Potential Prostate Cancer Marker Discovered

Images from the desorption electrospray ionization mass spectrometry analysis of prostate tissue samples are shown next to stained slides of the same samples. The images show that cholesterol sulfate is present in cancerous tissue and precancerous legions called high grade prostatic intraepithelial neoplasia, or PIN. A Purdue University-led research team discovered that cholesterol sulfate is a potential marker for prostate cancer. (Credit: Demian Ifa/Purdue Center for Analytical Instrumentation Development)

Studies by a Purdue University-led team have revealed a potential marker for prostate cancer that could be the starting point for less invasive testing and improved diagnosis of the disease.

The team used a new analysis technique to create a profile of the lipids, or fats, found in prostate tissue and discovered a molecular compound that appears to be useful in identifying cancerous and precancerous tissue. The profile revealed that cholesterol sulfate is a compound that is absent in healthy prostate tissue, but is a major fat found in prostate cancer tumors.
Graham Cooks, Purdue's Henry Bohn Hass Distinguished Professor of Chemistry, and Timothy Ratliff, the Robert Wallace Miller Director of the Purdue Center for Cancer Research, led the team.
"It was surprising to find a single compound that is distinctly present in cancerous tissue and not present in healthy tissue," said Cooks, who is co-director of Purdue's Center for Analytical Instrumentation Development. "We've been able to differentiate cancerous from healthy tissue using this new method in the past, but the difference was in the amounts of the same chemical compounds found in healthy tissue. There was no single differentiator of which one could say if it was present there was cancerous tissue."
Ratliff said this characteristic makes the compound a potential marker for the disease, which could lead to new blood or urine tests to screen for prostate cancer.
"Aside from skin cancer, prostate cancer is the most common cancer in men and is the second leading cause of cancer-related deaths," Ratliff said. "Unfortunately, the current screening test has a significant number of false positives because it uses a marker that is present with other non-cancerous conditions. As a result, many men have unnecessary biopsies, which are invasive, expensive and have the potential to cause infection. This new compound appears to be highly specific to prostate cancer cells, which would mean very few false positives."
The current prostate cancer test screens for a protein called prostate-specific antigen, or PSA, that is produced by the cells of the prostate. Elevated levels of PSA in the blood can signify prostate cancer, but non-cancerous conditions such as an enlarged or inflamed prostate also cause an increase in its levels, he said.
The findings of the study, which was funded by the Purdue University Center for Cancer Research and the National Institutes of Health, were published in the journal Analytical Chemistry.
The study was performed in collaboration with physician scientists from Indiana University School of Medicine, who co-authored the paper. They also provided the tissue samples and pathological analysis of the samples to check the new technique's results.
The team used a mass spectrometry analysis technique developed by Cooks and coworkers called desorption electrospray ionization, or DESI, to measure and compare the chemical characteristics of 68 samples of normal and cancerous prostate tissue.
Mass spectrometry works by first turning molecules into ions, or electrically charged versions of themselves, so that they can be identified by their mass. Conventional mass spectrometry requires chemical separations, manipulations of samples and containment in a vacuum chamber for ionization and analysis. The DESI technique eliminates these requirements by performing the ionization step in the air or directly on surfaces outside of the mass spectrometers, making the process much simpler, faster and more applicable to medical examination or surgical settings.
Cooks' research team also has developed software that turns the distribution and intensity of selected ions within a sample into a computer-generated image, much like what would be seen from a stained slide under the microscope. This chemical map of the sample can precisely show the location of cancerous tissue and the borders of tumors, Cooks said.
Livia Eberlin, co-author of the paper and a graduate student in Cooks' group, said the study showed promise in detecting precancerous lesions, as well.
"The DESI examination was able to distinguish a precancerous lesion in a small area of a sample made up of mostly healthy tissue," Eberlin said. "By evaluating the difference in the chemistry of cells, this technique can detect differences in diseased tissue that are otherwise indistinguishable. It could provide a new tool for pathologists to complement microscopic examination."
The team also plans to study differences in the chemistry of different types of prostate cancer tumors to see if there is a way to identify which are aggressive and which are not, she said.
Ratliff said the inability to tell the difference between aggressive and nonaggressive forms of prostate cancer causes problems in its treatment.
"A nonaggressive form of prostate cancer can be very slow to progress, and sometimes it is in the best interest of the patient not to go through rigorous treatments that reduce one's quality of life," he said. "The tests currently used to determine the probability that the cancer is an aggressive form are not very accurate, and about 30 percent of patients are misdiagnosed as having an aggressive form."
Additional co-authors of the paper include graduate students Allison Dill and Anthony Costa, and post doctoral researcher Demian Ifa from Purdue's Department of Chemistry and the Center for Analytical Instrumentation Development; Dr. Liang Cheng from the Indiana University School of Medicine Department of Pathology and Laboratory Medicine; and Dr. Timothy Masterson and Dr. Michael Koch from the Indiana University School of Medicine Department of Urology.
The team is already in the process of performing larger studies and plans to investigate the biological processes responsible for the expression of cholesterol sulfate in cancerous tissue.

Of Bugs and Brains: Gut Bacteria Affect Multiple Sclerosis

In the absence of bacteria in the intestines, pro-inflammatory Th17 cells do not develop in either the gut or the central nervous system; and animals do not develop disease (top panel). When animals are colonized with symbiotic segmented filamentous bacteria, Th17 cell differentiation is induced in the gut. Th17 cells promote experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis. In this way, non-pathogenic bacteria of the microbiota promote disease by shaping the immune response in both the gut and the brain

Biologists at the California Institute of Technology (Caltech) have demonstrated a connection between multiple sclerosis (MS) -- an autoimmune disorder that affects the brain and spinal cord -- and gut bacteria.
The work -- led by Sarkis K. Mazmanian, an assistant professor of biology at Caltech, and postdoctoral scholar Yun Kyung Lee -- appears online the week of July 19-23 in the Proceedings of the National Academy of Sciences.
Multiple sclerosis results from the progressive deterioration of the protective fatty myelin sheath surrounding nerve cells. The loss of myelin hinders nerve cells from communicating with one another, leading to a host of neurological symptoms including loss of sensation, muscle spasms and weakness, fatigue, and pain. Multiple sclerosis is estimated to affect about half a million people in the United States alone, with rates of diagnosis rapidly increasing. There is currently no cure for MS.
Although the cause of MS is unknown, microorganisms seem to play some sort of role. "In the literature from clinical studies, there are papers showing that microbes affect MS," Mazmanian says. "For example, the disease gets worse after viral infections, and bacterial infections cause an increase in MS symptoms."
On the other hand, he concedes, "it seems counterintuitive that a microbe would be involved in a disease of the central nervous system, because these are sterile tissues."
And yet, as Mazmanian found when he began examining the multiple sclerosis literature, the suggestion of a link between bacteria and the disease is more than anecdotal. Notably, back in 1993, Caltech biochemist Leroy Hood -- who was then at the University of Washington -- published a paper describing a genetically engineered strain of mouse that developed a lab-induced form of multiple sclerosis known as experimental autoimmune encephalomyelitis, or EAE.
When Hood's animals were housed at Caltech, they developed the disease. But, oddly, when the mice were shipped to a cleaner biotech facility -- where their resident gut bacterial populations were reduced -- they didn't get sick. The question was, why? At the time, Mazmanian says, "the authors speculated that some environmental component was modulating MS in these animals." Just what that environmental component was, however, remained a mystery for almost two decades.
But Mazmanian -- whose laboratory examines the relationships between gut microbes, both harmful and helpful, and the immune systems of their mammalian hosts -- had a hunch that intestinal bacteria were the key. "As we gained an appreciation for how profoundly the gut microbiota can affect the immune system, we decided to ask if symbiotic bacteria are the missing variable in these mice with MS," he says.
To find out, Mazmanian and his colleagues tried to induce MS in animals that were completely devoid of the microbes that normally inhabit the digestive system. "Lo and behold, these sterile animals did not get sick," he says.
Then the researchers decided to see what would happen if bacteria were reintroduced to the germ-free mice. But not just any bacteria. They inoculated mice with one specific organism, an unculturable bug from a group known as segmented filamentous bacteria. In prior studies, these bacteria had been shown to lead to intestinal inflammation and, more intriguingly, to induce in the gut the appearance of a particular immune-system cell known as Th17. Th17 cells are a type of T helper cell -- cells that help activate and direct other immune system cells. Furthermore, Th17 cells induce the inflammatory cascade that leads to multiple sclerosis in animals.
"The question was, if this organism is inducing Th17 cells in the gut, will it be able to do so in the brain and central nervous system?" Mazmanian says. "Furthermore, with that one organism, can we restore to sterile animals the entire inflammatory response normally seen in animals with hundreds of species of gut bacteria?"
The answer? Yes on all counts. Giving the formerly germ-free mice a dose of one species of segmented filamentous bacteria induced Th17 not only in the gut but in the central nervous system and brain -- and caused the formerly healthy mice to become ill with MS-like symptoms.
"It definitely shows that gut microbes have a strong role in MS, because the genetics of the animals were the same. In fact, everything was the same except for the presence of those otherwise benign bacteria, which are clearly playing a role in shaping the immune system," Mazmanian says. "This study shows for the first time that specific intestinal bacteria have a significant role in affecting the nervous system during MS -- and they do so from the gut, an anatomical location very, very far from the brain."
Mazmanian and his colleagues don't, however, suggest that gut bacteria are the direct cause of multiple sclerosis, which is known to be genetically linked. Rather, the bacteria may be helping to shape the immune system's inflammatory response, thus creating conditions that could allow the disease to develop. Indeed, multiple sclerosis also has a strong environmental component; identical twins, who possess the same genome and share all of their genes, only have a 25 percent chance of sharing the disease. "We would like to suggest that gut bacteria may be the missing environmental component," he says.
For their part, Th17 cells are needed for the immune system to properly combat infection. Problems only arise when the cells are activated in the absence of infection -- just as disease can arise, Mazmanian and others suspect, when the species composition of gut bacteria become imbalanced, say, by changes in diet, because of improved hygiene (which kills off the beneficial bacteria as well as the dangerous ones), or because of stress or antibiotic use. One impact of the dysregulation of normal gut bacterial populations -- a phenomenon dubbed "dysbiosis" -- may be the rising rate of multiple sclerosis seen in recent years in more hygienic societies.
"As we live cleaner, we're not just changing our exposure to infectious agents, but we're changing our relationship with the entire microbial world, both around and inside us, and we may be altering the balance between pro- and anti-inflammatory bacteria," leading to diseases like MS, Mazmanian says. "Perhaps treatments for diseases such as multiple sclerosis may someday include probiotic bacteria that can restore normal immune function in the gut… and the brain."
The work was supported by funding from the California Institute of Technology, the Weston Havens Foundation, and the Edward Mallinckrodt, Jr. Foundation.

Nanoparticles Shrink Tumors in Mice

The application of nanotechnology in the field of drug delivery has attracted much attention in recent years. In cancer research, nanotechnology holds great promise for the development of targeted, localized delivery of anticancer drugs, in which only cancer cells are affected.

A dorsal view of a mouse showing accumulation of nanoparticles in a tumor four hours after intravenous administration. Bright fluorescence is observed predominantly in the tumor.

Such targeted-therapy methods would represent a major advance over current chemotherapy, in which anticancer drugs are distributed throughout the body, attacking healthy cells along with cancer cells and causing a number of adverse side effects.
By carrying out comprehensive studies on mice with human tumors, UCLA scientists have obtained results that move the research one step closer to this goal. In a paper published July 8 in the journal Small, researchers at UCLA's California NanoSystems Institute and Jonsson Comprehensive Cancer Center demonstrate that mesoporous silica nanoparticles (MSNs), tiny particles with thousands of pores, can store and deliver chemotherapeutic drugs in vivo and effectively suppress tumors in mice.
The researchers also showed that MSNs accumulate almost exclusively in tumors after administration and that the nanoparticles are excreted from the body after they have delivered their chemotherapeutic drugs.
The study was conducted jointly in the laboratories of Fuyu Tamanoi, a UCLA professor of microbiology, immunology and molecular genetics and director of the signal transduction and therapeutics program at UCLA's Jonsson Comprehensive Cancer Center, and Jeffrey Zink, a UCLA professor of chemistry and biochemistry. Tamanoi and Zink are researchers at the California NanoSystems Institute (CNSI) and are two of the co-directors of the CNSI's Nano Machine Center for Targeted Delivery and On-Demand Release. The lead investigator on the research is Jie Lu, a postdoctoral fellow in Tamanoi's lab. Monty Liong and Zongxi Li, researchers from Zink's lab, also contributed to this work.
In the study, researchers found that MSNs circulate in the bloodstream for extended periods of time and accumulate predominantly in tumors. The tumor accumulation could be further improved by attaching a targeting moiety to MSNs, the researchers said.
The treatment of mice with camptothecin-loaded MSNs led to shrinkage and regression of xenograft tumors. By the end of the treatment, the mice were essentially tumor free, and acute and long-term toxicity of MSNs to the mice was negligible. Mice with breast cancer were used in this study, but the researchers have recently obtained similar results using mice with human pancreatic cancer.
"Our present study shows, for the first time, that MSNs are effective for anticancer drug delivery and that the capacity for tumor suppression is significant," Tamanoi said.
"Two properties of these nanoparticles are important," Lu said. "First, their ability to accumulate in tumors is excellent. They appear to evade the surveillance mechanism that normally removes materials foreign to the body. Second, most of the nanoparticles that were injected into the mice were excreted out through urine and feces within four days. The latter results are quite interesting and might explain the low toxicity observed in the biocompatabilty experiments we conducted."
Researchers at the Nano Machine Center for Targeted Delivery and On-Demand Release are modifying MSNs -- which are easily modifiable -- so that the nanoparticles can be equipped with nanomachines. For example, nanovalves are being attached at the opening of the pores to control the release of anticancer drugs. In addition, the interior of the pores is being modified so that the light-induced release of anticancer drugs can be achieved.
"We can modify both the particles themselves and also the attachments on the particles in a wide variety of ways, which makes this material particularly attractive for engineering drug-delivery vehicles," Zink said.
The team is now planning future research that involves testing MSNs in a variety of animal-model systems and carrying out extensive studies on the safety of MSNs.
"Comprehensive investigation with practical dosages which are adequate and suitable for in vivo delivery of anticancer drugs is needed before MSNs can reach clinics as a drug-delivery system," Tamanoi said.
The research received support from National Institutes of Health and the National Science Foundation. In addition, NanoPacific Holdings Inc. provided critical support for the animal experiments.

Gene Therapy a Step Closer to Mass Production

EUREKA project E! 3371 Gene Transfer Agents has made great advances in the development of novel non-viral carriers able to introduce genetic material into the target cells. These new agents, derivatives of cationic amphiphilic 1,4-dihydropyridine (1,4-DHP), avoid the problems of the recipient's immune system reacting against a viral carrier.

The project partners have developed methods to produce them in large amounts, which solves another of the problems with viral delivery. But the greatest advantage is that the new compounds are significantly more effective at delivering DNA into cell nuclei than other standard synthetic carriers; increasing the chance of the DNA successfully controlling the defective genes, and the disease.
Gene therapy involves the insertion of DNA into human cells within the body to treat disease. The technique is still in its early days, and has been demonstrated successfully only in the last decade. Most investigation has been into the possibilities for treating hereditary diseases related to a genetic defect, and the technique also has potential uses in treating the early stages of cancer, and in cardiovascular and neurodegenerative diseases.
Gene therapy faces many difficulties as a practical method; not the least of which is that DNA is a large and complicated structure which needs to be delivered and attached to the correct section of the recipient's set of DNA. A number of methods are in use or under investigation for introducing DNA into cells (a process known as transfection) -- using viruses, chemical agents or physical injection.
Viruses or chemical carriers
With viral carriers, the DNA to be introduced is injected into the virus, which carries it into the cell by way of a vesicle formed around the virus particle by the cell wall. Once inside the cell, the vesicle breaks down and the virus injects the DNA into the cell's nucleus. The viral route does, however, have major disadvantages. The immune system of the person receiving treatment often interferes with viral activity; and viruses can have unpredictable mutagenic side-effects. Also large-scale production of viral vectors is problematic.
A wide range of chemical agents are already known to be able to form a complex of 1,4-DHP with DNA and deliver it into the recipient's cells. These agents are much easier to produce on a large scale than viruses and do not usually cause an immune response. However they are not so effective at introducing the DNA as the viral carriers.
Seeking the best of both worlds
The challenge facing the partners in the EUREKA project was to combine the effectiveness of the viral vectors with the production advantages and lack of immune response shown by chemical agents. Scientists at the Latvian Institute of Organic Synthesis and the University of Kuopio in Finland had discovered new groups of possible DNA transfer agents: 1,4-DHP derivatives. These compounds were found to be more effective in gene transfer than two widely-used standard gene delivery agents (known as DOTAP and PEI 25) and the discovery was covered by a patent. This finding offered the exciting prospect of better efficiency from a non-viral carrier.
Professor Arto Urtti of Helsinki University (formerly from Kuopio) explains: "When these compounds are in solution and DNA is added, they bind together. The large, loose DNA molecule collapses and tiny particles of about 10-50nm in diameter are formed, composed of both DNA and carrier. When you present this to the cells, the nanoparticles bind to the cell surface, which folds inwards to form a vesicle within the cell. The particles then escape from the vesicle, releasing the DNA.
Researchers at Helsinki University found that out of all the compounds tested, the most effective were those which succeeded in transferring DNA into the nucleus. The mechanism by which the DNA enters the nucleus is not yet clearly understood, but it is known that gene transfer is more effective in cells which are actively dividing, e.g. cancer cells.
Dr Aiva Plotniece, Dr Arkadijs Sobolevs and their colleagues at the Latvian Institute then set out to synthesise dozens of different DHP derivative compounds. Dr Plotniece comments: "The great advantage of these compounds is the biologically active 1,4-DHP fragment, which with proper substitution, can show certain biological and physico-chemical properties. During the project we have designed different 1,4-DHPs, which allowed us to establish structure-activity relationships."
The third project partner, the independent Latvian chemical producer Bapeks, contributed its experience of larger-scale synthesis and advised the Latvian Institute researchers on how best to scale up the synthesis methodology. The compounds were then distributed to a number of other research colleagues in Latvia, Finland and Lithuania for further study. At present, project partners feel that the main uses will be in laboratory experiments, and much further research is needed before they can be used for gene transfer in the human body.
Partners in the EUREKA project believe that although more research is needed, the project has been very successful. "It was the first big, important project for us" says Dr Sobolevs. "We have significantly widened the potential uses of self-assembling 1,4-dihydropyridine derivatives into nanomedicine, gene delivery and even into drug delivery systems." The project team found that EUREKA support helped greatly in preparing, managing and reporting the project. It was also through EUREKA that the other partners were introduced to Bapeks.

Scientists 'Boot Up' a Bacterial Cell With a Synthetic Genome

Scientists have developed the first cell controlled by a synthetic genome. They now hope to use this method to probe the basic machinery of life and to engineer bacteria specially designed to solve environmental or energy problems.

Scanning electron micrographs of M. mycoides JCVI-syn1. Samples were post-fixed in osmium tetroxide, dehydrated and critical point dried with CO2 , then visualized using a Hitachi SU6600 scanning electron microscope at 2.0 keV.

The study will be published online by the journal Science, at the Science Express website, on May 20.
The research team, led by Craig Venter of the J. Craig Venter Institute, has already chemically synthesized a bacterial genome, and it has transplanted the genome of one bacterium to another. Now, the scientists have put both methods together, to create what they call a "synthetic cell," although only its genome is synthetic.
"This is the first synthetic cell that's been made, and we call it synthetic because the cell is totally derived from a synthetic chromosome, made with four bottles of chemicals on a chemical synthesizer, starting with information in a computer," said Venter.
"This becomes a very powerful tool for trying to design what we want biology to do. We have a wide range of applications [in mind]," he said.
For example, the researchers are planning to design algae that can capture carbon dioxide and make new hydrocarbons that could go into refineries. They are also working on ways to speed up vaccine production. Making new chemicals or food ingredients and cleaning up water are other possible benefits, according to Venter.
In the Science study, the researchers synthesized the genome of the bacterium M. mycoides and added DNA sequences that "watermark" the genome to distinguish it from a natural one.
Because current machines can only assemble relatively short strings of DNA letters at a time, the researchers inserted the shorter sequences into yeast, whose DNA-repair enzymes linked the strings together. They then transferred the medium-sized strings into E. coli and back into yeast. After three rounds of assembly, the researchers had produced a genome over a million base pairs long.
The scientists then transplanted the synthetic M. mycoides genome into another type of bacteria, Mycoplasm capricolum. The new genome "booted up" the recipient cells. Although fourteen genes were deleted or disrupted in the transplant bacteria, they still looked like normal M. mycoides bacteria and produced only M. mycoides proteins, the authors report.
"This is an important step we think, both scientifically and philosophically. It's certainly changed my views of the definitions of life and how life works," Venter said.
Acknowledging the ethical discussion about synthetic biology research, Venter explained that his team asked for a bioethical review in the late 1990s and has participated in variety of discussions on the topic.
"I think this is the first incidence in science where the extensive bioethical review took place before the experiments were done. It's part of an ongoing process that we've been driving, trying to make sure that the science proceeds in an ethical fashion, that we're being thoughtful about what we do and looking forward to the implications to the future," he said.
This research was funded by Synthetic Genomics, Inc. Three of the authors and the J. Craig Venter Institute hold Synthetic Genomics, Inc. stock. The J. Craig Venter Institute has filed patent applications on some of the techniques described in this paper.

How Ducks Host Influenza Unharmed: Could Findings Shield Humans from Bird Flu Viruses?

A University of Alberta-led research team has discovered an influenza detector gene that could potentially prevent the transmission of the virus to humans.

Mallard duck with fifteen ducklings. Researchers have identified the genetic detector that allows ducks to live, unharmed, as the host of influenza. 

Katharine Magor, a U of A associate professor of biology, has identified the genetic detector that allows ducks to live, unharmed, as the host of influenza. The duck's virus detector gene, called retinoic acid inducible gene -- I, or RIG-I, enables a duck's immune system to contain the virus, which typically spreads from ducks to chickens, where it mutates and can evolve to be a human threat like the H5N1 influenza virus. The first human H5N1 cases were in Hong Kong in 1997. Eighteen people with close contact to chickens became infected and six died.
Magor's research shows chickens do not have a RIG-I gene. A healthy chicken can die within 18 hours after infection, but researchers have successfully transferred the RIG-I gene from ducks to chicken cells. The chicken's defenses against influenza were augmented and RIG-I reduced viral replication by half.
One potential application of this research could affect the worldwide poultry industry by production of an influenza-resistant chicken created by transgenesis.
The work of Katharine Magor, her U of A PhD candidate Megan Barber, and researchers from the United States (Jerry Aldridge and Robert Webster) was published March 22, in the online, early edition of Proceedings from the National Academy of Sciences.

Life on Saturn's Moon Titan: Stand Well Back and Hold Your Nose!

Research by astrobiologist William Bains suggests that if life has evolved on the frozen surface of Saturn's moon, Titan, it would be strange, smelly and explosive compared to life on Earth.

Dr Bains will present his work at the National Astronomy Meeting in Glasgow on April 13.
"Hollywood would have problems with these aliens" says Dr. Bains. "Beam one onto the Starship Enterprise and it would boil and then burst into flames, and the fumes would kill everyone in range. Even a tiny whiff of its breath would smell unbelievably horrible. But I think it is all the more interesting for that reason. Wouldn't it be sad if the most alien things we found in the galaxy were just like us, but blue and with tails?"
Dr Bains, whose research is carried out through Rufus Scientific in Cambridge, UK, and MIT in the USA, is seeking to work out just how extreme the chemistry of life can be. Life on Titan, Saturn's largest moon, represents one of the more bizarre scenarios being studied. Titan is twice as large as our Moon and has a thick atmosphere of frozen, orange smog. At ten times our distance from the Sun, it is a frigid place, with a surface temperature of -180 degrees Celsius. Water is permanently frozen into ice and the only liquid available is liquid methane and ethane, which the Cassini/Huygens mission has shown is present in ponds and lakes on the surface of the moon.
"Life needs a liquid; even the driest desert plant on Earth needs water for its metabolism to work. So, if life were to exist on Titan, it must have blood based on liquid methane, not water. That means its whole chemistry is radically different. The molecules must be made of a wider variety of elements than we use, but put together in smaller molecules. It would also be much more chemically reactive," said Dr Bains.
The solubility of chemicals in liquid methane is very limited, and strongly dependent on molecular weight. With a few exceptions, molecules with more than 6 heavy (non-hydrogen) atoms are essentially insoluble. So a metabolism running in liquid methane will have to be built of smaller molecules than terrestrial biochemistry, which is typically built of modules of around 10 heavy atoms. However you can only build around 3400 molecules from such a small number of atoms if you are limited to the chemistry that terrestrial life uses i.e. carbon, nitrogen, oxygen, and sulphur and phosphorus in very limited chemical contexts.
Dr Bains explained, "Terrestrial life uses about 700 molecules, but to find the right 700 there is reason to suppose that you need to be able to make 10 million or more. The issue is not how many molecules you can make, but whether you can make the collection you need to assemble a metabolism. It is like trying to find bits of wood in a lumber-yard to make a table. In theory you only need 5. But you may have a lumber-yard full of offcuts and still not find exactly the right five that fit together. So you need the potential to make many more molecules than you actually need. Thus the 6-atom chemicals on Titan would have to include much more diverse bond types and probably more diverse elements, including sulphur and phosphorus in much more diverse and (to us) unstable forms, and other elements such as silicon."
Energy is another factor that would affect the type of life that could evolve on Titan. With Sunlight a tenth of a percent as intense on Titan's surface as on the surface of Earth, energy is likely to be in short supply.
"Rapid movement or growth needs a lot of energy, so slow-growing, lichen-like organisms are possible in theory, but velociraptors are pretty much ruled out," said Bains.

Tainted Produce More Likely for Shoppers in Low-Income Neighborhoods, Study Suggests

No one wants a mixed salad tossed with extra bacteria, mold and yeast, but those are just what you might find when you try to eat a healthier diet in poorer neighborhoods. A new study shows that the level of bacteria found on the fresh produce can vary according to the income level of the neighborhoods where it is for sale.
Researchers compared levels of bacteria, yeast and mold on identical products sold in six Philadelphia-area neighborhoods. They selected three of the neighborhoods because they had the city’s highest poverty levels. In these, consumer options tended to be small markets that offered less variety in fruits and vegetables.
The result: ready-to-eat salads and strawberries sold in stores in the poorer neighborhoods had significantly higher counts of microorganisms, yeasts and molds than the same products purchased elsewhere, while cucumbers had a higher yeast count and mold and watermelon contained more bacteria.
“Food deteriorates when there is microbial growth,” said study co-author Jennifer Quinlan, a professor of nutrition and biology at Drexel University. “The bacterial count is used to determine the quality of the produce and it was poorer quality, closer to being spoiled. Three of the things that had a higher bacteria count — strawberries, ready-to-go salad and fresh-cut watermelon — have been associated with food-borne illnesses.”
The study appears online and in the May issue of the American Journal of Preventive Medicine.
When your access to produce is of inferior quality, it discourages you from adding more fruits and vegetables to your diet. Part of the problem, Quinlan said, is that much of the food available in poorer neighborhoods is for sale in smaller stores that might not have the infrastructure to handle produce in the safest way.
“The food may be of poorer quality to begin with; then it may be transported to the stores and not be refrigerated properly,” she said. “Large supermarkets have entire units focused on food safety, refrigeration, sanitation. While a small facility with only one or two people may not have the resources.”
Although the bacteria that can cause spoilage are not the same bacteria that are dangerous from a standpoint of food-borne illness, consumers can take some important steps to ensure they get the freshest produce.
“One thing consumers can look for is that fresh-cut produce be refrigerated at the point of sale,” said Shelley Feist, executive director of Partnership for Food Safety Education. “When they get fresh produce home, it’s important to clean it thoroughly. Whole fresh produce should be rinsed under running tap water just before eating and produce should be kept separate from meat, poultry, raw eggs and fish to avoid cross-contamination.”

'Microtentacles' on Tumor Cells Appear to Play Role in How Breast Cancer Spreads

Two breast tumor cells attaching to each other. The red color shows the surface of both tumor cells, while the green color shows how the microtentacles from one cell encircle the neighboring cell

Researchers at the University of Maryland Marlene and Stewart Greenebaum Cancer Center have discovered that "microtentacles," or extensions of the plasma membrane of breast cancer cells, appear to play a key role in how cancers spread to distant locations in the body. Targeting these microtentacles might prove to be a new way to prevent or slow the growth of these secondary cancers, the scientists say.
They report in an article to be published online March 15, 2010, in the journal Oncogene that a protein called "tau" promotes the formation of these microtentacles on breast tumor cells which break away from primary cancers and circulate in the bloodstream. While twisted remnants of tau protein have been seen in the brain tissue of patients with Alzheimer's disease, this is the first report that tau could play a role in tumor metastasis by changing the shape of cancer cells. These tau-induced microtentacles can help the cells reattach to the walls of small blood vessels to create new pockets of cancer.
"Our study demonstrates that tau promotes the creation of microtentacles in breast tumor cells. These microtentacles increase the ability of circulating breast tumor cells to reattach in the small capillaries of the lung, where they can survive until they can seed new cancers," says the senior author, Stuart S. Martin, Ph.D., a researcher at the University of Maryland Greenebaum Cancer Center and associate professor of physiology at the University of Maryland School of Medicine. Michael A. Matrone, Ph.D., is the study's lead author.
Healthy cells are programmed to die -- a process called apoptosis -- after they break off of epithelial layers that cover internal organs in the body. They also can be crushed if they are forced through small capillaries. However, cancer cells are able to survive for weeks, months and even years in the body. Once they are trapped in small blood vessels, the cells can squeeze through microscopic gaps in the vessels' lining and spread to organs such as the brain, lung and liver.
"We hope that through our research, we will be able to identify drugs that will target the growth of these microtentacles and help to stop the spread of the original cancer. Drugs that reduce tau expression may hold potential to inhibit tumor metastasis," Dr. Martin says.
He notes that metastatic cancers are the leading cause of death in people with cancer, but methods used to treat primary tumors have limited success in treating metastatic cancer. In breast cancer, metastases can develop years after primary tumors are first discovered.
Tau is present in a subset of chemotherapy-resistant breast cancers and is also associated with poor prognosis, but Dr. Martin adds, "While tau expression has been studied in breast cancers for contributing to chemotherapy resistance, the protein's role in tumor cells circulating in the bloodstream hasn't been investigated. And that's the focus of our research."
In this recent study, the University of Maryland researchers analyzed breast tumor cells from 102 patients and found that 52 percent had tau in their metastatic tumors and 26 percent (27 patients) showed a significant increase in tau as their cancer progressed. Twenty-two of these patients even had tau in metastatic tumors despite having none in their primary tumors.
Dr. Martin says more studies are needed to determine if tau is a clear predictor of metastasis. Given the complex nature of tumors, there most likely are other factors involved in causing cancers to spread, he says.
"Metastasis is a very major concern for people diagnosed with cancer, and the discovery of these microtentacles and the role that tau plays in their formation is a very exciting development that holds great promise for developing new drugs," says E. Albert Reece, M.D., Ph.D., M.B.A., acting president of the University of Maryland, Baltimore, and dean of the University of Maryland School of Medicine.
The University of Maryland, Baltimore, has filed patents on the microtentacle discoveries of Dr. Martin's lab group and is looking to partner with biopharmaceutical companies on new drug development. The researchers identified these cell extensions while they were studying the effects of two drugs that prevent cell division, or mitosis. Most chemotherapy drugs target cell division, aiming to slow or stop tumor growth.
Dr. Martin says his team found that a popular chemotherapy drug, taxol, actually causes cancer cell microtentacles to grow longer and allows tumor cells to reattach faster, which may have important treatment implications for breast cancer patients. Their studies are continuing.
"We think more research is needed into how chemotherapies that slow down cell division affect metastasis. The timing of giving these drugs can be particularly important. If you treat people with taxol before surgery to shrink the primary tumor, levels of circulating tumor cells go up 1,000 to 10,000 fold, potentially increasing metastasis," he adds.
The study being published in Oncogene was funded by grants from the National Cancer Institute, the USA Medical Research and Materiel Command, and the Flight Attendants Medical Research Institute.

Chemotherapy Plus Synthetic Compound Provides Potent Anti-Tumor Effect in Pancreatic Cancers

Human pancreatic cancer cells dramatically regress when treated with chemotherapy in combination with a synthetic compound that mimics the action of a naturally occurring "death-promoting" protein found in cells, researchers at UT Southwestern Medical Center have found.

Researchers led by Dr. Rolf Brekken have shown in mice that pancreatic cancer cells dramatically regress when treated with chemotherapy in combination with a synthetic "death-promoting" compound. 

The research, conducted in mice, appears in the March 23 issue of Cancer Research and could lead to more effective therapies for pancreatic and possibly other cancers, the researchers said.
"This compound enhanced the efficacy of chemotherapy and improved survival in multiple animal models of pancreatic cancer," said Dr. Rolf Brekken, associate professor of surgery and pharmacology and the study's senior author. "We now have multiple lines of evidence in animals showing that this combination is having a potent effect on pancreatic cancer, which is a devastating disease."
In this study, Dr. Brekken and his team transplanted human pancreatic tumors into mice, then allowed the tumors to grow to a significant size. They then administered a synthetic compound called JP1201 in combination with gemcitabine, a chemotherapeutic drug that is considered the standard of care for patients with pancreatic cancer. They found that the drug combination caused regression of the tumors.
"There was a 50 percent regression in tumor size during a two-week treatment of the mice," Dr. Brekken said. "We also looked at survival groups of the animals, which is often depressing in human therapeutic studies for pancreatic cancer because virtually nothing works. We found not only significant decrease in tumor size, but meaningful prolongation of life with the drug combination."
The drug combination was also effective in an aggressive model of spontaneous pancreatic cancer in mice.
The compound JP1201 was created in 2004 by UT Southwestern researchers to mimic the action of a protein called Smac. The researchers discovered Smac in 2000 and found that this protein plays a key role in the normal self-destruction process present in every cell.
Cell death, or apoptosis, is activated when a cell needs to be terminated, such as when a cell is defective or is no longer needed for normal growth and development. In cancer cells, this self-destruct mechanism is faulty and lead to breaks in the cell-death cascade of events. The synthetic Smac, or Smac mimetic, developed at UT Southwestern inhibits these breaks, allowing the cell to die.
"In essence, we're inhibiting an inhibitor," Dr. Brekken said. "And we're allowing the apoptotic cascade to kick off, resulting in the death of cancer cells."
UT Southwestern researchers are using Smac mimetics in breast and lung cancer research, as well. Dr. Brekken said the next step is to develop a compound based on JP1201 that can be tested in humans in clinical trials.
Other UT Southwestern researchers involved in the study included lead author Dr. Sean Dineen, surgery resident; Dr. Christina Roland, surgery resident; Rachel Greer, student research assistant in the Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research; Juliet Carbon, senior research associate in surgery and in the Hamon Center; Jason Toombs, research assistant in surgery and in the Hamon Center; Dr. Puja Gupta, a pediatric hematology/oncology fellow; Dr. Noelle Williams, associate professor of biochemistry; and Dr. John Minna, director of the W.A. "Tex" and Deborah Moncrief Jr. Center for Cancer Genetics and of the Hamon Center.
The research was supported by Susan G. Komen for the Cure and Joyant Pharmaceuticals, a Dallas-based company and UT Southwestern spinoff that is developing medical applications of Smac-mimetic compounds.

Experts say U.S. doctors overtesting, overtreating

Too much cancer screening, too many heart tests, too many cesarean sections. A spate of recent reports suggest that too many Americans — maybe even President Obama — are being overtreated.

Is it doctors practicing defensive medicine? Or are patients so accustomed to a culture of medical technology that they insist on extensive tests and treatments?

A combination of both is at work, but now new evidence and guidelines are recommending a step back and more thorough doctor-patient conversations about risks and benefits.

As a medical journal editorial said this week about Obama's recent checkup, Americans including the commander in chief need to realize that "more care is not necessarily better care."

Obama's exam included prostate-cancer screening and a virtual colonoscopy. The PSA test for prostate cancer is not routinely recommended for any age and colon screening is not routinely recommended for patients younger than 50. Obama is 48. (PSA stands for prostate-specific antigen screening).

Earlier colon-cancer screening is sometimes recommended for high-risk groups — which a White House spokesman noted includes blacks. Doctors disagree on whether a virtual colonoscopy is the best method. But it's less invasive than traditional colonoscopies and doesn't require sedation — or the possible temporary transfer of presidential power, the White House said.

The colon exam exposed him to radiation "while likely providing no benefit to his care," Dr. Rita Redberg, editor of Archives of Internal Medicine, wrote in an online editorial. "People have come to equate tests with good care and prevention," Redberg, a cardiologist with the University of California, San Francisco, said in an interview Thursday. "Prevention is all the things your mother told you — eat right, exercise, get enough sleep, don't smoke — and we've made it into getting a new test."

This week alone, a New England Journal of Medicine study suggested that too many patients are getting angiograms — invasive imaging tests for heart disease — who don't really need them; and specialists convened by the National Institutes of Health said doctors are too often demanding repeat cesarean deliveries for pregnant women after a first C-section.

Experts dispute how much routine cancer screening saves lives.

Not all doctors and advocacy groups agree with the criticism of screening. Many argue that it can improve survival chances and that saving even a few lives is worth the cost of routinely testing tens of thousands of people.

While some patients clearly do benefit from screening, others clearly do not, said Dr. Richard Wender, former president of the American Cancer Society.

These include very old patients, who may unrealistically fear cancer and demand a screening test, when their risks are far higher of dying from something else, Wender said.

Doctors also often order tests or procedures to protect themselves against lawsuits — so-called defensive medicine — and also because the fee-for-service system compensates them for it, said Dr. Gilbert Welch, a Dartmouth University internist and health-outcomes researcher.

While many patients also demand routine tests, they're often bolstered by advertisements, medical information online — and by doctors, too, Welch said.

The new guidance from the cancer society last week on PSA testing, echoing others' advice on mammograms, is for doctors and patients to thoroughly discuss testing, including a patient's individual disease risks, general pros and cons of testing and possible harms it may cause.

Read More : seattletimes

Medical Identity Theft

     The latest addition to the world of fraud , medical identity theft. You might be wondering what really is " Medical Identity Theft" . It is in simple words , usage of ones health cards by some other person without the knowledge of its real owner. The owner of the card may come to the realization of the fraud only when his service provoder sent him bills for thousands of dollars for some surgeries that he never underwent.
                                     The irony is that most of the fraud are done by family members or close family friends. So the number of cases reported will be very rare. The hospital authorities also didn't check much details once they are provided with health cards , that also is a reason for this fraud to develop.

             To read a detailed report on Medical Identity Theft Read from here  :: Medical Identity Theft

Genetic Variant Offers Protection Against Tuberculosis and Leprosy

When people get exposed to the mycobacterium responsible for tuberculosis (TB), some will become sick with a disease that is a major cause of mortality around the world while others simply don't. Now, researchers reporting in the March 5th issue of the journal Cell, a Cell Press publication, can point to one important reason for this variation in susceptibility or resistance: genetic differences among individuals in levels of an immune enzyme (LTA4H) that is involved in the production of leukotriene B, a pro-inflammatory fatty acid immune signaling molecule.
It turns out individuals who are heterozygous for LTA4H, meaning they carry two versions of the enzyme-encoding gene and produce an average amount of the enzyme (not too little or too much), are less likely to succumb to tuberculosis. They also appear to gain protection against leprosy, a disease which is also caused by mycobacterial infection.
"TB is obviously a big problem," said Lalita Ramakrishnan of the University of Washington. "There isn't a good vaccine, notwithstanding the fact that the TB vaccine has been administered to more people than any other. On top of that, it requires long-term treatment for cure and there is an epidemic of drug-resistant TB. Increasingly, people are becoming infected with strains that are resistant to every antibiotic. On this backdrop, it made sense to go back to the drawing board and try to understand the pathogenesis of the disease."
In the new study, Ramakrishnan and her colleague David Tobin did just that, in an unbiased screen for TB susceptibility genes in the zebrafish. They then collaborated with University of Washington human geneticists Jay Vary, Thomas Hawn and Mary-Claire King and others in Vietnam and Nepal to validate their findings in human populations.
A second study in the same issue of Cell approached the question in another way. Kanury Rao and his colleagues at the International Centre for Genetic Engineering and Biotechnology in India used a genome-wide analysis to produce what now becomes a resource for TB researchers everywhere. They uncovered all of the "cellular machinery" within human macrophages -- the cells primarily targeted by TB -- that interact with the infectious mycobacteria and allow the infection to stably persist.
Rao's team uncovered 275 players within host cells that interact with each other to form a dense network. That picture allowed the researchers to make a detailed molecular-level description of what he refers to as "functional modules" within host cells that are engaged and perturbed by TB infection. Interestingly, they showed that the shape of that interaction varies depending on which isolated strain of TB one considers, suggesting that the different strains rely on somewhat different tactics for successful infection.
Rao's findings offer new leads in the fight against TB, he says. "We identify a core set of molecules which can be targeted through drug development efforts to treat both drug sensitive and multiple drug resistant forms of TB infection. Rather than targeting the pathogen itself, our studies highlight an alternate strategy wherein the host factors required to support pathogen survival can be used as targets for TB therapy."
The discovery of LTA4H as a TB susceptibility gene may have clinical implications too, even if it doesn't offer a direct path to a better vaccine, Ramakrishnan says. For one thing, the finding that medium activity of the immune enzyme is best when it comes to TB might help to explain something that has been known but not well understood in clinical circles: people with hard-to-treat TB sometimes improve when they are given anti-inflammatory, immunosuppressive therapies along with more standard drug treatments alone.
Ramakrishnan also notes that the same polymorphisms in LTA4H they uncovered were earlier linked to heart disease. That suggests that drugs that target this pathway in heart disease might be useful in the context of TB, she says.
The connection between infectious disease and heart disease also has implications for understanding the evolution of the immune system's inflammatory responses. "In general, people have thought that inflammation is a positive when it comes to fighting infection, but then it can cause modern-day disease," Ramakrishnan says. The finding that it is heterozygotes -- with intermediate activity of the immunity enzyme -- who fare best in the context of TB and leprosy suggests that in these infections also, inflammation has to be finely tuned for optimal protection.
The researchers include David M. Tobin, University of Washington, Seattle, WA; Jay C. Vary, Jr., University of Washington, Seattle, WA; John P. Ray, University of Washington, Seattle, WA; Gregory S. Walsh, Howard Hughes Medical Institute and Division of Basic Science, Fred Hutchinson Cancer Research Center, Seattle, WA; Sarah J. Dunstan, Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam, Oxford University, Oxford, UK; Nguyen D. Bang, Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease, Ho Chi Minh City, Vietnam; Deanna A. Hagge, Mycobacterial Research Laboratory, Anandaban Hospital, Kathmandu, Nepal; Saraswoti Khadge, Mycobacterial Research Laboratory, Anandaban Hospital, Kathmandu, Nepal; Mary-Claire King, University of Washington, Seattle, WA; Thomas R. Hawn, University of Washington, Seattle, WA; Cecilia B. Moens, Howard Hughes Medical Institute and Division of Basic Science, Fred Hutchinson Cancer Research Center, Seattle, WA; and Lalita Ramakrishnan, University of Washington, Seattle, WA.

Vitamin D Crucial to Activating Immune Defenses

Scientists at the University of Copenhagen have discovered that Vitamin D is crucial to activating our immune defenses and that without sufficient intake of the vitamin, the killer cells of the immune system -- T cells -- will not be able to react to and fight off serious infections in the body.
For T cells to detect and kill foreign pathogens such as clumps of bacteria or viruses, the cells must first be 'triggered' into action and 'transform' from inactive and harmless immune cells into killer cells that are primed to seek out and destroy all traces of a foreign pathogen.
The researchers found that the T cells rely on vitamin D in order to activate and they would remain dormant, 'naïve' to the possibility of threat if vitamin D is lacking in the blood.
Chemical Reaction that Enables Activation
In order for the specialized immune cells (T cells) to protect the body from dangerous viruses or bacteria, the T cells must first be exposed to traces of the foreign pathogen. This occurs when they are presented by other immune cells in the body (known as macrophages) with suspicious 'cell fragments' or 'traces' of the pathogen. The T cells then bind to the fragment and divide and multiply into hundreds of identical cells that are all focused on the same pathogen type. The sequence of chemical changes that the T cells undergo enables them to both be 'sensitized to' and able to deliver a targeted immune response.
Professor Carsten Geisler from the Department of International Health, Immunology and Microbiology explains that "when a T cell is exposed to a foreign pathogen, it extends a signaling device or 'antenna' known as a vitamin D receptor, with which it searches for vitamin D. This means that the T cell must have vitamin D or activation of the cell will cease. If the T cells cannot find enough vitamin D in the blood, they won't even begin to mobilize. "
T cells that are successfully activated transform into one of two types of immune cell. They either become killer cells that will attack and destroy all cells carrying traces of a foreign pathogen or they become helper cells that assist the immune system in acquiring "memory." The helper cells send messages to the immune system, passing on knowledge about the pathogen so that the immune system can recognize and remember it at their next encounter. T cells form part of the adaptive immune system, which means that they function by teaching the immune system to recognize and adapt to constantly changing threats.
Activating and Deactivating the Immune System
For the research team, identifying the role of vitamin D in the activation of T cells has been a major breakthrough. "Scientists have known for a long time that vitamin D is important for calcium absorption and the vitamin has also been implicated in diseases such as cancer and multiple sclerosis, but what we didn't realize is how crucial vitamin D is for actually activating the immune system -- which we know now. "
The discovery, the scientists believe, provides much needed information about the immune system and will help them regulate the immune response. This is important not only in fighting disease but also in dealing with anti-immune reactions of the body and the rejection of transplanted organs. Active T cells multiply at an explosive rate and can create an inflammatory environment with serious consequences for the body. After organ transplants, e.g. T cells can attack the donor organ as a "foreign invader." In autoimmune disease, hypersensitive T cells mistake fragments of the body's own cells for foreign pathogens, leading to the body launching an attack upon itself.
The research team was also able to track the biochemical sequence of the transformation of an inactive T cell to an active cell, and thus would be able to intervene at several points to modulate the immune response. Inactive or 'naïve' T cells crucially contain neither the vitamin D receptor nor a specific molecule (PLC-gamma1) that would enable the cell to deliver an antigen specific response.
The findings, continues Professor Geisler "could help us to combat infectious diseases and global epidemics. They will be of particular use when developing new vaccines, which work precisely on the basis of both training our immune systems to react and suppressing the body's natural defenses in situations where this is important -- as is the case with organ transplants and autoimmune disease."
Most Vitamin D is produced as a natural byproduct of the skin's exposure to sunlight. It can also be found in fish liver oil, eggs and fatty fish such as salmon, herring and mackerel or taken as a dietary supplement. No definitive studies have been carried out for the optimal daily dosage of vitamin D but as a large proportion of the population have very low concentrations of vitamin D in the blood, a number of experts recommend between 25-50mg micrograms a day

Viruses Helped Shape Human Genetic Variability

Viruses have played a role in shaping human genetic variability, according to a study published February 19 in the open-access journal PLoS Genetics. The researchers, from the Don C. Gnocchi and Eugenio Medea Scientific Institutes, the University of Milan and the Politecnico di Milano, Italy, used population genetics approaches to identify gene variants that augment susceptibility to viral infections or protect from such infections.
Viruses have represented a threat to human populations throughout history and still account for a large proportion of disease and death worldwide. The identification of gene variants that modulate the susceptibility to viral infections is thus central to the development of novel therapeutic approaches and vaccines. Due to the long relationship between humans and viruses, gene variants conferring increased resistance to these pathogens have likely been targeted by natural selection. This concept was exploited to identify variants in the human genome that modulate susceptibility to infection or the severity of the ensuing disease.
In particular, the authors based their study on the idea that populations living in different geographic areas have been exposed to different viral loads and therefore have been subjected to a variable virus-driven selective pressure. By analysing genetic data for 52 populations distributed worldwide, the authors identified variants that display higher frequency where the viral load is also high. Using this approach, they found 139 human genes that modulate susceptibility to viral infections; the protein products of several of these genes interact with one another and often with viral components.
The study relied on predictions generated in computer simulations; therefore, experimental validation of these results will be required. The authors conclude that approaches similar to the one they applied might be used to identify susceptibility variants for infections transmitted by pathogens other than viruses.

Genetic Link Between Misery and Death Discovered; Novel Strategy Probes 'Genetic Haystack'

Interaction between nerves (red) and tumor cells (blue) in an ovary provides one way by which stress biochemistry signals can be distributed to sites of disease in the body

In ongoing work to identify how genes interact with social environments to impact human health, UCLA researchers have discovered what they describe as a biochemical link between misery and death. In addition, they found a specific genetic variation in some individuals that seems to disconnect that link, rendering them more biologically resilient in the face of adversity.
Perhaps most important to science in the long term, Steven Cole, a member of the UCLA Cousins Center for Psychoneuroimmunology and an associate professor of medicine in the division of hematology-oncology, and his colleagues have developed a unique strategy for finding and confirming gene-environment interactions to more efficiently probe what he calls the "genetic haystack."
The research appears in the current online edition of Proceedings of the National Academy of Sciences.
Using an approach that blends computational, in vivo and epidemiological studies to focus their genetic search, Cole and his colleagues looked at specific groups of proteins known as transcription factors, which regulate gene activity and mediate environmental influences on gene expression by binding to specific DNA sequences. These sequences differ within the population and may affect a gene's sensitivity to environmental activation.
Specifically, Cole analyzed transcription factor binding sequences in a gene called IL6, a molecule that is known to cause inflammation in the body and that contributes to cardiovascular disease, neurodegeneration and some types of cancer.
"The IL6 gene controls immune responses but can also serve as 'fertilizer' for cardiovascular disease and certain kinds of cancer," said Cole, who is also a member of UCLA's Jonsson Comprehensive Cancer Center and UCLA's Molecular Biology Institute. "Our studies were able to trace a biochemical pathway through which adverse life circumstances -- fight-or-flight stress responses -- can activate the IL6 gene.
"We also identified the specific genetic sequence in this gene that serves as a target of that signaling pathway, and we discovered that a well-known variation in that sequence can block that path and disconnect IL6 responses from the effects of stress."
To confirm the biochemical link between misery and death, and the genetic variation that breaks it, the researchers turned to epidemiological studies to prove that carriers of that specific genetic variation were less susceptible to death due to inflammation-related mortality causes under adverse social-environmental conditions.
They found that people with the most common type of the IL6 gene showed an increased risk of death for approximately 11 years after they had been exposed to adverse life events that were strong enough to trigger depression. However, people with the rarer variant of the IL6 gene appeared to be immune to those effects and showed no increase in mortality risk in the aftermath of significant life adversity.
This novel method of discovery -- using computer modeling and then confirming genetic relationships using test-tube biochemistry, experimental stress studies and human genetic epidemiology -- could speed the discovery of such gene and environmental relationships, the researchers say.
"Right now, we have to hunt down genetic influences on health through blind searches of huge databases, and the results from that approach have not yielded as much as expected," Cole said. "This study suggests that we can use computer modeling to discover gene-environment interactions, then confirm them, in order to focus our search more efficiently and hopefully speed the discovery process.
"This opens a new era in which we can begin to understand the influence of adversity on physical health by modeling the basic biology that allows the world outside us to influence the molecular processes going on inside our cells."
Other authors on the study were Jesusa M. G. Arevalo, Rie Takahashi, Erica K. Sloan and Teresa E. Seeman, of UCLA; Susan K. Lutgendorf, of the University of Iowa; Anil K. Sood, of the University of Texas; and John F. Sheridan, of Ohio State University. Funding was provided by the National Institutes of Health, the UCLA Norman Cousins Center and the James L. Pendleton Charitable Trust. The authors report no conflict of interest.

Blocking Inflammation Receptor Kills Breast Cancer Stem Cells, Study Finds

Scientists at the University of Michigan Comprehensive Cancer Center have uncovered an important link between inflammation and breast cancer stem cells that suggests a new way to target cells that are resistant to current treatments.
The researchers identified a receptor, CXCR1, on the cancer stem cells which triggers growth of stem cells in response to inflammation and tissue damage. A drug originally developed to prevent organ transplant rejection blocks this receptor, killing breast cancer stem cells and preventing their metastasis in mice, according to the study.
Cancer stem cells, the small number of cells that fuel a tumor's growth, are believed to be resistant to current chemotherapies and radiation treatment, which researchers say may be the reason cancer so often returns after treatment.
"Developing treatments to effectively target the cancer stem cell population is essential for improving outcomes. This work suggests a new strategy to target cancer stem cells that can be readily translated into the clinic," says senior study author Max S. Wicha, M.D., Distinguished Professor of Oncology and director of the U-M Comprehensive Cancer Center. Wicha was part of the team that first identified stem cells in breast cancer.
Results of the current study appear online Jan. 4 in the Journal of Clinical Investigation and will appear in the journal's February print issue.
CXCR1 is a receptor for Interleukin-8, or IL-8, a protein produced during chronic inflammation and tissue injury. When tumors are exposed to chemotherapy, the dying cells produce IL-8, which stimulates cancer stem cells to replicate. Addition of the drug repertaxin to chemotherapy specifically targets and kills breast cancer stem cells by blocking CXCR1.
Mice treated with repertaxin or the combination of repertaxin and chemotherapy had dramatically fewer cancer stem cells than those treated with chemotherapy alone. In addition, repertaxin-treated mice developed significantly fewer metastases than mice treated with chemotherapy alone.
"These studies suggest that important links between inflammation, tissue damage and breast cancer may be mediated by cancer stem cells. Furthermore, anti-inflammatory drugs such as repertaxin may provide a means of blocking these interactions, thereby targeting breast cancer stem cells," Wicha says.
Repertaxin has been tested in early phase clinical trials to prevent rejection after organ transplantation. In these studies, side effects seem to be minimal. There are no reports of using repertaxin to treat cancer.
Note to patients: This work was done in cell cultures and mice. Repertaxin is not available to patients at this time and no clinical trials are yet planned.
Breast cancer statisitics: 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.
Additional authors: Christophe Ginestier, Suling Liu, Mark Diebel, Hasan Korkaya, Ming Luo, Marty Brown, Jun-Lin Guan, Gabriela Dontu, all from U-M; and Julien Wicinski, Olivier Cabaud, Emmanuelle Charafe-Jauffret, Daniel Birnbaum, all from Universite de la Mediterranee, Marseille, France
Funding: National Institutes of Health, Breast Cancer Foundation, Taubman Institute, Department of Defense, Inserm, Institut Paoli-Calmettes, Institut National du Cancer, Ligue Nationale Contre le Cancer
Disclosure: The University of Michigan has filed for patent protection on this technology, and is currently looking for a commercialization partner to help bring the technology to market.

Natural Compounds in Pomegranates May Prevent Growth of Hormone-Dependent Breast Cancer

Eating fruit, such as pomegranates, that contain anti-aromatase phytochemicals reduces the incidence of hormone-dependent breast cancer, according to results of a study published in the January issue of Cancer Prevention Research, a journal of the American Association for Cancer Research.

Pomegranate is enriched in a series of compounds known as ellagitannins that, as shown in this study, appear to be responsible for the anti-proliferative effect of the pomegranate.
"Phytochemicals suppress estrogen production that prevents the proliferation of breast cancer cells and the growth of estrogen-responsive tumors," said principal investigator Shiuan Chen, Ph.D., director of the Division of Tumor Cell Biology and co-leader of the Breast Cancer Research Program at City of Hope in Duarte, Calif.
Previous research has shown that pomegranate juice -- punica granatum L -- is high in antioxidant activity, which is generally attributed to the fruit's high polyphenol content. Ellagic acid found in pomegranates inhibits aromatase, an enzyme that converts androgen to estrogen. Aromatase plays a key role in breast carcinogenesis; therefore, the growth of breast cancer is inhibited.
Chen, along with Lynn Adams, Ph.D., a research fellow at Beckman Research Institute of City of Hope, and colleagues, evaluated whether phytochemicals in pomegranates can suppress aromatase and ultimately inhibit cancer growth.
After screening and examining a panel of 10 ellagitannin-derived compounds in pomegranates, the investigators found that those compounds have the potential to prevent estrogen-responsive breast cancers. Urolithin B, which is a metabolite produced from ellagic acid and related compounds, significantly inhibited cell growth.
"We were surprised by our findings," said Chen. "We previously found other fruits, such as grapes, to be capable of the inhibition of aromatase. But, phytochemicals in pomegranates and in grapes are different."
According to Gary Stoner, Ph.D., professor in the Department of Internal Medicine at Ohio State University, additional studies will be needed to confirm the chemopreventive action of Urolithin B against hormone-dependent breast cancer.
"This is an in vitro study in which relatively high levels of ellagitannin compounds were required to demonstrate an anti-proliferative effect on cultured breast cancer cells," said Stoner, who is not associated with this study. "It's not clear that these levels could be achieved in animals or in humans because the ellagitannins are not well absorbed into blood when provided in the diet."
Stoner believes these results are promising enough to suggest that more experiments with pomegranate in animals and humans are warranted.
Powel Brown, M.D., Ph.D., medical oncologist and chairman of the Clinical Cancer Prevention Department at the University of Texas M. D. Anderson Cancer Center, agreed with Stoner's sentiments and said these results are intriguing. He recommended that future studies focus on testing pomegranate juice for its effect on estrogen levels, menopausal symptoms, breast density or even as a cancer preventive agent.
"More research on the individual components and the combination of chemicals is needed to understand the potential risks and benefits of using pomegranate juice or isolated compounds for a health benefit or for cancer prevention," Brown said. "This study does suggest that studies of the ellagitannins from pomegranates should be continued."
Until then, Stoner said people "might consider consuming more pomegranates to protect against cancer development in the breast and perhaps in other tissues and organs."

Flower Power May Reduce Resistance to Breast Cancer Drug Tamoxifen

Feverfew plant used in herbal medicines.

Combining tamoxifen, the world's most prescribed breast cancer agent, with a compound found in the flowering plant feverfew may prevent initial or future resistance to the drug, say researchers at Georgetown Lombardi Comprehensive Cancer Center.
The finding, reported online Feb. 12 in The FASEB Journal, provides new insight into the biological roots of that resistance, and also tests a novel way to get around it.
"A solution to tamoxifen resistance is sorely needed, and if a strategy like this can work, it would make a difference in our clinical care of breast cancer," says the study's lead investigator, Robert Clarke, PhD, DSc, a professor of oncology and physiology & biophysics at Lombardi, a part of Georgetown University Medical Center (GUMC). Clarke is also the interim director of GUMC's Biomedical Graduate Research Organization.
Clarke added that the purified research chemical they tested, parthenolide, a derivative of feverfew, is being tested by other scientists as treatment for a variety of cancers, as well as other health conditions. Feverfew has long been a staple of natural medicine, and is particularly known for its effects on headaches and arthritis. Latin for "fever reducer," feverfew is a common garden bush with small daisy-like flowers.
"The chemical clearly has potential, and we ought to be able to figure out fairly quickly if it can help solve tamoxifen's resistance problem," Clarke says.
Tamoxifen is a treatment of choice for breast cancer that is estrogen receptor positive (ER+), meaning that the hormone estrogen drives cancer growth. Most newly diagnosed breast cancers -- about 70 percent -- fall into that category. But about half of these cancers do not initially respond to tamoxifen, which is designed to block the hormone from binding to the cell's protein receptor, and many patients that do respond are at risk for developing resistance and cancer relapse.
In this study, Clarke and a team of researchers set out to study if, as previous research had suggested, tamoxifen resistance is regulated by the protein complex NF-κB (nuclear factor kappa B), which is often found to be over-expressed in ER+ breast cancer. NF-κB is known to help cells survive when damaged. The researchers had earlier discovered that NF-κB is over-expressed in cells that are resistant to tamoxifen, and they had found that resistance to another tamoxifen-like drug, fulvestrant, was controlled by a protein (Bcl2) that is, itself, regulated by NF-κB.
"Our scientific quest was to see if blocking NF-?B affects tamoxifen resistance, and if it does, why?" says Clarke.
They conducted a variety of tests using parthenolide, which has been shown to act on NF-κB. They found that in resistant breast cancer cells, the chemical blocked the activity of NF-κB, making the cells sensitive once again to tamoxifen. They then silenced NF-B in tamoxifen resistant cells, and found that this had the same effect as using parthenolide.
They further found that increased activation of NF-κB can alter sensitivity of tamoxifen by modulating the protein CASP8, which is involved in programmed cell death. That then affects Bcl2, which also helps push a damaged cell to die.
"When you give tamoxifen to a breast cancer cell, that is essentially a pro-death signal, because you are blocking the cell's access to estrogen, and the cell recognizes this is a mortal blow," Clarke says. "Such a damaged cell uses CASP8 and Bcl2 to trigger the cell machinery needed for dying.
"But the cell has ways to counteract the pro-death signal, and one important one is to activate NF-κB, which can control expression of genes necessary for survival," he says. "Now the cell thinks it should be living, not dying."
Because NF-κB controls CASP8 and Bcl2, it can turn those proteins essentially off, Clarke says. "The pro-survival signals override the pro-death signals."
Still, as much as this study advances the understanding of tamoxifen resistance, there is much that is not understood, he adds. "We don't know when NF-κB becomes over-expressed in the transformation of tamoxifen-sensitive to a tamoxifen-resistant breast cancer cells, and we don't know of other adaptations the cell may have made," he says. "It is probably fair to say this is a hideously complex process."
To that end, Clarke cannot predict how many women who try a combination of tamoxifen and parthenolide will benefit. He says the science is much too early to make any recommendations and strongly warns women against adding feverfew supplements to their cancer treatment.
Still, he is hopeful. "Every breast tumor slightly different, but we know many do use NF-κB because excess amounts of the protein are found in these cancers," he says. "That suggests they may be sensitive to targeted approaches that shut down this pro-survival signal."
The study was funded by grants from the U.S. Department of Defense, the Army Medical Research and Material Command, and the National Institutes of Health. The authors disclose no potential financial conflicts.