Screen Developed to Identify New Anticancer Drug Targets

Tumor suppressor genes normally control the growth of cells, but cancer can spring up when these genes are silenced by certain chemical reactions that modify chromosomes. Among the most common culprits responsible for inactivating these genes are histone deacetylases, a class of enzymes that remove acetyl groups from DNA-scaffolding proteins, and DNA methyltransferases, a family of enzymes that add methyl groups to DNA.

Drugs that counteract these enzymes, and thus reactivate tumor suppressor genes, are promising cancer therapies. For example, histone deacetylase inhibitors have been approved for the treatment of a type of T cell lymphoma, and are being tested in clinical trials for the treatment of a wide range of cancers. Similarly, DNA methyltransferase inhibitors have been approved to treat a certain kind of leukemia, and are undergoing clinical studies for the treatment of other cancers. But these medications can have serious side effects.

Now, Fox Chase Cancer Center postdoctoral associate Andrey Poleshko, PhD, along with Research Professor Richard A. Katz, PhD, and their colleagues have developed a screen to identify proteins that work in conjunction with these enzymes to repress gene expression. They will present their results at the AACR 102nd Annual Meeting 2011 on Tuesday, April 5.

Finding additional proteins that inactivate tumor suppressor genes, and understanding how they work, could lead to the broadening of this class of therapies beyond the two enzyme families, Poleshko said. "If we can find a way to block the action of such proteins, it may be possible to reactivate aberrantly silenced tumor suppressor genes and restore controlled growth in certain cancer cells," he noted. Such an approach would avoid interfering directly with the vital chromosome-modifying enzymes.

The researchers genetically programmed human cells to glow fluorescent green upon reactivation of the silent genes they harbor. By shutting down the activity of genes one by one and observing whether cells turned green, they were able to identify factors that help to suppress gene expression.

The method was efficient enough to permit screening of the entire genome, including 21,122 genes, and revealed 128 factors that are involved in regulating gene expression.

Research Assistant Professor Margret B. Einarson and Professor Anna Marie Skalka from Fox Chase are co-authors on the study.

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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Fox Chase Cancer Center, via EurekAlert!, a service of AAAS.

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Computational Software Provides Rapid Identification of Disease-Causing Gene Variations

Scientists from the University of Utah and Omicia, Inc., a privately held company developing tools to interpret personal genome sequences, have announced the publication in Genome Research of a new software tool called VAAST, the Variant Annotation, Analysis and Selection Tool -- a probabilistic disease-causing mutation finder for individual human genomes.'

The dramatic decline in DNA sequencing costs is making personal genome sequencing a reality. Already, significant progress has been made in applying whole genome sequencing to cancer prognosis and early childhood disease. Examples include the 2010 publications on Miller Syndrome in Nature Genetics and Science, and similar studies aimed at identifying the unknown genetic defects responsible for some early childhood diseases.

However, a data interpretation bottleneck has limited the utility of personal genome information for medical diagnosis and preventive care. VAAST is a new algorithm to assist in overcoming this bottleneck. VAAST is the product of a collaboration between Mark Yandell, Ph.D., Associate Professor of Human Genetics at the University of Utah School of Medicine, and colleagues, and the Omicia scientific team under the leadership of Martin Reese, Ph.D., the company's CEO and Chief Scientific Officer.

In the Genome Research paper, Yandell and colleagues show that VAAST provides a highly accurate, statistically robust means to rapidly search personal genomes for genes with disease-causing mutations. The authors demonstrate that as few as three genomes from unrelated children, or those of the parents and their two children, are sufficient to identify disease causing mutations.

"The big challenge in genomic medicine today is how to sift through the millions of variants in a personal genome sequence to identify the disease-relevant variations," said Dr. Reese. "It's a classic needle in a haystack problem, and VAAST goes a long way toward solving it. We look forward to integrating VAAST into the Omicia Genome Analysis System currently under development for clinical applications."

Dr. Yandell added: "VAAST solves many of the practical and theoretical problems that currently plague mutation hunts using personal genome sequences. Our results demonstrate that this tool substantially improves upon existing methods with regard to statistical power, flexibility, and scope of use. Further, VAAST is automated, fast, works across all variant population frequencies and is sequencing platform independent."

In a separate paper published this week in the American Journal of Human Genetics, Gholson Lyon, M.D., Ph.D., previously at University of Utah and now at the Children's Hospital of Philadelphia, and colleagues report the use of VAAST as part of an international effort to identify the mutation responsible for a newly discovered childhood disease. This new illness, which they are tentatively calling Ogden Syndrome, is characterized by aged appearance, craniofacial abnormalities, cardiac arrhythmias and other symptoms. The team used X-chromosome exon capture and next-generation sequencing and the VAAST tool to quickly and unambiguously identify the disease-causing mutation in the NAA10 gene that has resulted in this fatal disease in children of two unrelated families.

"VAAST can identify disease-causing mutations with greater accuracy, using far fewer individuals and more rapidly than was previously possible," said Dr. Lyon. "We are now applying VAAST to many other unknown conditions, including rare Mendelian disorders and other common disorders such as ADHD and autism."

Commenting on the significance of this development, Eric J. Topol, M.D., Director, Scripps Translational Science Institute and Chief Academic Officer, Scripps Health, commented: "One of most important and exciting opportunities in genomic medicine is the newfound ability to pinpoint the root cause of an unknown idiopathic disease in an individual. The VAAST tool will markedly facilitate this and represents a major advance in the field. It fulfills a significant unmet need of interpreting whole genome sequences and will have a remarkable impact on accurate genomic diagnosis of many individuals going forward."

The development of VAAST was funded by the National Human Genome Research Institute through an American Recovery and Reinvestment Act Grand Opportunity (GO) grant. GO grants focus on transformative technologies and large, potentially high-impact projects.

Journal References:

1. Mark Yandell, Chad D. Huff, Hao Hu, Marc Singleton, Barry Moore, Jinchuan Xing, Lynn B. Jorde, Martin G. Reese. A probabilistic disease-gene finder for personal genomes. Genome Research, 2011; DOI: 10.1101/gr.123158.111
2. Alan F. Rope, Kai Wang, Rune Evjenth, Jinchuan Xing, Jennifer J. Johnston, Jeffrey J. Swensen, W. Evan Johnson, Barry Moore, Chad D. Huff, Lynne M. Bird, John C. Carey, John M. Opitz, Cathy A. Stevens, Tao Jiang, Christa Schank, Heidi Deborah Fain, Reid Robison, Brian Dalley, Steven Chin, Sarah T. South, Theodore J. Pysher, Lynn B. Jorde, Hakon Hakonarson, Johan R. Lillehaug, Leslie G. Biesecker, Mark Yandell, Thomas Arnesen, Gholson J. Lyon. Using VAAST to Identify an X-Linked Disorder Resulting in Lethality in Male Infants Due to N-Terminal Acetyltransferase Deficiency. American Journal of Human Genetics, 2011; DOI: 10.1016/j.ajhg.2011.05.017

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Artificial Pancreas Being Developed to Ease Diabetes Burden

The 25.8 million Americans who have diabetes may soon be free of finger pricks and daily insulin dosing. Mayo Clinic endocrinologists Yogish Kudva, M.B.B.S., and Ananda Basu, M.B.B.S., M.D., are developing an artificial pancreas that will deliver insulin automatically and with an individualized precision never before possible.

As part of this effort, Drs. Kudva and Basu will present their latest findings on how the mundane movements of everyday life affect blood sugar to the American Diabetes Association meeting this month in San Diego.

"The effects of low-intensity physical activity, mimicking activities of daily living, measured with precise accelerometers on glucose variability in type 1 diabetes had not been examined," says Dr. Kudva.

Among his newest findings is that even basic physical activity after meals has a profound impact on blood sugar levels for people with type 1 diabetes. "You would expect this result, but we wanted to know to what extent this phenomena would happen in people with type 1 diabetes," Dr. Kudva says.

Diabetics who engaged in low-grade physical activity after eating had blood sugar levels close to those of people with fully functioning pancreases. Those who remained sedentary after their meal, however, had elevated blood sugars.

The researchers plan to incorporate these findings into an artificial pancreas being developed at Mayo Clinic. The "Closed Loop System" under development includes a blood sugar monitor, an automatic insulin pump, a set of activity monitors that attach to the body and a central processing unit.

Clinical trials of the artificial pancreases are likely to begin in November with a handful of inpatient volunteers. Study participants will follow strict diet, exercise and insulin-delivery regimens in Mayo's Clinical Research Unit. Data will then be fed into an insulin-delivery algorithm, which mimics the body's natural process of monitoring and responding to glucose levels in the bloodstream.

"Physical activity enhances insulin action, hence lowering blood glucose concentration," Dr. Kudva says. "Real-time detection of physical activity -- and modeling of its effect on glucose dynamics -- is vital to design an automatic insulin delivery system."

Dr. Kudva and other Mayo researchers have spent nearly 15 years working on various aspects of diabetes and obesity. They are collaborating on the artificial pancreas and developing an algorithm that will afford patients the peace of mind to eliminate their daily routine of diabetes maintenance.

Dr. Basu will present findings that blood sugar levels decrease faster in the mornings in healthy adults than at dinner time, suggesting a diurnal pattern to natural insulin action. He proposes further study of this phenomenon and possible incorporation into the algorithm that drives the Closed Loop System.

The research has been funded by grants from the National Institutes of Health.

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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Mayo Clinic.

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Chirality: New Method to Consistently Make Left-Handed or Right-Handed Molecules

Many organic molecules are non-superimposable with their mirror image. The two forms of such a molecule are called enantiomers and can have different properties in biological systems. The problem is to control which enantiomer you want to produce -- a problem that has proved to be important in the pharmaceutical industry. Researchers at the University of Gothenburg have now come up with a new method to control the process.

"Organic chemists think that it's impossible to create only one of the enantiomers without introducing some kind of optical activity into the reaction, but I've succeeded," says Theonitsa Kokoli at the University of Gothenburg's Department of Chemistry. "My method will allow the industry to produce the version they want without the use of a catalyst."

The phenomenon of non-superimposable mirror-image molecular structures is known as chirality. The two enantiomers can be compared to a pair of hands; they are non-superimposable mirror images of each other. A consequence of the different properties in biological systems is that a molecule can behave either as Dr Jekyll or Mr Hyde. The different characteristics in the enantiomers can be harmless, like in the limonene molecule. One enantiomer smells like orange and the other like lemon.

Thalidomide is a good example of how different forms of the same molecule can have disastrous consequences. One of the enantiomers was calming and eased nausea in pregnant women, while the other caused serious damage to the fetus. The thalidomide catastrophe is one of the reasons that a lot of research is devoted to chirality, as it is absolutely vital to be able to control which form of the molecule that is produced. Research on chirality has resulted in several Nobel Prizes over the years.

In biomolecules like DNA and proteins only one of the enantiomers exists in nature. In contrast to biomolecules, the same does not apply when chiral compounds are created synthetically in the lab. Generally an equal amount of both enantiomers is produced. One way of creating an excess of one enantiomer is to use a chiral catalyst, but this only transfers the properties that are already present in the catalyst.

"I've been working with absolute asymmetric synthesis instead, where optical activity is created," says Kokoli. "This is considered impossible by many organic chemists. I've used crystals in my reactions, where the two forms have crystallised as separate crystals, which in itself is fairly unusual. The product that was formed after the reactions comprised just one enantiomer."

While the results of Kokoli's research are particularly significant for the pharmaceuticals industry, they can also be used in the production of flavourings and aromas.

The thesis has been successfully defended on May 6, 2011.

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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by University of Gothenburg.

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Tapeworm Drug Inhibits Colon Cancer Metastasis

A compound that for about 60 years has been used as a drug against tapeworm infection is also apparently effective against colon cancer metastasis, as studies using mice have now shown. The compound silences a gene that triggers the formation of metastases in colon cancer.

Professor Ulrike Stein (Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine, (MDC)) and her research group made this discovery in collaboration with Professor Robert H. Shoemaker of the National Cancer Institute (NCI) in Frederick, Maryland. The results are reported in the Journal of the National Cancer Institute. Plans are already underway with Professor Peter M. Schlag (Charité Comprehensive Cancer Center) to conduct a clinical trial.

Colon cancer is one of the most common tumor diseases in Western countries. In Germany alone, there are approximated 73 000 new cases of the disease every year. Despite surgery, chemotherapy and radiation therapy, only about half of the affected patients are cured.

The reason is that around 20 percent of the colon cancer patients already have metastases at diagnosis and in about one third of the patients, metastasis occurs despite successful initial treatment. Of these patients with metastatic colon cancer, the five-year survival rate is only about 10 percent. By contrast, for nonmetastatic colon cancer patients the survival rate is 90 percent.

Scientists have known for several years that the gene S100A4/metastasin can initiate colon cancer metastasis. Five years ago Professor Stein, working together with Professor Schlag and Professor Walter Birchmeier (MDC), showed how this gene is regulated. They found that the beta-catenin gene, when mutant, activates this S100A4/metastasin gene, thus triggering colon cancer metastasis. Beta-catenin normally regulates cellular adhesion.

The scientists looked for compounds that block the expression of the metastasin gene. They screened 1280 compounds and found what they were looking for: niclosamide, a drug until now approved for use to treat intestinal parasite infections from tapeworms.

Surprisingly, the researchers discovered that niclosamide inhibits the beta catenin-driven expression of the S100A4/metastasin gene, both in the cell culture and in mice. The animals had fewer metastases. Next, the researchers want to conduct clinical trials to find out whether the compound is also effective in patients with metastasizing colon cancer.

Journal Reference:

1. Ulrike Sack, Wolfgang Walther, Dominic Scudiero, Mike Selby, Dennis Kobelt, Margit Lemm, Iduna Fichtner, Peter M. Schlag, Robert H. Shoemaker, Ulrike Stein. Novel Effect of Antihelminthic Niclosamide on S100A4-Mediated Metastatic Progression in Colon Cancer. Journal of the National Cancer Institute, 2011; DOI: 10.1093/jnci/djr190

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Progress Using Induced Pluripotent Stem Cells to Reverse Blindness

Researchers have used cutting-edge stem cell technology to correct a genetic defect present in a rare blinding disorder, another step on a promising path that may one day lead to therapies to reverse blindness caused by common retinal diseases such as macular degeneration and retinitis pigmentosa which affect millions of individuals.

In a study appearing in an advance online publication of the journal Stem Cells on June 15, 2011, investigators used recently developed technology to generate induced pluripotent stem (iPS) cells from a human patient with an uncommon inherited eye disease known as gyrate atrophy. This disorder affects retinal pigment epithelium (RPE) cells, the cells critical to the support of the retina's photoreceptor cells, which function in the transmission of messages from the retina to parts of the brain that interpret images.

"When we generate iPS cells, correct the gene defect that is responsible for this disease, and guide these stem cells to become RPE cells, these RPE cells functioned normally. This is exciting because it demonstrates we can fix something that is out of order. It also supports our belief that in the future, one might be able to use this approach for replacement of cells lost or malfunctioning due to other more common diseases of the retina," said lead study author cell biologist Jason Meyer, Ph.D., assistant professor of biology in the School of Science at Indiana University-Purdue University Indianapolis.

Macular degeneration is the most common cause of blindness, affecting an estimated 25-30 million people worldwide. One and a half million people worldwide are affected by retinitis pigmentosa.

Because iPS cells can be derived from the specific patient who needs them, use of these cells may avoid the problem of transplant rejection. In the study, vitamin B-6 also was used to treat the damaged RPE cells producing healthy cells that functioned normally. The retina is a relatively easily accessible part of the central nervous system, which makes it an attractive target for correction with iPS cells. Researchers are hopeful that once the gene defect responsible for a blinding disorder is corrected in iPS cells, these cells may be able to restore vision.

In addition to Meyer of the School of Science at IUPUI, "Optic Vesicle-like Structures Derived from Human Pluripotent Stem Cells Facilitate a Customized Approach to Retinal Disease Treatment" is co-authored by Sara E. Howden, Kyle A. Wallace, Amelia D. Verhoeven, Lynda S. Wright, Elizabeth E. Capowski, Jessica M. Martin, Shulan Tian, Ron Stewart, Bikash Pattnaik, James Thomson and David M. Gamm, all of the University of Wisconsin; and Isabel Pinilla of Blesa University Hospital and the Instituto Aragones de Ciencias de la Salud in Spain. Meyer is also a primary investigator with the Stark Neurosciences Research Institute at Indiana University School of Medicine. Thomson is also associated with the University of California -- Santa Barbara.

Journal Reference:

1. Jason S. Meyer, Sara E. Howden, Kyle A. Wallace, Amelia D. Verhoeven, Lynda S. Wright, Elizabeth E. Capowski, Isabel Pinilla, Jessica M. Martin, Shulan Tian, Ron Stewart, Bikash Pattnaik, James Thomson, David M. Gamm. Optic Vesicle-like Structures Derived from Human Pluripotent Stem Cells Facilitate a Customized Approach to Retinal Disease Treatment. Stem Cells, 2011; DOI: 10.1002/stem.674

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Eight Substances Added to U.S. Report on Carcinogens, Including Formaldehyde, May Increase Cancer Risk

The U.S. Department of Health and Human Services has added eight substances to its Report on Carcinogens, a science-based document that identifies chemicals and biological agents that may put people at increased risk for cancer.

The industrial chemical formaldehyde and a botanical known as aristolochic acids are listed as known human carcinogens. Six other substances -- captafol, cobalt-tungsten carbide (in powder or hard metal form), certain inhalable glass wool fibers, o-nitrotoluene, riddelliine, and styrene -- are added as substances that are reasonably anticipated to be human carcinogens. With these additions, the 12th Report on Carcinogens now includes 240 listings. It is available at http://ntp.niehs.nih.gov/go/roc12.

"Reducing exposure to cancer-causing agents is something we all want, and the Report on Carcinogens provides important information on substances that pose a cancer risk," said Linda Birnbaum, Ph.D., director of both the National Institute of Environmental Health Sciences (NIEHS) and the National Toxicology Program (NTP). "The NTP is pleased to be able to compile this report."

John Bucher, Ph.D., associate director of the NTP added, "This report underscores the critical connection between our nation's health and what's in our environment."

The Report on Carcinogens is a congressionally mandated document that is prepared for the HHS Secretary by the NTP. The report identifies agents, substances, mixtures, or exposures in two categories: known to be a human carcinogen and reasonably anticipated to be a human carcinogen. A listing in the Report on Carcinogens does not by itself mean that a substance will cause cancer. Many factors, including the amount and duration of exposure, and an individual's susceptibility to a substance, affect whether a person will develop cancer.

Once a substance is nominated by the public or private sector and selected for consideration, it undergoes an extensive evaluation with numerous opportunities for scientific and public input. There were at least six opportunities for public input on each substance. The NTP used established criteria to evaluate the scientific evidence on each candidate substance under review. The NTP drew upon the scientific expertise of several federal agencies, including the National Institutes of Health, Centers for Disease Control and Prevention, Agency for Toxic Substances and Disease Registry, U.S. Food and Drug Administration, U.S. Environmental Protection Agency, U.S. Consumer Product Safety Commission, and Occupational Safety and Health Administration.

"The strength of this report lies in the rigorous scientific review process," said Ruth Lunn, Dr.P.H., director of the NTP Office of the Report on Carcinogens. "We could not have completed this report without the significant input we received from the public, industry, academia, and other government agencies."

A detailed description of each substance listed in the Report on Carcinogens is included in the new report.

Two known human carcinogens:

Aristolochic acids have been shown to cause high rates of bladder or upper urinary tract cancer among individuals with kidney or renal disease who consumed botanical products containing aristolochic acids. Aristolochic acids are a family of acids that occur naturally in some plant species. Despite a warning issued in 2001 by the U.S. Food and Drug Administration that advised consumers to discontinue use of any botanical products containing aristolochic acids, they can still be purchased on the Internet and abroad, and may be found as a contaminant in herbal products used to treat a variety of symptoms and diseases, such as arthritis, gout, and inflammation.

Formaldehyde was first listed in the 2nd Report on Carcinogens as a substance that was reasonably anticipated to be a human carcinogen, after laboratory studies showed it caused nasal cancer in rats. There is now sufficient evidence from studies in humans to show that individuals with higher measures of exposure to formaldehyde are at increased risk for certain types of rare cancers, including nasopharyngeal (the nasopharnyx is the upper part of the throat behind the nose), sinonasal, as well as a specific cancer of the white blood cells known as myeloid leukemia. Formaldehyde is a colorless, flammable, strong-smelling chemical that is widely used to make resins for household items, such as composite wood products, paper product coatings, plastics, synthetic fibers, and textile finishes. Formaldehyde is also commonly used as a preservative in medical laboratories, mortuaries, and some consumer products, including some hair straightening products.

Six substances reasonably anticipated to be human carcinogens:

Captafol was found to induce cancer in experimental animal studies, which demonstrated that dietary exposure to captafol caused tumors at several different tissue sites in rats and mice. Captafol is a fungicide that had been used to control fungal diseases in fruits, vegetables, ornamental plants, and grasses, and as a seed treatment. It has been banned in the United States since 1999, but past exposures may still have an effect on health.

Cobalt-tungsten carbide (in powder and hard metal form) showed limited evidence of lung cancer in workers involved in cobalt-tungsten carbide hard metal manufacturing. Cobalt-tungsten carbide is used to make cutting and grinding tools, dies, and wear-resistant products for a broad spectrum of industries, including oil and gas drilling, as well as mining. In the United States, cobalt-tungsten hard metals are commonly referred to as cemented or sintered carbides.

Certain inhalable glass wool fibers made the list based on experimental animal studies. Not all glass wool or artificial fibers were found to be carcinogenic. The specific glass wool fibers referred to in this report have been redefined from previous reports on carcinogens to include only those fibers that can enter the respiratory tract, are highly durable, and are biopersistent, meaning they remain in the lungs for long periods of time. Glass wool fibers generally fall into two categories for consumers: low-cost, general purpose fibers, and premium, special purpose fibers. The largest use of general purpose glass wool is for home and building insulation, which appears to be less durable and less biopersistent, and thus less likely to cause cancer in humans.

o-Nitrotoluene is listed because experimental animal studies showed tumor formation at many different tissue sites in rats and mice. o-Nitrotoluene is used as an intermediate in the preparation of azo dyes and other dyes, including magenta and various sulfur dyes for cotton, wool, silk, leather, and paper. It is also used in preparing agricultural chemicals, rubber chemicals, pesticides, petrochemicals, pharmaceuticals, and explosives. Workers in the United States are likely exposed to o-nitrotoluene through the skin or from breathing it during production and use. o-Nitrotoluene has also been detected in air and water near facilities that produce munitions, and near military training facilities.

Riddelliine has been found to cause cancer of the blood vessels in rats and mice, leukemia and liver cancer in rats, and lung tumors in mice. This botanical should not be confused with the drug Ritalin, prescribed for the treatment of attention deficit hyperactivity disorder. Riddelliine is found in certain plants of the genus Senecio, a member of the daisy family, grown in sandy areas in the western United States and other parts of the world. Some common names for Senecio plants are ragwort and groundsel. Riddelliine-containing plants are not used for food in the United States, and have no known commercial uses. However, at least 13 Senecio species have been identified that are used in herbal medicines or possibly as food in other parts of the world. Exposure in humans could result from eating or drinking herbal medicine or teas, honey, or foods contaminated by parts of Senecio plants or after consuming products from animals that have fed on the plants.

Styrene is on the list based on human cancer studies, laboratory animal studies, and mechanistic scientific information. The limited evidence of cancer from studies in humans shows lymphohematopoietic cancer and genetic damage in the white blood cells, or lymphocytes, of workers exposed to styrene. Styrene is a synthetic chemical used worldwide in the manufacture of products such as rubber, plastic, insulation, fiberglass, pipes, automobile parts, food containers, and carpet backing. People may be exposed to styrene by breathing indoor air that has styrene vapors from building materials, tobacco smoke, and other products. The greatest exposure to styrene in the general population is through cigarette smoking. Workers in certain occupations may potentially be exposed to much higher levels of styrene than the general population.

The Report on Carcinogens, Twelfth Edition, is prepared by the National Toxicology Program, an interagency program headquartered at the National Institute of Environmental Health Sciences, part of the National Institutes of Health.

The NTP was established in 1978. The program was created as a cooperative effort to coordinate toxicology testing programs within the federal government, strengthen the science base in toxicology, develop and validate improved testing methods, and provide information about potentially toxic chemicals to health, regulatory, and research agencies, scientific and medical communities, and the public. The NTP is headquartered at the NIEHS. For more information about the NTP, visit http://ntp.niehs.nih.gov.

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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by NIH/National Institute of Environmental Health Sciences, via EurekAlert!, a service of AAAS.

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Circulating Levels of a Lung Protein Found to Be 'Strongly Predictive' of Cardiovascular Disease

A blood protein known as surfactant protein-D (SP-D), which is mainly synthesised in the lungs, has been described as "a good predictor" of cardiovascular disease following a large study in North America. Reporting the study online June 8 in the European Heart Journal, the investigators said that circulating SP-D levels were clearly associated with CVD and total mortality in patients with angiographically diagnosed coronary artery disease independent of other well established risk factors (such as age, smoking, cholesterol and C-reactive protein levels).

In the lungs SP-D has a role in the body's defensive response tot the many microorganisms and antigens inhaled each day, by binding to their surface and promting their clearance from the body. Blood levels of SP-D increase when the lungs are inflamed and not working well -- for example, when someone catches a cold, flu or other respiratory tract infection. Blood levels also increase in those who smoke or develop a chronic lung condition such as asthma, emphysema or obstructive pulmonary disease (COPD).

In healthy people with normal lung function blood levels of SP-D are low, but when lung function is impaired (as with infections, smoking or COPD), SP-D leaks from the lungs into the blood and then into the circulation, increasing the risk of atherosclerosis.

This study aimed to determine whether or not circulating SP-D is related to cardiovascular morbidity and mortality in two independent cohorts: first, a large cohort of patients having coronary angiography for suspected coronary artery disease (CAD); and second, a "replication" cohort of ex- and current smokers with mild airflow restriction but without a known history of CVD.

"We've known for a long time that chronic lung inflammation is associated with an increased risk of cardiovascular and total mortality," said investigator Dr Don Sin from the Providence Heart and Lung Institute at St Paul's Hospital, and University of British Columbia, Vancouver, Canada. "However, apart from lung function tests, there are no universally accepted biomarkers that could clearly predict these events. Recent studies have identified SP-D as a promising biomarker of lung inflammation and injury -- for example, circulating SP-D levels are nearly 40% higher in active smokers than in lifetime non-smokers, and rise further in subjects with impaired lung function. It was our hypothesis that in the systemic circulation SP-D may promote atherosclerosis."

Plasma SP-D levels were measured in 806 patients having coronary angiography. These patients were derived from the Vancouver Coronary Angiography Cohort referred for angiography between 1992 and 1995. Coronary artery disease (CAD) was defined as any lesion causing at least 20% stenosis (and severe CAD at least 50%). Follow-up continued until 2007, with primary outcome defined as CVD mortality. The replication cohort was derived from the Lung Health Study and included subjects with mild or moderate COPD.

The angiography patients who died during follow-up (30% of the cohort) had significantly higher plasma SP-D levels than those who survived (median 85.4 vs. 64.8 ng/mL; P < 0.0001). Those in the highest quintile of SP-D had a 4.4-fold higher risk of CVD mortality than those in the lowest quintile, independent of age, sex, and plasma lipid levels.

Eight per cent of the patients in this group had CAD (verified by angiography), 71% had severe CAD, and 29% had angiographic evidence of triple vessel disease. CVD accounted for 45% of the total deaths in this group.

In the group of current and ex-smokers serum SP-D levels were higher in those who died or were hospitalised for CVD than in those who did not (median 99.8 vs. 90.6 ng/mL; P = 0.0001).

Dr Sin described the association between circulating SP-D levels and CVD as "strong" but emphasised that the study was designed to determine causality. "Based on our data," he said, "we cannot determine whether SP-D was intrinsically involved in the pathogenesis of cardiovascular events or an epiphenomenon of lung inflammation."

However, he agreed that circulating SP-D levels were a strong predictor of future CVD mortality, independent of other risk factors. "Our data certainly implicate lung inflammation in the pathogenesis of heart and blood vessel disease and raise the possibility of using this protein as a biomarker for risk stratification in CVD patients above and beyond the traditional biomarkers of serum cholesterol and C-reactive protein. SP-D may provide a simple blood test to determine who has lung disease and is also at high risk of heart and blood vessel disease. Such patients could be targeted for interventions such as smoking cessation and drug therapy to lower their heart disease risk."

Journal Reference:

1. Hill J, Heslop C, Man SF, et al. Circulating surfactant protein-D and the risk of cardiovascular morbidity and mortality. Eur Heart J, 2011 DOI: 10.1093/eurheartj/ehr124

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Chasing EHEC Via Computer: Scientists in Germany Provide Free Access to Enteric Pathogen's Genetic Regulation Data

Just a few genes make enterohaemorrhagic E. coli (EHEC) extremely dangerous to humans. If it were not for these genes, EHEC would hardly differ from harmless enteric bacteria. Bioinformatics scientists from the Saarbrücken Cluster of Excellence want to exploit this similarity to find starting points for effective drugs against the EHEC pathogen. In a very short time, the scientists have constructed EhecRegNet, a database and analysis platform that incorporates all known interactions between enteric E. coli genes. Using integrated simulations, genetic switches for the dangerous EHEC genes can be identified much faster and used medically. The virtual laboratory will thus help biomedical scientists and pharmacists all over the world to develop new drugs.

All human beings carry roughly one to two kg of bacteria in their bodies. The most common enteric bacterium is Escherichia coli, which is also the best-studied microorganism on earth. "Its genetic composition has been documented in detail and we know of around 3,500 gene interactions, i.e., ca. 40% of the regulatory processes that go on in the bacterium," says Jan Baumbach, who heads a research group at the Cluster of Excellence for computer science at Saarland University. Together with his team at the Max Planck Institute for Informatics in Saarbrücken, he quickly realised that the current rampant EHEC pathogen is closely related to normal intestinal bacteria. "We assume that no more than ten genes make the EHEC pathogen life-threatening. Some genes emerged a long time ago, over the course of evolution, but others were modified through an inter-bacterial exchange of plasmids. It is a kind of primitive sex that the bacteria use to transmit genetic information. This often leads to resistance to antibiotics," the bioinformatics scientist explains.

His research team has registered all the information concerning the harmless enteric bacteria's genome and interactions in a database, which also lists the genetic data of the dangerous EHEC pathogen. On the computer, the EhecRegNet system compares the genetic data of the EHEC bacteria with the data from harmless bacteria to track down genetic switches in EHEC. The goal is to use these switches to disable the genes which cause severe renal failure in some patients. "Genes can be switched on and off, much like a light bulb. But first you have to find the right switch. At the moment, you could say that we are throwing stones at the light bulb to put out the light. We still do not know where the switches are for EHEC, but we do know where they are located in evolutionarily related harmless bacteria. That is our starting point," says Baumbach. The computer simulations will allow scientists to locate the switches for dangerous genes much faster than with expensive testing in biomedical laboratories.

Knowledge of around 80 to 90 per cent about interactions in normal enteric bacteria can be transferred to the EHEC pathogen by utilizing the computer simulations. This knowledge about harmless bacteria has been gathered by biologists and medical scientists over the last twenty years. "We cannot afford spending so much time with the EHEC bacteria, but we can take a short cut and use the available information about harmless bacteria and transfer knowledge about their genetic regulation to EHEC. It will save us time-consuming, expensive and even dangerous work in the laboratory," says Baumbach. Comparing the data on the computer is much faster. In this way, scientists hope to be able to find out which switches to flip in the genome in order to reduce EHEC's virulence.

Still, the scientist cautions against becoming too euphoric: "It may take years before a drug is actually approved for the market. However, it is possible that we will soon be able to pinpoint promising targets in experiments." The Saarbrücken-based scientists are therefore offering free access to their EhecRegNet web platform, in order to involve all biomedical scientists and pharmacists around the world in the search for drugs against the EHEC pathogen. "We envision a new generation of drugs which, in contrast to antibiotics, will not kill whole populations of bacteria. We want to use the genetic pathways in the bacteria to switch specific genes on and off," says Baumbach.

This could render the bacteria harmless or susceptible to the defence mechanisms of the immune system. "Perhaps this way we will be able to combat pathogens using their own genetic program in the future," Baumbach suggests. Less aggressive bacteria are often flushed out of the intestine with diarrhea. The EHEC pathogens circumvent this natural mechanism with their strong adhesion to the intestinal wall.

Jan Baumbach's research group at the Saarbrücken Cluster of Excellence "Multimodal Computing and Interaction" at Saarland University has already constructed similar web platforms for corynebacteria which, among other things, trigger diphtheria, and for tuberculosis. With the help of complex computational methods, bioinformatics scientists use these platforms to compare harmless laboratory strains of bacteria with disease-causing bacteria. "Our computer simulations drastically reduce the number of necessary trials in animals and experiments in test tubes. This, in turn, cuts the time until medical scientists and pharmacists can develop drugs based on the genetic switches," Jan Baumbach adds.

The new database and analysis platform for E. coli and EHEC gene Regulatory Networks can be found at: www.ehecregnet.de

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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Max-Planck-Gesellschaft, via EurekAlert!, a service of AAAS.

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Detecting Lung Cancer Early: Researchers Lay Foundation for Future Blood Test

A person's blood reveals whether he or she has lung cancer, according to researchers at the University of Bonn in Germany. In collaboration with colleagues at the Cologne University Hospital, they are developing a blood test for smokers which could save human lives in the future, since the earlier a lung tumor is detected, the better the chances of survival are.

The study has just been published in the journal Clinical Cancer Research.

Scientists working with Professor Dr. Joachim L. Schultze have identified over 480 molecules whose concentration in the blood changes when a person develops lung cancer. These molecules are present in the blood cells either in increased or decreased quantities. "In lung cancer patients, typical patterns which can be detected with a measuring program thus emerge," explains Prof. Schultze. The molecules are nucleic acids which form in the body when certain genes are transcribed.

The changes in the blood also occur if the tumor is still in a very early stage. In lung cancer, there are four different stages, explains Prof. Schultze: "The prognosis for patients in stage 3 and 4 is still very poor even today; even with the most modern therapies, the point of death can only be postponed." Lung cancer in stage 1, on the other hand, can be treated surgically and it can even be cured in many cases. "Today, however, a tumor is seldom detected so early, namely in only about 15% of all cases. If a simple screening blood test would increase this percentage, a large proportion of lung cancer patients could survive," says Prof. Schultze. By contrast, to date, over 80% of all lung cancer patients die within two years after diagnosis, since the tumor is already too far advanced.

Screening for lung cancer: Results within a day

In the future, a lung cancer screening test may become part of routine practice: The doctor takes a blood sample from his/her patient, and within 24 hours, he knows with a high degree of certainty whether the patient has lung cancer or not − even if the patient does not yet have any symptoms.

For many years, the team working with Prof. Joachim Schultze has investigated the blood of over 200 smokers. About half of them had lung cancer; the others were either entirely healthy or suffered from another lung disease. "It was important to us that a subsequent test not only be able to differentiate lung cancer patients from healthy subjects, but also from persons with chronic lung diseases." The researchers then examined the research subjects' blood using biochips for certain nucleic acids and in doing so, they found the typical patterns.

The researchers are presently planning an analogous but much larger study with ten times as many patients, in order to confirm the results. If the present results prove to be true in such a study, there would no longer be anything standing in the way of developing the blood test to the point of being ready to be put on the market.

Journal Reference:

1. T. Zander, A. Hofmann, A. Staratschek-Jox, S. Classen, S. Debey-Pascher, D. Eggle, S. Ansén, M. Hahn, M. Beyer, R.K. Thomas, B. Gathof, C. Mauch, K.-S. Delank, W. Engel-Riedel, H.-E. Wichmann, E. Stoelben, J.L. Schultze, J. Wolf. Blood-based gene expression signatures in non-small cell lung cancer. Clinical Cancer Research, 2011

Courtesy: ScienceDaily

Cell Phones and Cancer: Assessment Classifies Radiofrequency Electromagnetic Fields as Possibly Carcinogenic to Humans

The WHO/International Agency for Research on Cancer (IARC) has classified radiofrequency electromagnetic fields as possibly carcinogenic to humans (Group 2B), based on an increased risk for glioma, a malignant type of brain cancer¹, associated with wireless phone use.

Background

Over the last few years, there has been mounting concern about the possibility of adverse health effects resulting from exposure to radiofrequency electromagnetic fields, such as those emitted by wireless communication devices. The number of mobile phone subscriptions is estimated at 5 billion globally.

From May 24-31 2011, a Working Group of 31 scientists from 14 countries has been meeting at IARC in Lyon, France, to assess the potential carcinogenic hazards from exposure to radiofrequency electromagnetic fields. These assessments will be published as Volume 102 of the IARC Monographs, which will be the fifth volume in this series to focus on physical agents, after Volume 55 (Solar Radiation), Volume 75 and Volume 78 on ionizing radiation (X‐rays, gamma‐rays, neutrons, radio‐nuclides), and Volume 80 on non‐ionizing radiation (extremely low‐frequency electromagnetic fields).

The IARC Monograph Working Group discussed the possibility that these exposures might induce long‐term health effects, in particular an increased risk for cancer. This has relevance for public health, particularly for users of mobile phones, as the number of users is large and growing, particularly among young adults and children.

The IARC Monograph Working Group discussed and evaluated the available literature on the following exposure categories involving radiofrequency electromagnetic fields:

• occupational exposures to radar and to microwaves;
• environmental exposures associated with transmission of signals for radio, television and wireless telecommunication; and
• personal exposures associated with the use of wireless telephones.

Results

The evidence was reviewed critically, and overall evaluated as being limited² among users of wireless telephones for glioma and acoustic neuroma, and inadequate³ to draw conclusions for other types of cancers. The evidence from the occupational and environmental exposures mentioned above was similarly judged inadequate. The Working Group did not quantitate the risk; however, one study of past cell phone use (up to the year 2004), showed a 40% increased risk for gliomas in the highest category of heavy users (reported average: 30 minutes per day over a 10‐year period).

Conclusions

Dr Jonathan Samet (University of Southern California, USA), overall Chairman of the Working Group, indicated that "the evidence, while still accumulating, is strong enough to support a conclusion and the 2B classification. The conclusion means that there could be some risk, and therefore we need to keep a close watch for a link between cell phones and cancer risk."

"Given the potential consequences for public health of this classification and findings," said IARC Director Christopher Wild, "it is important that additional research be conducted into the long‐ term, heavy use of mobile phones. Pending the availability of such information, it is important to take pragmatic measures to reduce exposure such as hands‐free devices or texting. "

The Working Group considered hundreds of scientific articles; the complete list will be published in the Monograph. It is noteworthy to mention that several recent in‐press scientific articles⁴ resulting from the Interphone study were made available to the working group shortly before it was due to convene, reflecting their acceptance for publication at that time, and were included in the evaluation.

A concise report summarizing the main conclusions of the IARC Working Group and the evaluations of the carcinogenic hazard from radiofrequency electromagnetic fields (including the use of mobile telephones) will be published in The Lancet Oncology in its July 1 issue, and in a few days online.

Notes:

1. International experts shared the complex task of tackling the exposure data, the studies of cancer in humans, the studies of cancer in experimental animals, and the mechanistic and other relevant data. 1 237 913 new cases of brain cancers (all types combined) occurred around the world in 2008 (gliomas represent 2/3 of these). Source: Globocan 2008

2. 'Limited evidence of carcinogenicity': A positive association has been observed between exposure to the agent and cancer for which a causal interpretation is considered by the Working Group to be credible, but chance, bias or confounding could not be ruled out with reasonable confidence.

3. 'Inadequate evidence of carcinogenicity': The available studies are of insufficient quality, consistency or statistical power to permit a conclusion regarding the presence or absence of a causal association between exposure and cancer, or no data on cancer in humans are available.

4 a. 'Acoustic neuroma risk in relation to mobile telephone use: results of the INTERPHONE international case‐ control study' (the Interphone Study Group, in Cancer Epidemiology, in press)

b. 'Estimation of RF energy absorbed in the brain from mobile phones in the Interphone study' (Cardis et al., Occupational and Environmental Medicine, in press)

c. 'Risk of brain tumours in relation to estimated RF dose from mobile phones -- results from five Interphone countries' (Cardis et al., Occupational and Environmental Medicine, in press)

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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by World Health Organization/International Agency for Research on Cancer.

Courtesy: ScienceDaily