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Researchers Arul Chinnaiyan and Scott Tomlins. Researchers have identified a gene that is overexpressed in up to 20 percent of breast cancers and that could

be blocked in the lab by a currently available blood pressure drug. (Credit: University of Michigan Health System) 

University of Michigan Health System (2009, June 7). Breast Cancer Gene Can Be Blocked By Blood Pressure Drug. ScienceDaily  –  Researchers have identified a gene that is overexpressed in up to 20 percent of breast cancers and that could be blocked in the lab by a currently available blood pressure drug, according to a new study from the University of Michigan Comprehensive Cancer Center. 

The gene, called AGTR1, caused normal breast cells to behave like cancer cells. This behavior was reversed by treatment with the blood pressure drug losartan. Tumors in mice that expressed AGTR1 shrunk by 30 percent eight weeks after treatment with losartan, a drug approved by the U.S. Food and Drug Administration to treat high blood pressure.

“We suspect our analysis has uncovered a new crop of potentially important breast cancer genes. What’s also exciting is this gene is blocked by a drug that’s already available on the market,” says study author Arul Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology and S.P. Hicks Endowed Professor of Pathology at the U-M Medical School.

Results of the study appear online the week of June 1 in the Proceedings of the National Academy of Sciences.

The researchers looked at gene expression profiling data from nearly 3,200 microarrays available in the Oncomine database, a tool that allows rapid comparison of thousands of genes in human cancers. The researchers found genes that were dramatically overexpressed within subsets of tumors.

The gene that came up most often was ERBB2, which is better known as HER2, a gene that is overexpressed in 25 percent to 30 percent of all human breast cancers. HER2 is blocked by the targeted therapy Herceptin.

The next most commonly seen gene behind ERBB2 was AGTR1, which was seen in 10 percent to 20 percent of breast tumors. Specifically, AGTR1 was overexpressed only in tumors that were ERBB2-negative and that expressed the estrogen receptor, known as ER-positive. AGTR1 was found to be as much as 100-fold overexpressed in some tumors.

“AGTR1 is very analogous to HER2 or ERBB2. HER2 is a bona fide treatment target for patients with that type of breast cancer. This research defines a novel subtype of ER-positive breast cancer that we hope can be similarly targeted for treatment,” says Chinnaiyan, a Howard Hughes Medical Institute investigator.

The researchers tested in cell cultures and in mice the effect of losartan on AGTR1-positive tumors. When losartan was introduced, the AGTR1-positive tumors were reduced, while AGTR1-negative tumors were not affected. In the mice studies, losartan shrank AGTR1-positive tumors by 20 percent after two weeks and by 30 percent after eight weeks.

“Losartan may be a viable therapy for women with AGTR1 over-expressing breast tumors. This study lays the groundwork for a clinical trial to test losartan to treat breast cancers positive for AGTR1,” Chinnaiyan says.

Researchers are discussing a possible clinical trial, but one is not currently designed or recruiting for participants.

Additional authors include Daniel R. Rhodes, Bushra Ateeq, Qi Cao, Scott A. Tomlins, Rohit Mehra, Bharathi Laxman, Shanker Kalyana-Sundaram, Robert J. Lonigro, Beth E. Helgeson, Mahaveer S. Bhojani, Alnawaz Rehemtulla, Celina G. Kleer, Daniel F. Hayes, Peter C. Lucas and Sooryanarayana Varambally.

Funding was provided by the Department of Defense Era of Hope Scholar Award, Early Detection Research Network Biomarker Devleopmental Lab, Department of Defense, U-M Cancer Center Bioinformatics Core, Rackham Predoctoral Fellowship, Clinical Translational Research Award from the Burroughs Welcome Foundation and Doris Duke Charitable Foundation Distinguished Clinical Scientist Award. Losartan was provided by Merck U.S.A.

The University of Michigan has filed a patent on AGTR1 and is currently seeking a commercial partner to help bring this technology to market.

Breast cancer statistics: 194,280 Americans will be diagnosed with breast cancer this year and 40,610 will die from the disease, according to the American Cancer Society.

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June 8, 2009

Influenza A(H1N1) – update 45

As of 06:00 GMT, 8 June 2009, 73 countries have officially reported 25,288 cases of influenza A(H1N1) infection, including 139 deaths.

Nanoviricides, Inc. has recently announced a novel treatment for flu that isn’t dodged by the influenza virus’s exceptional ability to mutate. Their drug, FluCide, functions by targeting viruses in the bloodstream and lungs. It then neutralizes and disables the viral particles, regardless of strain. This could be more effective than antibody treatments because antibodies are extremely specific and unable to bind viruses that have a high rate of mutation. It also has an advantage over vaccines because they also utilize antibodies to treat viral infections. FluCide is particularly interesting and relevant at this point in time because of the recent outbreak of swine flu in various areas of the United States. Swine flu is a highly variable type of infection because pigs are able to act as a transitional species for influenze viruses. This means that the genes of various types of flu (bird, human, and swine) can be re-assorted in their bodies, which creates extremely variable viruses that are particularly resistant to traditional treatment. FluCide is still in the process of being tested, but if it passes, it would change the way shifty flu infections are treated. 

Interesting links

http://www.nanoviricides.com/products.html 

http://www.azonano.com/news.asp?newsID=11122

BiologyNews.net, June 8, 2009  —  The results of a new analysis have provided good evidence to suggest that Tai Chi is beneficial for arthritis. Specifically, it was shown to decrease pain with trends towards improving overall physical health, level of tension and satisfaction with health status.

Musculoskeletal pain, such as that experienced by people with arthritis, places a severe burden on the patient and community and is recognized as an international health priority. Exercise therapy including such as strengthening, stretching and aerobic programs, have been shown to be effective for arthritic pain. Tai Chi, is a form of exercise that is regularly practiced in China to improve overall health and well-being. It is usually preformed in a group but is also practiced individually at one’s leisure, which differs from traditional exercise therapy approaches used in the clinic.

Recently, a new study examined the effectiveness of Tai Chi in decreasing pain and disability and improving physical function and quality of life in people with chronic musculoskeletal pain. The study is published in the June issue of Arthritis Care & Research (http://www3.interscience.wiley.com/journal/77005015/home). Led by Amanda Hall of The George Institute in Sydney, Australia, researchers conducted a systematic review and meta-analysis. They analyzed seven eligible randomized controlled trials that used Tai Chi as the main intervention for patients with musculoskeletal pain. The results demonstrate that Tai Chi improves pain and disability in patients suffering arthritis.

The authors state, “The fact that Tai Chi is inexpensive, convenient, and enjoyable and conveys other psychological and social benefits supports the use this type of intervention for pain conditions such as arthritis.”

“It is of importance to note that the results reported in this systematic review are indicative of the effect of Tai Chi versus minimal intervention (usual health care or health education) or wait list control,” the authors note. Establishing the specific effects of Tai Chi would require a placebo-controlled trial, which has not yet been undertaken.

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It turns out that from the perspective of cell biology, Nietzsche may have been right after all: that which does not kill us does make us stronger. In a review article published in the June 2009 print issue of The FASEB Journal (http://www.fasebj.org), scientists from the Mayo Clinic explain how cell receptors (called “death receptors”) used by the body to shut down old, diseased, or otherwise unwanted cells (called “apoptosis”) may also be used to make cells heartier when facing a wide range of illnesses, from liver disease to cancer.

“Increasing our knowledge of how death receptors function will allow us to develop better and more effective therapies for several human diseases,” said Gregory J. Gores, M.D., Chair of the Division of Gastroenterology and Hepatology at the Mayo Clinic in Rochester, Minn., and one of the scientists involved in the work.

In their article, Gores and his colleague, Maria Guicciardi, also from the Mayo Clinic, described the various molecular pathways activated by death receptors and the proteins involved in the process. Specifically, they looked at how these proteins interact with each other and how they redistribute within a cell. Death receptors are an essential tool for the immune system to eliminate cells that have been overtaken by viruses, undergone potentially harmful genetic modifications, or have become too old to function properly. Understanding the exact sequence of events that occurs after death receptors are activated, including identifying key proteins involved in the processes, may allow researchers to develop entirely new therapeutics. These therapeutics not only would give doctors the ability to choose when and if certain cells are taken out of service, but they would also give doctors the ability to trigger cells to shift into “survival mode.”

“As far as names are concerned, nothing in biology sounds more intimidating than ‘death receptors,'” said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. “Fortunately for us, when scientists look at the intricate machinery of how cells die, they dig up clues to longer, healthier lives.”

Source : Federation of American Societies for Experimental Biology

It turns out that from the perspective of cell biology, Nietzsche may have been right after all: that which does not kill us does make us stronger. In a review article published in the June 2009 print issue of The FASEB Journal (http://www.fasebj.org), scientists from the Mayo Clinic explain how cell receptors (called “death receptors”) used by the body to shut down old, diseased, or otherwise unwanted cells (called “apoptosis”) may also be used to make cells heartier when facing a wide range of illnesses, from liver disease to cancer.

“Increasing our knowledge of how death receptors function will allow us to develop better and more effective therapies for several human diseases,” said Gregory J. Gores, M.D., Chair of the Division of Gastroenterology and Hepatology at the Mayo Clinic in Rochester, Minn., and one of the scientists involved in the work.

In their article, Gores and his colleague, Maria Guicciardi, also from the Mayo Clinic, described the various molecular pathways activated by death receptors and the proteins involved in the process. Specifically, they looked at how these proteins interact with each other and how they redistribute within a cell. Death receptors are an essential tool for the immune system to eliminate cells that have been overtaken by viruses, undergone potentially harmful genetic modifications, or have become too old to function properly. Understanding the exact sequence of events that occurs after death receptors are activated, including identifying key proteins involved in the processes, may allow researchers to develop entirely new therapeutics. These therapeutics not only would give doctors the ability to choose when and if certain cells are taken out of service, but they would also give doctors the ability to trigger cells to shift into “survival mode.”

“As far as names are concerned, nothing in biology sounds more intimidating than ‘death receptors,'” said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. “Fortunately for us, when scientists look at the intricate machinery of how cells die, they dig up clues to longer, healthier lives.”

Source : Federation of American Societies for Experimental Biology

June 2009  —  A recent outbreak of Clostridium difficile in Mississippi has demonstrated the potentially deadly rise of antibiotic-resistance in bacteria today. While C. difficile is often inhibited by antibiotics, these cases displayed an unusually high amount of resistance to common antibacterial agents. Instead, the drugs inhibited large amounts of healthy bacteria in the digestive tract of the patients. The overuse of antibiotics and the evolution of these “super-bugs” has urged scientists to look into the development of new drugs targeting new parts of bacterial cells. Unfortunately, C. difficile is becoming more common and more deadly in hospitals around the nation. Not only is this bacteria showing resistance to antibiotic agents, but it is becoming more and more virulent, secreting higher levels of toxins than earlier strains. The prospect of hypervirulent, severe strains of evolved bacteria is something that doctors and medical researchers will need to address as soon as possible.

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Stuart Bradford

The New York Times, June 8, 2009, by Tara Parker-Pope  —  Earlier this year, Harold and Freda Mitchell of Como, Miss., both came down with a serious stomach bug. At first, doctors did not know what was wrong, but the gastrointestinal symptoms became so severe that Mrs. Mitchell, 66, was hospitalized for two weeks. Her husband, a manufacturing supervisor, missed 20 days of work.

A local doctor who had worked in a Veterans Affairs hospital recognized the signs of Clostridium difficile, a contagious and potentially deadly bacterium. Although the illness is difficult to track, health officials estimate that in the United States the bacteria cause 350,000 infections each year in hospitals alone, with tens of thousands more occurring in nursing homes. While the majority of cases are found in health care settings, 20 percent or more may occur in the community. The illness kills an estimated 15,000 to 20,000 people annually.

“It’s been the worst thing I’ve ever tried to get through in my life,” said Mrs. Mitchell, who remains weakened by the ordeal. “I really did think I was going to die.”

What is so frightening about C. difficile is that it is often spurred by antibiotics. The drugs wipe out the targeted illness, like a urinary tract or upper respiratory infection, but they also kill off large portions of the healthy bacteria that normally live in the digestive tract. If a person comes into contact with C. difficile, or already has it, the disruption to the beneficial bacteria creates an opportunity for the harmful bacteria to flourish.

The public health community has been sounding the alarm for years about the overuse of antibiotics and the emergence of “superbugs” – bacteria that have developed immunity to a wide number of antibiotics. But the C. difficile problem shows that the threat is not generalized or hypothetical, but immediate and personal.

“One of the things that we counsel consumers about is to make sure that an antibiotic is really necessary,” said Dr. Dale N. Gerding, an infectious disease specialist at the Stritch School of Medicine at Loyola University in Chicago. “There are many good reasons for taking an antibiotic, but an illness like sinusitis or bronchitis winds up being treated with antibiotics even though it will go away by itself anyway.”

Even appropriate use of antibiotics can put a person at risk. Dr. Gerding said his own adult son came down with a C. difficile infection after taking antibiotics for tonsillitis.

The typical treatment for C. difficile is another course of antibiotics, typically the drug vancomycin. But the situation can quickly turn tragic. The Centers for Disease Control and Prevention has reported on several cases of pregnant and postpartum women who developed life-threatening C. difficile infections after being treated for minor infections. In some instances, a C. difficile infection can be treated only by emergency surgery to remove the patient’s colon. Doctors say many patients report that they continue to suffer from regular bouts of diarrhea even after the infection is gone. About 20 percent of patients with the infection suffer a relapse, and C. difficile support groups have emerged on the Internet.

In the case of the Mitchell family, Mr. Mitchell had been taking antibiotics for another health problem, and the treatment apparently led to his C. difficile infection. Mrs. Mitchell probably contracted the illness from her husband. The spores from C. difficile are hardy, and contaminated surfaces must be scrubbed down with bleach to eradicate the germ. Doctors say Mrs. Mitchell’s illness is unusual because most people are protected by their own bacterial flora and wouldn’t be vulnerable to C. difficile if they had not been taking antibiotics, even after close exposure. The risk of contracting C. difficile outside the health care setting remains low, at about 7 cases per 100,000 people, studies show.

C. difficile is not a new illness, but it appears to be spreading at an alarming rate. The rate of C. difficile infection among hospital patients doubled from 2001 to 2005, according to an April 2008 report from the C.D.C. The rise in C. difficile cases around the world is linked with the growing use of all antibiotics, particularly a class of drugs called fluoroquinolones, which came into widespread use around 2001. The use of acid-suppressing drugs, including proton pump inhibitors like Prilosec, also may be a risk factor, although studies have been contradictory.

In addition to becoming more common, C. difficile is also becoming more deadly. Several years ago, the mortality rate from a C. difficile infection was around 1 to 2 percent. But today, various studies estimate that the death rate is 6 percent. The reason is that a hypervirulent strain has emerged that emits higher levels of toxins than earlier strains.

Many patients are far more familiar with another superbug, methicillin-resistant Staphylococcus aureus, or MRSA, which can cause a severe and potentially deadly skin infection. MRSA started off primarily as a hospital-based infection but has become increasingly common in the community.

Hospitals may become more motivated to control C. difficile if the Centers for Medicare and Medicaid Services decides to withhold reimbursement for cases of hospital-acquired C. difficile infections. The system already withholds reimbursement for certain other preventable hospital infections.

In addition to careful use of antibiotics, patients and hospital visitors should always be vigilant about hand washing, and visitors should not sit on a patient’s hospital bed or use a patient’s restroom if it can be avoided. Patients should always report severe diarrhea symptoms to a doctor, particularly if they have taken antibiotics recently.

“Up until about 2002, this was a very mild disorder and very few people ever died from it,” said Dr. Perry Hookman, a gastroenterologist and associate professor of medicine at the Miller School of Medicine at the University of Miami. “But in the past few years the bugs have become hypervirulent, more severe and now it’s a global threat.”

BiologyNews.net, June 8, 2009  —  A mineral found in health food stores could be the key to developing a new line of antibiotics for bacteria that commonly cause diarrhea, tooth decay and, in some severe cases, death.

The trace mineral selenium is found in a number of proteins in both bacterial cells and human cells called selenoproteins. University of Central Florida Associate Professor William Self’s research shows that interrupting the way selenoproteins are made can halt the growth of the super bug Clostridium difficile and Treponema denticola, a major contributor to gum disease.

Infections of Clostridium difficile (commonly known as C-diff) lead to a spectrum of illnesses ranging from severe diarrhea to colitis, which can cause death. It’s a life-threatening problem in hospitals and nursing homes worldwide, and the number of cases is on the rise. There are an estimated 500,000 cases per year in the United States alone. Between 15,000 to 20,000 people die each year while infected with this superbug. Treponema denticola is one of leading causes of gum disease and costs individuals thousands of dollars in dental care each year.

Self’s findings are published in the May and June editions of the Journal of Biological Inorganic Chemistry and the Journal of Bacteriology. The National Institutes of Health and the Florida Department of Health funded the research, which was conducted at UCF during the past three years.

“It’s the proof of principle that we are excited about,” Self said from his research lab at UCF. “No one has ever tried this approach, and it could potentially be a source for new narrow spectrum antibiotics that block bacteria that require selenium to grow.”

The key discovery occurred when the team found that the gold drug Auranofin, used to treat arthritis, impacted selenium’s metabolism process. The chemical reaction changes the selenium, which prevents bacteria from using it to grow. Auranofin is an FDA-approved gold salt compound that is used to control inflammation and is already known to inhibit the activity of certain selenoproteins. Since certain bacteria, such as C. difficile, require selenoproteins for energy metabolism, the drug acts as a potent antimicrobial halting the growth of the bacteria.

The initial studies with C. difficile led to studies with T. denticola, known for several years to require selenium for growth. While testing the gold salt, Self’s group also uncovered another surprise; the stannous salts found in many antimicrobial toothpastes in the form of stannous fluoride also inhibited the synthesis of selenoproteins. Previous independent research had already established that stannous salts are more effective at preventing tooth decay and inhibiting growth of T. denticola, but the mechanism of this inhibition of growth was not yet known. These findings could lead to new approaches to preventing gum disease.

“No one has tried to block the metabolism of selenium before as a therapeutic approach,” Self said. “That’s what’s new and exciting and could lead to a whole host of other possibilities, including a better understanding of how the gold salt works for arthritis.”

Self said more research is needed, and he already has another grant proposal before the NIH that would move his research forward.

Source : University of Central Florida