular advanced malignancies.
The study, which is the first to investigate the relationship between weight gain and type of breast cancer, found that the most extremely obese women were up to three times more likely to have regional or distant metastases than women with less weight gain.
The study of more than 44,161 postmenopausal women who were not taking hormone therapy found that the more weight a woman gained, the greater her risk for all types, stages, and grades of breast cancer.
Heather Spencer Feigelson Ph.D., M.P.H of the American Cancer Society and colleagues found that in comparison to women who gained 20 pounds or less during adulthood, women who gained over 60 pounds were almost twice as likely to have ductal type tumors and more than 1.5 times more likely to have lobular type cancers.
The risk for metastatic disease increased for all women who gained weight, with the risk was greater than three-fold for women who gained over 60 pounds.
Heather Spencer Feigelson Ph.D., M.P.H of the American Cancer Society and colleagues found that the weight gain increased the risk of estrogen receptor positive tumors, but not of tumors that did not present estrogen receptors.
Experts believe that breast cancer risk is linked to increased lifetime levels of circulating estrogen and fat tissue increases circulating estrogen resulting in a greater risk.
According to the American Cancer Society breast cancer is the second leading cause of cancer death among U.S. women, after lung cancer, and more than 200,000 people are diagnosed and another 40,000 die from it each year.
Globally more than 1.2 million men and women develop breast cancer every year.
Dr. Feigelson and her team say the findings illustrate the relationship between adult weight gain and breast cancer, and the importance of maintaining a healthy body weight through-out adulthood.
The research is published in the July 1 issue of CANCER.

• Medical Studies/Trials, Published: 2006 May 23

Approximately 15% of Asians living in New York City are chronically infected with hepatitis B virus, according to a new study by New York University School of Medicine researchers and their colleagues.
Chronic hepatitis B infection usually will lead to liver inflammation and can progress to cirrhosis and liver cancer. The reported infection rate is 35 times higher than the rate in the general U.S. population.
The new study appears in Morbidity and Mortality Weekly, published by the Centers for Disease Control and Prevention (CDC).
A total of 1,836 people were screened at 12 health care centers and community sites in New York City as part of the NYC Asian American Hepatitis B Program, which provides free screening, vaccination and treatment. It is funded by the New York City Council and the New York State and City Departments of Health. Nearly all of the participants were born in Asia; mainly in China and Korea. The infection rate within the Asian American community was drawn from an analysis of 925 people who had never been previously tested for hepatitis B.
A person's country of birth, gender and age influenced the prevalence of chronic infection, according to the study. The infection rate was highest--greater than 30 percent--in men between 20 and 39 who were born in mainland China.
"These rates are extraordinarily high and underscore the need for more intensive screening in this population," says Henry Pollack, M.D., Associate Professor of Pediatrics at NYU School of Medicine, and the study's lead author. "There needs to be much more public awareness of this problem and physicians caring for this population need to be more attentive to screening for hepatitis B," he says.
Hepatitis B is transmitted through unprotected sex, sharing of needles, contact with infected blood, or from mother to child at birth, but not through casual contact such as hugging or coughing. Symptoms start when the immune system starts attacking the cells in the liver that are infected with the virus. Liver damage can take decades to progress. An estimated 400 million people worldwide are chronically infected with hepatitis B.
The viral infection is widespread across Asia and if left unchecked, it causes liver cancer, which is a leading cause of death in many Asian countries. New York City has the largest Asian population in the United States--about 800,000 people, according to the 2000 U.S. Census.
"Hepatitis B is probably responsible for 80 percent of hepatocellular cancers worldwide," says Dr. Pollack. When infection occurs in young children, an estimated 15 percent to 40 percent will develop chronic liver disease, including cirrhosis and liver cancer. "In newborns there is a 90 percent chance of developing chronic hepatitis B," he says.
Over the last 15 years, the transmission of hepatitis B from mothers to newborns in the United States has been drastically reduced with the help of neonatal screening and vaccination. In China, prophylaxis efforts have only just begun, due to a lack of resources across the country. China has 150 million people who are chronically infected with hepatitis B, says Dr. Pollack. In the 1990s there was a large influx of immigrants from China to the United States. So now the U.S. faces a somewhat under-recognized public health challenge, he says, because the disease has been considered controlled.
About one in five persons screened in the new study who were born in China were infected with chronic hepatitis B. In general, the infection rate among those tested closely mirrored rates reported in the study participants' native countries and regions, says Dr. Pollack. Once diagnosed, proper evaluation and care and, in many cases, specific antiviral treatment, is the key to avoiding long-term complications of the disease. Hepatitis B infection can be effectively prevented by vaccination. All persons susceptible to infection in the new study were vaccinated against hepatitis B. Partners and other household members were also tested and vaccinated if susceptible.
The long-term goal of The Asian American Hepatitis B Program is to establish a national model for hepatitis B prevention in Asian American communities, according to Mariano J. Rey, M.D., Director of the Centers for Health Disparities Research at NYU School of Medicine and the program's administrative principal investigator.

• Medical Research News, Published: 2006 May 23

Selenium, an essential dietary mineral that can act as an antioxidant when incorporated into proteins, has been shown in many studies to reduce the incidence of cancers -- notably lung, colorectal and prostate.
"The problem is, nobody seems to know how the mechanism works, and that's not trivial," said Alan Diamond, professor of human nutrition at the University of Illinois at Chicago and principal investigator in an ongoing multidisciplinary study set up at UIC to help answer that question.
"Knowing how it works allows you to maximize-out its benefits," he said.
Diamond and his colleagues report in the May 23 issue of the Proceedings of the National Academy of Sciences on research findings using specially bred transgenic mice that suggest it is the level of selenium-containing proteins in the body that is instrumental in preventing cancer, and that dietary selenium plays a role in stimulating the body's level of these selenoproteins.
Two genetically manipulated mice were mated. One was prone to developing prostate cancer. The other had lower levels of selenoproteins. Approximately 50 offspring that carried both traits were studied to see if the reduced levels of selenoproteins accelerated cancer development. As the researchers suspected, it did.
"It's a hardcore link in an animal model system of selenium-containing proteins to prostate cancer and, by extrapolation, the mechanism by which selenium prevents cancer," said Diamond.
Further research is underway to corroborate the stimulating effect of dietary selenium in enhancing levels of protective selenoproteins. Diamond added that much work remains to be done to discover exactly how selenoproteins play their protective role, and in whom.
At least 25 different selenoproteins have been found in the human body. But what role each plays is not known, nor is it known if certain persons are genetically more -- or less -- receptive to the benefits of these proteins, or to a selenium supplement, Diamond said.
The effectiveness of selenium may be due to its effects on a single selenoprotein, or combinations of several members of this class. One selenoprotein in particular, glutathione peroxidase, is of special interest to Diamond and his associates. They plan to run new tests using new mice genetically modified to reduce levels of just this one selenoprotein.
"If reductions result in accelerated prostate cancer, then we have our player," he said.
Other UIC faculty participating in the study include Veda Diwadkar-Navsariwala, post-doctoral researcher in human nutrition; Gain Prins, professor of urology; Steven Swanson, associate professor of medicinal chemistry and pharmacognosy; Lynn Birch, research specialist in urology; Vera Ray, clinical assistant professor of pathology; Sadam Hedayat, distinguished professor of statistics; and Daniel Lantvit, research specialist in pharmaceutical sciences.

• Medical Studies/Trials, Published: 2006 May 21

Anti-TNF (tumor necrosis factor) therapies are a tried and tested type of medication used for treating rheumatoid arthritis and the drugs provide benefit to many of thousands of patients worldwide.
Rheumatoid arthritis is a chronic autoimmune disease which causes chronic inflammation of the lining of the joints and can cause long-term joint damage, chronic pain, immobility and disability.
According to the Arthritis Foundation as many as 2 million Americans suffer from rheumatoid arthritis.
But now a new but controversial review is saying that rheumatoid arthritis patients treated with the new and potent "TNF-blocking" drugs have a higher risk of developing cancer and serious infections.
Dr. Eric Matteson, a professor of medicine and consultant in rheumatology at the Mayo Clinic says the review findings clearly indicate that the drugs contribute to the risk.
However this view is not consistent with other published studies examining the relationship between anti-TNF therapy in rheumatoid arthritis and malignancy and many and other experts disagree.
They query whether the drugs or the disease itself is responsible for the increased risk and say it is difficult to ascertain to what degree the drugs play a role.
The study says that more than half a million patients have been treated with TNF-blocking antibodies mainly because they have not responded to other treatments.
There are currently two types of anti-TNF agents available, infliximab (Remicade) and adalimumab (Humira).
Both drugs work by neutralizing the tumor necrosis factor(TNF), a protein believed to play a major role in rheumatoid arthritis and they are recognised as increasing the risk of serious infection.
In the new study the authors reviewed and analyzed nine randomized, placebo-controlled trials of the two drugs.
The trials involved as many as 3,500 patients receiving anti-TNF antibody treatment and more than 1,500 controls receiving a placebo treatment.
The researchers say they found that patients taking one of the two TNF-based treatments had a 3.3 times higher risk of developing cancer and 2.2 times the risk of serious infection than patients taking the placebo.
They also say that malignancies were significantly more common in people receiving higher doses, compared with patients receiving lower doses of anti-TNF antibodies.
According to the researchers one in every 154 people treated with either drug developed a cancer within six to 12 months, and one in 59 people developed a serious infection within three to 12 months.
An explanation for such a drug-related risk remains unclear but experts suggest that the drugs possibly interfere with the body's normal defenses against infection and against cancerous cells.
The general consensus appears to be that even if the drugs are responsible, the benefits probably outweigh the risks.
Matteson and his colleagues are now hoping to use the same methods to assess other medicines in their post-marketing phase.
Patients taking Anti-TNF medications are advised to continue to take their medication and discuss any concerns with their doctor.
The review is published in the current issue of the Journal of the American Medical Association.

• Women's Health News, Published: 2006 May 01

According to experts in reproductive health, the combination of HPV testing with HPV vaccines is the best hope for preventing cervical cancer.
Throughout the world cervical cancer affects more than 400,000 women annually and, after breast cancer, is the second-most-common malignancy found in women.
Human papilloma virus (HPV) causes a common sexually transmitted disease and but can also be responsible for cervical cancer if left untreated and many people have HPV with no apparent symptoms.
Experts have focused on the emerging role of HPV testing as a standard of care for cervical cancer screening, and the development of the first vaccine to protect against the two most high-risk forms of HPV.
Virtually all cervical cancers are caused by HPV.
Although regular use of cytology (Pap testing) has dramatically reduced the incidence of cervical cancer in many countries, it is not foolproof.
Experts believe that success can be increased by 40 percent by effectively following up on women whose Pap results are normal but who test positive for high-risk HPV.
Experts recommend most women should have a yearly Pap test and a pelvic exam to detect the beginnings of cervical cancer.
Cervical cancer if diagnosed early has a high survival rate and a yearly Pap smear checks for abnormal cells and certain infections and can predict future problems.

• Medical Studies/Trials, Published: 2006 May 04

A substantial proportion of women have beliefs about their personal risk of breast cancer, and expectations about the performance of mammography that are abnormally high or unrealistic, according to a survey conducted at University of Michigan Health Systems in Ann Arbor, Michigan.
A survey was administered to women who came to an outpatient clinic for screening mammography. The participants were 397 women ranging from 40-83 years old. The responses to the survey questions showed that 16% thought that their personal risk of breast cancer was 50% or higher. These numbers compare to American Cancer Society reports that indicate that the chance of a woman having invasive breast cancer some time during her life is about 1 in 8.
The survey also found that 20.6% of the women agreed with the statement 'mammograms detect all breast cancers' and 11.4% were neutral about this statement. "Women have high expectations of mammography because patients in general (not specifically women), tend to have a view of all medical tests being yes or no, 'positive' or 'negative'; the general public as well as some health care professionals do not completely understand concepts of accuracy, sensitivity and specificity, false negatives, and false positives," said Marilyn Roubidoux, MD, co-investigator of the study. "People assume that if a mammogram can detect cancer the size of a pin, then it can detect all cancers bigger than a pin. The reality is much more complicated than that," she said.
Most of the women (94%) had had a prior mammogram; 14.1% had prior benign biopsy. Eighty-four percent of the respondents had one year of post high school education, 55% were college graduates, and 23% had graduate degrees.
"The purpose of the study was to identify the significant predictors of repeat mammography behavior. Specifically looking at the relative impact of the pain experience, emotional distress and anxiety, and satisfaction with the health care experience," said Tricia Tang, PhD, who was the principal investigator and the designer and administrator of the survey. "By understanding better which factor carries more weight, we can develop interventions, be it patient-based, provider-based, or clinic operations based."
"As stated, women in this study were highly educated and likely well informed about procedures such as mammograms. With more information, expectations are more accurate, thereby minimizing the negative physical and emotional aspects associated with this type of procedure," said Tang.
"The results in the survey were expected," said Marilyn Roubidoux, MD, co-investigator. "After working with patients for many years and doing their biopsies, their beliefs about mammography are revealed in conversations and these now are shown in a more objective way in the survey."

• Medical Studies/Trials , Published: 2006 May 04

Significant changes in tumor growth can be detected through short interval follow-up CT in patients receiving chemotherapy for non-small cell lung cancer, a recent study found.
These growths may have important clinical implications in the management of patients, enabling early discontinuation of potentially toxic chemotherapy drugs.
The study, lead by Dr. John F. Bruzzi of the department of diagnostic imaging at the MD Anderson Cancer Center in Houston, TX was done to determine whether short term follow-up CT in patients with non-small cell lung cancer can detect significant changes in tumor size due to disease progression or response to therapy.
The study, which was performed within a thirty-one day time period, had 41 patients, both male and female, ranging from 26-85 years of age. Short-term restaging scans in each patient comprised at least two serial CT studies performed during this time period. A significant change in tumor size was observed in seven of the patients, four of whom had poorly differentiated tumors. There was a 33% decrease in tumor size in one patient in response to chemotherapy. In five patients, tumors increased extensively in size by 20-48% over a period of 31 days or less. This prompted either a change or discontinuation of chemotherapy in all five patients.
"We found that 17% of patients with non-small-cell lung cancer being treated with chemotherapy had a significant change in tumor size on restaging CT performed within thirty-one days of their baseline CT scan," said Dr. Bruzzi.
"Twelve percent of these patients had tumor progression, while 3% had tumor shrinkage. This response occurred regardless of initial tumor stage, tumor histology or type of treatment received. This means that an early restaging CT that detects tumor progression can allow the clinician to change or discontinue chemotherapy earlier than might otherwise be done, thereby helping to reduce exposure of the patient to costly and potentially toxic chemotherapy agents that are ineffective; it also gives greater confidence to the clinician in continuing therapy that is producing a good tumor response," said Dr. Bruzzi.
"We believe now that the value of performing early restaging CT should be assessed in a controlled prospective study of a more homogenous population of patients with lung cancer, which could perhaps also incorporate volumetric measurements of tumor size and assess the relative values of restaging CT and CT-PET scanning," stated Dr. Bruzzi.
The full results of this study will be presented on Thursday, May 4, 2006 during the American Roentgen Ray Society Annual Meeting in Vancouver, BC.

• Medical Studies/Trials, Published: 2006 April 26

A discovery made at The Walter and Eliza Hall Institute provides new insights into enhancing the function of the protein SOCS3, which regulates the response of cells to external stimuli.
SOCS3 (Suppressors of Cytokine Signalling) controls the responses of cells to cytokines (growth factors). It is important that cytokine signalling is properly regulated within the human body. If SOCS3 permits cytokine signalling to be too "loud", then the excess of growth signals can cause crippling inflammatory diseases such as Rheumatoid Arthritis or diseases where cells multiply uncontrollably - cancer.
Conversely, if cytokine signalling is overly repressed by SOCS3, then bone marrow is deprived of sufficient white blood cells required to rejuvenate the damaged immune system following chemotherapy. An unfortunate side effect of chemotherapy is damage caused to the bone marrow that produces the white blood cells of the immune system. This leaves cancer patients prey to opportunistic infections that can delay and adversely affect their recovery.
A cytokine called G-CSF (developed in previous years at WEHI) is in clinical use worldwide to stimulate the restoration of bone marrow and the reinvigoration of the immune system in chemotherapy patients. The success of G-CSF (or Granulocyte Colony Stimulating Factor) depends on the complementary proper functioning of SOCS3.
A research team at WEHI has determined the three-dimensional structure of SOCS3. This discovery about the structure may enable the design of selective inhibitors of SOCS3 that might be useful in extending the activity of G-CSF in restoring white blood cells.
The structure also showed that SOCS3 contains a region that could be engineered out, improving the stability of SOCS3. This newly engineered version of SOCS3 also has the potential to enhance its repressive functions, which may allow inflammatory diseases to be treated more effectively.

• Medical Science News, Published: 2006 April 06

The biological processes underlying diseases such as rheumatoid arthritis and cancer are fundamentally linked, and should be linked in how they are treated with drugs, a series of MIT studies indicates.
The researchers applied an engineering approach to cell biology, using mathematical and numerical tools normally associated with the former discipline.
In a series of three papers, the latest of which appeared in the March 24 issue of Cell, Professors Douglas A. Lauffenburger, Peter K. Sorger and Michael B. Yaffe, all members of MIT's Center for Cancer Research, led a team of scientists and engineers in looking at how cells make life-or-death decisions. Understanding what tips a cell toward survival or death is key to treating diseases and fighting cancer through radiation, drug therapy and chemotherapy.
The researchers looked at tumor necrosis factor (TNF), a substance produced by the immune system that promotes cell death, and two prosurvival hormones, epidermal growth factor (EGF) and insulin. TNF and EGF induce conflicting prosurvival and prodeath signals, and the "crosstalk" between these signals is not well understood. The MIT studies provide the first big picture of how these two key factors interact in time and space.
The studies uncovered a surprising link between inflammatory diseases and cancer that may change how these diseases are treated in the future.
Researchers have been exploring ways to use drugs in combination to increase their therapeutic value in fighting tumors. The results of the three MIT studies have implications for how two classes of drugs involving TNF and EGF affect common biological processes in the body.
Drugs that inhibit TNF are used to treat debilitating chronic inflammatory diseases such as rheumatoid arthritis. Yet TNF, which causes inflammation, also leads to generation of the EGF signals that play a role in many cancers. (The breast cancer drug Herceptin, for example, works by blocking EGF-induced signals.) "TNF is supposed to kill cells. It's counterintuitive that it simultaneously promotes cell survival by sending an 'autocrine' EGF signal to itself," said Sorger, a professor of biology and head of MIT's Center for Cell Decision Processes. Autocrine EGF messages are analogous to mailing yourself a letter. In the case of TNF, cells also mail back the response via another hormone, IL-1.
"With what we now understand about the interactions between these two factors, we should aim for increasing the therapeutic value from these drugs," Sorger said. "There is a fundamental molecular connection between diseases such as rheumatoid arthritis and cancer. Their protein cascades are connected; one stimulates the process of the other."
"In drug development, we want to identify the really important hubs in the network we should be targeting and when we should be targeting them," said Yaffe, an associate professor of biology and biological engineering. "It's key to figure out the most critical point in the cell cycle for the drug to intervene. This work will help accomplish that goal."
Among the cells lining the intestines of a person with inflammatory bowel disease, two different camps are at war. TNF launches an attack, killing many of the epithelial surface cells, while EGF struggles to keep the cells alive and dividing to repair the damage.
In every cell, genes create proteins, the building blocks of life. Besides carrying out the functions of keeping the cell alive, some proteins such as TNF and EGF work as signals, turning on or off other genes. In a cascade effect, the proteins from these genes may affect still more genes. What's more, a single protein behaves differently at different points in time: A protein may do one thing early after stimulation and something else later on.
Researchers want to be able to predict how cells will respond to tiny molecular changes that spur them to develop, multiply or die. If researchers knew exactly how much of a certain protein was needed to kill a cancer cell and exactly when in the cell's life cycle it would be most lethal, drugs could be custom-designed to destroy malignant cells while leaving normal cells intact, Yaffe said.
But for many cell-decision networks, there is simply not enough information about the signaling proteins and reactions to construct a believable model that would allow accurate predictions to be made. Can you design an effective model without measuring every one of the tens of thousands of proteins in a cell?
"There are a lot of variables and a limited set of observations," Lauffenburger said of cell biology. "How can you abstract what's going on underneath the surface? We're never going to have complete knowledge, but the question was, could we construct a model that admits that we don't know everything, but we know enough to do something useful?" Lauffenburger is head of MIT's Biological Engineering Division and is the Whitaker Professor of Bioengineering.
To answer that question, the team used an engineering approach typically applied to manufacturing or software. "At some point, we need to bring new tools to bear on complexity, and those new tools are engineering-based mathematical and numerical tools," Sorger said. "Just as we can engineer extremely complicated systems like jets that we can't understand in their totality just by looking at them, we can do the same thing in biology." Modeling signaling pathways with computers is one of the tactics of MIT's Center for Cell Decision Processes.
"Models store our aggregate biological knowledge in a tractable way and are used to identify which proteins and pathways are most critical for mediating cell responses," Yaffe said. The research team plugged measurements of thousands of signaling proteins gathered in painstaking laboratory experiments into the models, providing a "firm theoretical grounding" to intuit how protein network interactions affect cell behavior, Yaffe said.
Yaffe divided cell signals into two major dimensions that can be plotted on a graph with a stress/death axis and a survival/growth axis. Where the conflicting factors fall on the graph determines whether the cell upon which they are acting lives or dies. "Our study gives us a broader functional sampling of a lot of things at the same time," he said.
Using this new approach involves teams of researchers, a concept unusual in traditional cell biology. Working as a team, computational scientists remain in close touch with their laboratory-based collaborators. Interdisciplinary scientists working at the interface of biology and computation is the way of the future, according to Kevin A. Janes, graduate student in biological engineering and one of the study's co-authors.
The payoff is high. Combining broad protein-based measurements and computation revealed the big picture, uncovering connections between spheres of biology previously believed to be distinct. "We are finding that things that once appeared to be biologically independent are closely connected," Sorger said. "We are not just collections of independent parts."

• Medical Studies/Trials, Published: 2006 Mar 17

San Diego State University researcher Roger Sabbadini has brought scientists one step closer to finding a cure for cancer with the creation of an antibody that hinders the growth of tumors by preventing blood vessel formation.
As published in the March 14 issue of Cancer Cell, a leading oncology journal, Sabbadini and his research team have created an antibody, Sphingomab, that can be used as a drug to reduce the size of tumors in experimental animal models of human cancer. The antibody works as a molecular sponge by soaking up sphingosine-1-phosphate (S1P), a molecule that has been proven to stimulate the growth of new blood vessels. S1P has been identified as a mediator of tumor cell proliferation and protector of tumor cells from chemotherapy drugs. By neutralizing S1P, the Sphingomab antibody inhibits the new blood vessel formation that tumors require to thrive, a process called 'tumor angiogenesis.'
The group's research tested the antibody in mice tissue implanted with drug-resistant human breast, ovarian and lung cancer cell lines, as well as a mouse skin cancer cell line. In ovarian cancer models, two of five subjects displayed no tumors, and three subjects had tumors with 68 percent less volume than those in the control group. Tumors were reduced by about 60 percent in volume in lung and breast cancer models.
"This groundbreaking research provides new hope for therapeutic treatments for forms of cancer that are resistant to current therapeutics," Sabbadini said. "The Sphingomab antibody is especially powerful as it is shown to prevent tumors from a variety of cancers, as opposed to being effective against only one type of cancer."
Sabbadini's previous sphingolipid research led to the founding of Lpath Inc.
"It has become a dream of mine to be a part of great anti-cancer research, as my mother is a cancer survivor," said Bradley Sibbald, a master's degree candidate in SDSU's molecular biology program and a co-author of the study. "With the creation of this antibody, I now have a new investigative tool to help cure cancers with liquid tumors, which is the focus of my current research."
The research team was primarily comprised of current and former students of SDSU, as well as researchers affiliated with Lpath Inc. Besides Sibbald, other authors of the study include Barbara Visentin, John Vekich, Amy Cavalli and Kelli Moreno, all former SDSU students. Other contributing researchers include Rosalia Matteo and William Garland, both with Lpath Inc., and University of Texas Anderson Cancer Center researchers Shuangxing Yu, Yiling Lu, Hassan Hall, Vikas Kundra and Gordon Mills.
Sabbadini will present the team's findings at the annual conference for the American Association of Cancer Researchers, April 1 - 5, in Washington D.C. Additionally, Lpath Inc. is preparing an application to the U.S. Food and Drug Administration for approval to use the antibody for human clinical trials.
Lpath is a theranostics company focused on bioactive signaling lipids as targets for treating and diagnosing important human diseases. For more information on Lpath, visit www.lpath.com.

• Medical Research News, Published: 2004 Oct 21

Strong-flavored onions can be harsh on your social life, but they're potentially great for fighting cancer. Researchers at Cornell University have found, in preliminary lab studies, that members of the onion family with the strongest flavor ? particularly New York Bold, Western Yellow and shallots ? are the best varieties for inhibiting the growth of liver and colon cancer cells.
"No one knows yet how many daily servings of onions you'd have to eat to maximize protection against cancer, but our study suggests that people who are more health-conscious might want to go with the stronger onions rather than the mild ones," says study leader Rui Hai Liu, M.D., Ph.D., a chemist with Cornell's Department of Food Science in Ithaca, N.Y.
Researchers have known for some time that onions may help fight cancer, but the current study is believed to be the first to compare cancer-fighting abilities among commonly consumed onion varieties. The new study will appear in the Nov. 3 print issue of the Journal of Agricultural and Food Chemistry, a peer-reviewed journal of the American Chemical Society, the world's largest scientific society.
Liu and his associates analyzed 10 common onion varieties and shallots for total antioxidant activity and their ability to fight the growth of cancer in human cell lines. Although shallots resemble onions, they are actually a separate, distinctive species. Fresh, uncooked samples were used, with extracts taken from the bulbs with the outer skin removed.
Shallots and onion varieties with the strongest flavor ? Western Yellow, New York Bold and Northern Red ? had the highest total antioxidant activity, an indication that they may have a stronger ability to destroy charged molecules called free radicals, an excess of which are thought to increase the risk of disease, particularly cancer, the researcher says.
Onion varieties with the mildest flavor ? Empire Sweet, Western White, Peruvian Sweet, Mexico, Texas 1015, Imperial Valley Sweet and Vidalia ? had the lowest total antioxidant activity, Liu says.
In tests against liver and colon cancer cells, onions were significantly better at inhibiting the growth of colon cancer cells than liver cancer cells, an indication that they are potentially better at fighting colon cancer, the researcher says. The strongest cancer-fighters tested were the New York Bold variety, Western Yellow and shallots. The sweetest tasting onions, including the beloved Vidalia, showed relatively little cancer-fighting ability, he notes.
Green onions and cocktail onions were not tested in this study, nor did the researcher test whether cooking made a difference in terms of cancer-fighting ability. Liu cautions that human studies are needed before any definitive links between onion consumption and cancer-prevention can be established.
While popular as fried "rings," onions are known mostly for their ability to add flavor to a variety of food dishes, including meats, pizza, soups and salads. But they are increasingly becoming known for their potential health benefits. Onions are rich in a flavor compound known as quercetin, a potent antioxidant that has been linked to protection against cataracts and heart disease as well as cancer. They are also sodium, fat and cholesterol free.
Onions are the third-most consumed vegetable crop in the United States, with a per capita consumption estimated around 19 pounds per year and a retail value estimated at $3 billion to $4 billion, according to the National Onion Association.
Onions can be part of a healthy diet. The National Cancer Institute recommends eating at least five servings of fruits and vegetables a day.

• Medical Study News, Published: 2004 June 29

Cancer treatments, including the most commonly used chemotherapy agents as well as the newest biologic and targeted therapy drugs, can harm a patient's heart, sometimes fatally - but many physicians do not adequately monitor their patients for such damage or manage their care to minimize it.
So say cardiologists at The University of Texas M. D. Anderson Cancer Center, who published, in the June 29 issue of the journal Circulation, the first large scale review detailing cardiovascular complications that often occur in cancer therapy, as well as ways to prevent or treat them.
The study draws on 30 years of experience at M. D. Anderson Cancer Center as well as on the current body of research on the cardiotoxicity of various agents.
The findings are important because both patients and doctors may not be aware of the spectrum of heart problems that can arise from cancer treatment, or know that many of these problems can be managed, says the study's lead author, Edward T. H. Yeh, M.D., professor and chairman of the Department of Cardiology.
"Many cancer survivors will actually be at greater risk from cardiac disease as from recurrent cancer," says Yeh. "Now that cancer is often being treated as a chronic, manageable disease, it is critical that this treatment doesn't substantially weaken a patient's heart."
In fact, Yeh and a team of nine other cardiologists from M. D. Anderson found in their review of 29 anticancer agents that there is no class of cancer drug that is free of potential damage to the heart, the organ that seems to be most sensitive to toxic effects of anticancer agents.
Generally speaking, patients at most risk for cardiotoxicity are those who are aged and have other illnesses, such as diabetes or existing heart disease, he says. But cardiotoxicity can occur in any patient, either during treatment or months, even years after treatment.
Even the newest targeted therapies, designed to attack only cancer cells, can cause cardiotoxicity, Yeh says. For example, monoclonal antibody drugs such as Avastin, Erbitux, and Rituxin produce a significant amount of hypertension as well as hypotension in patients. "They seem to have more general toxicity than many other agents, but the problems they produce usually involve changes in blood pressure, which can be easily treated if recognized," Yeh says.
Some agents, however, are clearly more dangerous, especially in large doses. For example, patients using the common class of chemotherapy drugs known as anhracyclines/anthraquinolones that includes adriamycin should be closely monitored because these agents frequently produce irreversible chronic heart failure or left ventricular dysfunction, says Yeh. "This is probably the most problematic class of anticancer drugs, but with experience, cardiotoxicity can be limited," he says.
Alkylating agents, another class of common chemotherapy drugs, have other toxic effects. Platinol and Cytoxan, the most widely used alkylating agents, can produce heart problems that range from chronic heart failure to hypertension, if the total dose is high. Chemotherapy drugs known as "antimetabolites," which include the widely used agent 5-fluorouracil (5-FU), can produce ischemia, which can lead to heart attacks if not treated. However, heart problems are relatively rare in the "antimicrotubules" class of chemotherapy drugs, of which Taxol is a member.
Other non-chemotherapy drugs noted for their high risk of cardiotoxicity includes Inerleukin-2, which frequently results in hypotension or arrhythmias; Gleevec which can cause heart failure; Trisenox, from which fatal "QT prolongation" can result; and Thalidomide, which can produce a variety of serious heart ailments.
On the other hand, the researchers found that Herceptin is less toxic than generally believed, although it can cause chronic heart failure and left ventricular dysfunction.
"We found a profile of cardiotoxicity for the most often used anticancer drugs, but it is important to know that every patient has different risk factors that will determine how their hearts handle the treatment," says Yeh. "Monitoring and management is key to surviving cancer with a good and lasting heart."
The study was funded by the Department of Cardiology at M. D. Anderson Cancer Center. Co-authors include Michael Ewer, M.D., Ann Tong, M.D., Daniel Lenihan, M.D., S. Wamique Yusuf, M.D., Joseph Swafford, M.D., Christopher Champion, M.D., Jean-Bernard Durand, M.D., Harry Gibbs, M.D., and Alireza Zafarmand, M.D.

• Medical Research News, Published: 2005 Jan 12

A little anxiety can be a good thing when it comes to cancer symptoms according to researchers at Washington University School of Medicine in St. Louis. They report that people with low overall anxiety levels were more apt to ignore symptoms of rectal cancer for long periods of time, thereby delaying treatment. In contrast, people with at least moderate levels of anxiety tended to quickly recognize symptoms such as rectal bleeding as a sign of serious illness.
"Almost everyone has heard about people who had cancer symptoms long before they sought help. I was curious about the psychology behind this," says Stephen Ristvedt, Ph.D., assistant professor of medical psychology in psychiatry and investigator at the Siteman Cancer Center. "Most people assume the explanation is fear or denial or a reluctance to hear the 'C-word' from a doctor. So, I was surprised to find those who are generally optimistic and unconcerned had the longest delays."

The study will be reported in the May 2005 issue of Psycho-Oncology and is currently available online at the journal's web site.
The study examined 69 patients diagnosed with rectal tumors and treated in the Section of Colon and Rectal Surgery at Washington University School of Medicine. The patients were asked to indicate the length of two time periods: how much time passed between when they first experienced a symptom and when they realized it was potentially serious--the symptom appraisal time--and the time between that realization and the time they contacted a doctor--the action appraisal time.
In addition, each patient was assessed with standardized psychological tests to measure their sensitivity to threat and disposition toward anxiety. Individuals who score low on these tests tend to be confident, relaxed, optimistic, carefree, uninhibited, and outgoing. Those who score high are usually cautious, tense, apprehensive, fearful, inhibited, and shy.
The patients also were asked to rate their overall health before the cancer diagnosis and to indicate whether they visited a doctor regularly and got cancer screenings.
The analysis showed that, regardless of psychological profile, 71 percent of the patients did not at first believe their rectal bleeding or other symptoms were signs of cancer. They attributed the symptoms to hemorrhoids, diet, physical injury, stress or ulcers.
Among all the patients, the symptom appraisal time ranged from less than a week to around two years, with a median of seven weeks. Sixteen patients took six months or more to conclude their symptoms might be serious.
The longest symptom appraisal times were associated with those who scored low on the psychological tests of general anxiety. By one measure, the low scorers took a median of 30 weeks to appraise their symptoms as serious; high scorers took less than half that long.
"We found that people who are typically less responsive to threatening things take longer to seek medical attention, and they tend not to go in for routine screening because they just are not concerned enough," Ristvedt says. "They rate their overall health better, even though in these cases they were seriously ill."
The study found little difference in symptom appraisal times between men and women, but younger people took slightly longer than older patients to decide their symptoms were serious, as did those with fewer years of education compared to those with more education.
Action appraisal time was considerably shorter than symptom appraisal time among all the patients, having a median of one week. Action appraisal time was not affected by the patients' psychological profiles or other parameters measured. It appeared that once most patients decided the symptoms were signs of serious illness, they quickly sought medical help.
Ristvedt's findings suggest a different approach will be needed to ensure that carefree people pay attention to signs of disease. "We would like to figure out how to reach these people and get them to understand that their positive attitude may actually interfere with healthy behaviors," Ristvedt says.
Next, Ristvedt plans to extend his study to both colon and rectal cancers to see if the correlation between personality traits and symptom recognition can be replicated in larger groups and for the less-defined set of symptoms characteristic of colon cancer.

• Women's Health News, Published: 2004 June 14

Symptoms experienced by women that are more severe or frequent than expected and of recent occurrence warrant further diagnostic investigation because they are more likely to be associated with both benign (non-cancerous) and malignant (cancerous) ovarian masses, according to a study in the June 9 issue of the Journal of the American Medical Association (JAMA).
"Ovarian cancer has often been called the 'silent killer' because symptoms are not thought to develop until advanced stages when chance of cure is poor," the authors provide as background information in the article. The authors looked at previous research which found that "80 percent to 90 percent of women with early stage disease will report symptoms for several months prior to diagnosis." The authors continue, "Identification of early symptoms may have important clinical implications because 5-year survival for early stage disease is 70 percent to 90 percent compared with 20 to 30 percent for advanced-stage disease."
In this study, Barbara A. Goff, M.D., from the University of Washington School of Medicine, Seattle, and colleagues compared the frequency, severity, and duration of symptoms between women with ovarian masses (n=128) and women in the control group who visited two primary care clinics (n=1,709). The women were asked to complete an anonymous survey of symptoms experienced over the past year (July 2001 - January 2002). Severity of symptoms was rated on a 5-point scale, duration was recorded, and frequency was indicated as number of episodes per month.
"In the clinic population, 72 percent of women had recurring symptoms with a median (mid-point) number of two symptoms. The most common were back pain (45 percent), fatigue (34 percent), bloating (27 percent), constipation (24 percent), abdominal pain (22 percent), and urinary symptoms [urgency/frequency] (16 percent)," the researchers found. "Comparing ovarian cancer cases to clinic controls resulted in an [increased] odds ratio of 7.4 for increased abdominal size; 3.6 for bloating; 2.5 for urinary urgency; and 2.2 for pelvic pain. Women with malignant masses typically experienced symptoms 20 to 30 times per month and had significantly more symptoms of higher severity and more recent onset than women with benign masses or controls. The combination of bloating, increased abdominal size, and urinary symptoms was found in 43 percent of those with cancer but in only 8 percent of those presenting to primary care clinics."
"While our current study did find that women who present to primary care clinics frequently have vague symptoms that can be associated with ovarian cancer, the important difference is that these symptoms are less severe and less frequent when compared with women with ovarian cancer. Typically, symptoms occur 2 to 3 times per month and are often associated with menses, which may explain why these vague symptoms become less common and less severe as women age. In addition, women with ovarian cancer typically have symptoms of recent onset and have multiple symptoms that coexist. This study adds further evidence that ovarian cancer is not a silent disease," the authors conclude.

• Medical Study News , Published: 2004 Sept 08

A new study suggests that eating more vegetables, fruit and protein before pregnancy may lower the risk of having a child who develops leukemia, the most common childhood cancer in the United States.
"This is the first time researchers have conducted a systematic survey of a woman's diet and linked it to the risk of childhood leukemia," said Dr. Kenneth Olden, director of the National Institute of Environmental Health Sciences, the federal agency that funded the study. NIEHS is a component of the National Institutes of Health.
The study was conducted by researchers at the University of California, Berkeley, and the study results are published in the August 2004 issue of Cancer Causes and Control.
Researchers compared 138 women who each had a child diagnosed with acute lymphoblastic leukemia (ALL) with a control group of 138 women whose children did not have cancer. The children of all the women in the study were matched by sex, age, race, and county of residence at birth.
After comparing the women's diets in the 12 months prior to pregnancy, researchers found that the higher the intake of vegetables, fruit and foods in the protein group, the lower the risk of having a child with leukemia.
One of the more surprising results of the study is the emergence of protein sources, such as beef and beans, as a beneficial food group in lowering childhood leukemia risk. "The health benefits of fruits and vegetables have been known for a long time," said principal investigator Gladys Block, professor of epidemiology and public health nutrition at U.C. Berkeley. "What we found in this study is that the protein foods group is also very important."
The researchers looked further and found that glutathione was the nutrient in the protein group with a strong link to lower cancer risk. Glutathione is an antioxidant found in both meat and legumes, and it plays a role in the synthesis and repair of DNA, as well as the detoxification of certain harmful compounds.
Within the fruit and vegetable food groups, certain foods - including carrots, string beans and cantaloupe - stood out as having stronger links to lower childhood leukemia risk. The researchers point to the benefits of nutrients, such as carotenoids, in those foods as potential protective factors. National guidelines recommend that people eat at least five servings of fruits and vegetables every day, and two to three servings of foods from the protein group.
"Fetal exposure to nutritional factors has a lot to do with what mom eats," said Christopher Jensen, a nutritional epidemiologist at U.C. Berkeley and lead author of the paper. "These findings show how vital it is that women hoping to get pregnant, as well as expectant moms, understand that critical nutrients in vegetables, fruit and foods containing protein, such as meat, fish, beans and nuts, may protect the health of their unborn children."
The few studies that have been conducted on maternal diet and childhood cancer risk looked only at specific foods or supplements, and results have been mixed. This study is the first attempt to capture a woman's overall dietary pattern - using a 76-food-item questionnaire - and its relationship to the development of leukemia in a child. Researchers also studied the use of vitamin supplements, but did not find a statistically significant link to childhood leukemia risk.
A growing number of scientists believe that genetic changes linked to cancer later in life begin in the womb. "It goes back to the old saying to expectant mothers, 'You're eating for two,'" said co-author Patricia Buffler, U.C. Berkeley professor of epidemiology and head of the federally funded Northern California Childhood Leukemia Study. "We're starting to see the importance of the prenatal environment, since the events that may lead to leukemia are possibly initiated in utero. Leukemia is a very complex disease with multiple risk factors. What these findings show is that the nutritional environment in utero could be one of those factors."

• Medical Research News, Published: 2005 Mar 02

Liquorice - the black stuff we love to eat, contains a compound - glycyrrhizic acid which may stop people with a herpes virus from developing cancer. A research team at New York University found the compound - glycyrrhizic acid - possibly has the ability to stop the virus triggering a form of cancer called Kaposi sarcoma.
This form of cancer causes tumours to develop in tissues beneath the skins' surface and is usually found in people with a depressed immune system. Many of the viruses that infect people can remain dormant in cells for long periods and when they are reactivated, they can cause pain and distress. While progress for the treatment of active infections is good, treating latent infections remains difficult; progress has been slow.
The New York team showed that glycyrrhizic acid (GA) has the ability to kill cells harbouring the herpes virus associated with Kaposi sarcoma.
GA was able to disrupt the virus' ability to stay dormant in a cell, with the potential to trigger disease. It interferred with the production of crucial proteins and the delicate balance between virus and cell was destroyed, meaning death to the infected cells.
This the first time an anti-viral agent has been found that specifically targets the genes required to maintain the virus in a latent state.
It is a promising lead in the development of new drugs to combat latent viral infections.
Dr Jeffrey Cohen, from the US National Institutes Of Health, commented that liquorice, though a seemingly unlikely candidate for the treatment of virus-associated cancers, other traditional drugs have also proved highly effective for some infectious diseases.
Wormwood plant extracts, a traditional Chinese medication for the treatment of fevers, contain artemisinin - derivatives of this compound are first-line treatments for drug-resistant malaria.
Liquorice, derived from the root of Glycyrrhiza glabra, has been used for more than 4,000 years as a flavouring agent in foods, beverages, and tobacco and is also used as an alternative medicine for the treatment of gastric and duodenal ulcers, sore throat, bronchitis, cough, arthritis, adrenal insufficiency, and allergic diseases.

• Department of Health Care and Epidemiology, University of British Columbia, Published: 2006 Feb 21

Purpose: Epidemiological studies have found an inverse association between acute infections and cancer development. In this paper, we review the evidence examining this potentially antagonistic relationship. Methods: In addition to a review of the historical literature, we examined the recent epidemiological evidence on the relationship between acute infections and subsequent cancer development in adult life. We also discuss the impact of chronic infections on tumor development and the influence of the immune system in this process. Results: Exposures to febrile infectious childhood diseases were associated with subsequently reduced risks for melanoma, ovary, and multiple cancers combined, significant in the latter two groups. Epidemiological studies on common acute infections in adults and subsequent cancer development found these infections to be associated with reduced risks for meningioma, glioma, melanoma and multiple cancers combined, significantly for the latter three groups. Overall, risk reduction increased with the frequency of infections, with febrile infections affording the greatest protection. In contrast to acute infections, chronic infections can be viewed as resulting from a failed immune response and an increasing number have been associated with an elevated cancer risk. Conclusion: Infections may play a paradoxical role in cancer development with chronic infections often being tumorigenic and acute infections being antagonistic to cancer.

• Medical Studies/Trials, Published: Monday, 6-Mar-2006

Phoenix-based Biomarker Technologies announced the launch of a clinical study for its revolutionary blood test that detects breast cancer. Previous clinical studies have shown the test to significantly exceed the accuracy of mammograms.
The upcoming study will examine women's blood for a number of cancer related biomarkers, which are specific proteins having concentrations that are measurably different in patients with breast cancer. The BT Test is a first-of-its-kind blood diagnostic that detects the presence of breast cancer at the molecular level.
"We expect the results of this clinical study to demonstrate an even higher level of accuracy than either film or digital mammography," said William Gartner, CEO and President of Biomarker Technologies. "With this greatly improved diagnostic accuracy, the BT Test will ultimately become a critical tool in detecting breast cancer without the discomfort and inconvenience of a mammogram."
The study will involve 430 women referred for biopsy, 125 women referred for other types of cancer, and 300 healthy subjects. The study is expected to take four months to complete, with the collection of blood samples beginning in early March 2006.
Breast cancer is the leading cause of cancer in women, and studies have shown that early detection leads to a 97 percent, five-year survival rate. Gartner said that the BT test can provide higher sensitivity, a broader range of age applicability, and ease of administration and patient convenience while greatly increasing the number of early detections.
"This clinical study will move the BT Test forward in its FDA approval as first a supplementary and then a stand-alone screening tool for early breast cancer detection," said Gartner. "With fewer false negative and false positive diagnoses, this cost-effective blood test may not only offer vastly superior early-detection capabilities in routine examinations, but may also help patients avoid unnecessary needle biopsies."
The study will also examine using the BT Test together with the Riboflavin Carrier Protein biomarker from RCP Diagnostics LLC, which may enhance the sensitivity of the BT Test beyond the expected level of accuracy.

• Women's Health News, Published: Thursday, 29-Dec-2005

It was a good year in women's health, notably breast cancer treatment and detection. The December issue of Mayo Clinic Women's HealthSource hails these important advances of 2005.
Breast cancer treatment
The results of several clinical trials established the value of two types of breast cancer drugs in preventing breast cancer recurrence, significantly improving disease-free survival rates.
In two large clinical trials, trastuzumab (Herceptin), which has been available for women with advanced breast cancer, was found to help women with early-stage HER-2 positive breast cancer -- an aggressive form of the disease that tends to respond poorly to hormone treatment. Women with early-stage HER-2 positive breast cancer who received Herceptin in combination with standard chemotherapy treatment had a 52 percent decrease in breast cancer recurrence when compared with women receiving chemotherapy alone.
Other studies published this year showed aromatase inhibitors (AIs) are an effective hormone treatment for postmenopausal women with hormone-positive early-stage breast cancer.
That's significant because for at least two decades, the drug tamoxifen has been the gold standard add-on therapy used after initial treatment. Recent clinical trials have shown that AIs, which block an enzyme responsible for producing small amounts of estrogen in postmenopausal women, often show better disease-free survival rates than does tamoxifen alone or when used after several years of tamoxifen or as a first-line therapy for early-stage breast cancer.
Breast cancer detection
Several recent studies have shown that MRI --- which uses magnetic energy and intravenous material to create detailed images of the breast -- is significantly more sensitive than mammography in detecting breast cancers in high-risk women.
Researchers of a recent study concluded that combining MRI with mammography would pick up twice as many breast cancers in women at high risk. This advance is especially important for women with mutations on genes BRCA1 or BRCA2. They are typically at greater risk of developing breast cancer in their younger years, when dense breast tissue can make mammography X-rays difficult to interpret.

• Medical Study News, Published: Tuesday, 1-Nov-2005

A novel test for lung cancer uses inner cheek cells to identify the disease in high-risk patients.
In a new study presented at CHEST 2005, the 71st annual international scientific assembly of the American College of Chest Physicians (ACCP), scientists found that buccal mucosa, or cells scraped from the inner part of the cheek, may contain information that separates patients with lung cancer from high-risk negatives, a finding that may support cheek cell analysis as a simple and inexpensive early screening method for patients at risk for lung cancer.
"Previous research has shown that cell nuclear changes can extend a significant distance from the site of a malignancy. We have already conducted a successful clinical trial for our sputum test for lung cancer. New data suggest that the effects of lung cancer can also be measured as far away as skin cells in the mouth," said lead researcher Bojana Turic, MD, Director of Clinical and Regulatory Affairs, Perceptronix, Inc, Vancouver, BC, Canada. "Although a clinical test based on buccal cells is still in development, the method of analyzing cheek cells to detect cancer is showing interesting results."
Dr. Turic and colleagues analyzed randomized cheek scrapings of 150 confirmed lung cancer patients and 990 high-risk patients, using Automated Quantitative Cytometry (AQC). Able to detect subtle changes in buccal cell nuclei, the AQC system analyzes several thousand cells per specimen and reduces the data to a single score that predicts the likelihood of the presence of cancer. Of the buccal specimens collected, the AQC showed 66 percent sensitivity at 70 percent specificity overall, and 61 percent sensitivity for stage I lung cancer, which comprised 47 of the 150 cases.
"Stage I lung cancer is considered treatable, but most lung cancers are currently detected beyond stage I," said Dr. Turic. "We believe that early detection is the key to reducing lung cancer mortality and have focused our approach around detecting stage I lung cancer."
Although the test is not intended for screening the general population, researchers are hopeful that the AQC method will become an accurate, noninvasive, inexpensive, and easy-to-administer lung cancer detection test for patients at risk for lung cancer.
"A sufficient amount of cells can be collected by scraping the inside of the cheek with a small wooden spatula similar to a tongue depressor," said Dr. Turic. "Ultimately, this test could be administered in primary care settings or dental offices. The procedure is simple enough that specimen collection could be done by patients themselves." Researchers stress that additional clinical testing of the AQC method is needed, using a sufficient number and appropriate sample of patients in order to validate the test's performance.
Researchers have also developed a sputum test that utilizes the AQC method. They hope to receive Canadian regulatory approval in early 2006. Both tests are intended to provide pulmonary physicians with valuable information to help them manage patients at risk of developing or suspected of having lung cancer.
"Each year, great strides are made in the detection, diagnosis, and treatment of lung cancer," said W. Michael Alberts, MD, FCCP, President of the American College of Chest Physicians. "As with any new cancer screening or therapy, rigorous testing must be conducted in order to establish its safety and efficacy. Therefore, we must remain cautious but hopeful regarding new advances in their initial testing stages."

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