New Colon Cancer Marker Identified

A research team at the University of Colorado Cancer Center has identified an enzyme that could be used to diagnose colon cancer earlier. It is possible that this enzyme also could be a key to stopping the cancer.

Colon cancer is the third most common cancer in Americans, with a one in 20 chance of developing it, according to the American Cancer Society. This enzyme biomarker could help physicians identify more colon cancers and do so at earlier stages when the cancer is more successfully treated.

The research was led by Cancer Center investigator Vasilis Vasiliou, PhD, professor of molecular toxicology at the University of Colorado School of Pharmacy, and published online in Biochemical and Biophysical Research Communications. Vasiliou's laboratory specializes in understanding the role of enzymes called aldehyde dehydrogenases in drug metabolism, metabolic diseases, cancer and normal and cancer stem cells.

Vasiliou's team studied colon cancers from 40 patients and found a form of this enzyme known as ALDH1B1 present in every colon cancer cell in 39 out of the 40 cases. The enzyme, which is normally found only in stem cells, was detected at extraordinarily high levels.

"Other potential colon cancer biomarkers have been identified in the past, but none thus far are present in such a high percent of the cancer cells and virtually none are overexpressed like this one," says Cancer Center investigator David Orlicky, PhD, associate professor of pathology at the CU medical school and a member of the research team.

This finding is particularly timely as it was recommended last week at the Human Genome 2011 annual meeting that a chemical analysis for biomarkers should always accompany genotyping in early detection of colon cancer, says Vasiliou, who attended the meeting in Dubai.

It appears that ALDH1B1 aids the development or growth of these cancer cells because it would not be present in every cell at such high levels if it were simply a byproduct of the cancer. Based on this finding, the enzyme may provide a way to treat the disease, says Ying Chen, PhD, lead author and assistant professor of molecular toxicology at the CU School of Pharmacy.

The team is now studying how this enzyme is up-regulated into colon cancer cells and its exact role in the physiology of the tumor cells, Vasiliou says. The team also is seeking to understand the substrate, inhibitors and activators of ALDH1B1.

"Our efforts are focused on developing a drug that could turn into a toxic compound and kill the cancer cell when acted upon by the enzyme," Vasiliou says. "It would act like a suicide pill, if you will."

Vasiliou's team is collaborating in this work with laboratories at the National Cancer Institute, Scripps Research Institute in California, University of Melbourne in Australia, University of Heidelberg in Germany and Oxford University in the United Kingdom.

"This work will be considered a landmark in the understanding of basic metabolic processes within the colon cancer cell," Orlicky says.

Journal Reference:

1. Ying Chen, David J. Orlicky, Akiko Matsumoto, Surendra Singh, David C. Thompson, Vasilis Vasiliou. Aldehyde dehydrogenase 1B1 (ALDH1B1) is a potential biomarker for human colon cancer. Biochemical and Biophysical Research Communications, 2011; 405 (2): 173 DOI: 10.1016/j.bbrc.2011.01.002

Courtesy: ScienceDaily

HIV Integration Requires Use of a Host DNA-Repair Pathway

The human immunodeficiency virus (HIV), the cause of AIDS, makes use of the base excision repair pathway when inserting its DNA into the host-cell genome, according to a new study led by researchers at the Ohio State University Comprehensive Cancer Center -- Arthur G. James Cancer Hospital and Richard J. Solove Research Institute. Crippling the repair pathway prevents the virus from completing this critical step in the retrovirus's life cycle.

The findings offer potential new targets for novel anti-HIV drugs that may not lead as quickly to viral resistance as current drugs, the researchers say.

"HIV continues to develop resistance to current therapies," says first author Kristine Yoder, assistant professor of molecular virology, immunology and medical genetics. "But the proteins we talk about in this paper are made by the cell, so drugs that target them might not lead to resistance as quickly as drugs that target viral proteins. And while targeting host proteins does have the potential for side effects, studies of mice suggest that targeting some of these genes may not lead to significant side effects."

The paper was published online March 23 in the journal PLoS ONE.

Cells normally use base excision repair to fix oxidative damage to DNA caused by reactive molecules such as hydrogen peroxide and oxygen radicals, which form during energy production and other metabolic processes.

For this study, Yoder and her colleagues investigated the role of the repair pathway in the virus insertion process by engineering four strains of mouse fibroblast cells that each lacked a component of the pathway. Specifically, they deleted genes for three glycosylase enzymes -- Ogg1, Myh, and Neil1 -- and one polymerase gene, Pol-beta.

They found that the loss of any of these elements reduced the ability of HIV DNA to integrate with host-cell DNA by about 60 to 70 percent. In an additional experiment, the researchers restored the polymerase in cells that lacked it, and this enabled the HIV DNA to again integrate at its normal level.

"Overall, our findings indicate that HIV infection and integration efficiency depends on the presence of base excision repair proteins, and that these proteins might make novel new targets for the treatment of HIV infection," Yoder says.

An American Recovery and Reinvestment Act grant from the National Institute of Allergy and Infectious Diseases supported this research.

Journal Reference:

1. Kristine E. Yoder, Amy Espeseth, Xiao-hong Wang, Qingming Fang, Maria Teresa Russo, R. Stephen Lloyd, Daria Hazuda, Robert W. Sobol, Richard Fishel. The Base Excision Repair Pathway Is Required for Efficient Lentivirus Integration. PLoS ONE, 2011; 6 (3): e17862 DOI: 10.1371/journal.pone.0017862

Courtesy: ScienceDaily

Nanoscale Whiskers from Sea Creatures Could Grow Human Muscle Tissue

Minute whiskers of nanoscale dimensions taken from sea creatures could hold the key to creating working human muscle tissue, University of Manchester researchers have discovered.

Scientists have found that cellulose from tunicates, commonly known as sea squirts, can influence the behaviour of skeletal muscle cells in the laboratory.

These nanostructures are several thousand times smaller than muscle cells and are the smallest physical feature found to cause cell alignment.

Alignment is important since a lot of tissue in the body, including muscle, contains aligned fibres which give it strength and stiffness.

Cellulose is a polysaccharide -- a long chain of sugars joined together -- usually found in plants and is the main component of paper and certain textiles such as cotton.

It is already being used for a number of different medical applications, including wound dressings, but this is the first time it has been proposed for creating skeletal muscle tissue.

Tunicates grow on rocks and human-made structures in coastal waters around the world.

Cellulose extracted from tunicates is particularly well suited for making muscle tissue due to its unique properties.

University of Manchester academics Dr Stephen Eichhorn and Dr Julie Gough, working with PhD student James Dugan, chemically extract the cellulose in the form of nanowhiskers. One nanometre is one billionth of a metre and these minute whiskers are only 10s of nanometres wide -- far thinner than a human hair.

When aligned and parallel to each other, they cause rapid muscle cell alignment and fusion.

The method is both simple and relatively quick, which could lead to doctors and scientists having the ability to create the normal aligned architecture of skeletal muscle tissue.

This tissue could be used to help repair existing muscle or even grow muscle from scratch.

Creating artificial tissue which can be used to replace damaged or diseased human muscles could revolutionise healthcare, and be of huge benefit to millions of people all over the world.

Dr Eichhorn thinks the cellulose extracted from the creatures could lead to a significant medical advancement. He added: "Although it is quite a detailed chemical process, the potential applications are very interesting.

"Cellulose is being looked at very closely around the world because of its unique properties, and because it is a renewable resource, but this is the first time that it has been used for skeletal muscle tissue engineering applications.

"There is potential for muscle precision engineering, but also for other architecturally aligned structures such as ligaments and nerves."

PhD student James Dugan has become the first UK student to win the American Chemical Society's Cellulose and Renewable Material Division award for his work on nanowhiskers.

Story Source:

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

Courtesy: ScienceDaily

Pushing HIV out the Door: How Host Factors Aid in the Release of HIV Particles

Human Immunodeficiency Virus (HIV) -- which causes AIDS -- invades human immune cells and causes them to produce new copies of the virus, which can then infect new cells. A research team led by Professor Don C. Lamb (LMU Munich) and Priv.-Doz. Dr. Barbara Müller of Heidelberg University Hospital have now analyzed the involvement of particular components of the infected cell in virion release, and discovered that the enzyme VPS4A plays a more active role in the process than was previously thought.

VPS4A was already known to act after virus budding was complete. Using an advanced microscopy technique, the group was able to show that complexes containing about a dozen VPS4A molecules form at points in the membrane at which newly assembled virions later emerge.

According to Lamb, "We can now demonstrate in detail, for the first time, how host proteins interact with components of HIV, to enable them to bud from infected cells. Our ultimate goal is to elucidate the entire life cycle of the virus." "With the methods we have at our disposal, we can also study the effects of drugs on infected cells, which may allow us to improve their efficacy or even lead to the development of new classes of active compounds."

The research is published in Nature Cell Biology.

Viruses are like pirates: they board a suitable cell and alter its course to suit their own purpose. More specifically, they smuggle their own genetic material into a host cell and reprogram the cell to produce new virus particles. For release of the newly synthesized viruses, HIV exploits cellular proteins involved in the loading, sorting and budding of cellular vesicles known as ESCRT proteins. During budding, HIV makes use of ESCRT to cut the last connection between the virion coat and the cell surface, allowing it to exit the cell. The enzyme VPS4A forms part of the ESCRT machinery and is known to be necessary for the disassembly of the complex after use, allowing its components to be recycled.

The results from ultrasensitive live-cell imaging experiments showed that VPS4A also acts at an earlier stage in the budding process. In the new work, the researchers labeled the enzyme by fusing it with the Green Fluorescent Protein (GFP). This allowed them to track the protein in living cells. By recording the fluorescent signals, they observed how several VPS4A molecules came together to form larger complexes. "In this case, we were able to count how many enzyme molecules assembled at the HIV budding site during its interaction with the nascent virion" says Müller.

Complexes made up of about three dodecamers of VPS4A were observed to undergo transient activation (for about a minute) at a budding site. Shortly thereafter, the virions were observed to emerge from the cell at these locations. Because virion release does not follow immediately upon activation of the enzyme, the investigators believe that at least one further intermediate step is required for budding.

Perhaps this postulated step can be pinned down in a later project. "Our current methodology allows us to monitor the assembly of individual virions, and we are working on further refinements that will allow us to follow the complete life cycle of HIV," says Lamb. "We can already visualize some steps of the life cycle at the level of a single virus, observe interactions and determine the kinetics of different processes. Of course, this means that we can also label therapeutic agents and observe what effects they have in infected cells. This can help us to optimize the currently available drugs and even allow us to develop new ones." (göd)

The study was carried out in the context of three Clusters of Excellence, the Center for Integrated Protein Science Munich (CIPSM), the Nanosystems Initiative Munich (NIM) and CellNetworks Heidelberg. The work was also supported by the German Research Foundation (DFG) as part of Priority Program 1175 Dynamics of Cellular Membranes and Their Exploitation by Viruses.

Journal Reference:

1. Viola Baumgärtel, Sergey Ivanchenko, Aurélie Dupont, Mikhail Sergeev, Paul W. Wiseman, Hans-Georg Kräusslich, Christoph Bräuchle, Barbara Müller, Don C. Lamb. Live-cell visualization of dynamics of HIV budding site interactions with an ESCRT component. Nature Cell Biology, 2011; DOI: 10.1038/ncb2215

Courtesy: ScienceDaily

Giftedness Linked to Prenatal Exposure of Higher Levels of Testosterone

A longstanding debate as to whether genius is a byproduct of good genes or good environment has an upstart challenger that may take the discussion in an entirely new direction. University of Alberta researcher Marty Mrazik says being bright may be due to an excess level of a natural hormone.Mrazik, a professor in the Faculty of Education's educational psychology department, and a colleague from Rider University in the U.S., have published a paper in Roeper Review linking giftedness (having an IQ score of 130 or higher) to prenatal exposure of higher levels of testosterone. Mrazik hypothesizes that, in the same way that physical and cognitive deficiencies can be developed in utero, so, too, could similar exposure to this naturally occurring chemical result in giftedness.

"There seems to be some evidence that excessive prenatal exposure to testosterone facilitates increased connections in the brain, especially in the right prefrontal cortex," said Mrazik. "That's why we see some intellectually gifted people with distinct personality characteristics that you don't see in the normal population."

Mrazik's notion came from observations made during clinical assessments of gifted individuals. He and his fellow researcher observed some specific traits among the subjects. This finding stimulated a conversation on the role of early development in setting the foundation for giftedness.

"It gave us some interesting ideas that there could be more to this notion of genius being predetermined from a biological perspective than maybe people gave it credit for," said Mrazik. "It seemed that the bulk of evidence from new technologies (such as Functional MRI scans) tell us that there's a little bit more going on than a genetic versus environmental interaction."

Based on their observations, the researchers made the hypothesis that this hormonal "glitch" in the in-utero neurobiological development means that gifted children are born with an affinity for certain areas such as the arts, math or science. Mrazik cautions that more research is needed to determine what exact processes may cause the development of the gifted brain.

He notes that more is known about what derails the brain's normal development, thus charting what makes gifted people gifted is very much a new frontier. Mrazik hopes that devices such as the Functional MRI scanner will give them a deeper understanding of the role of neurobiology in the development of the gifted brain.

"It's really hard to say what does put the brain in a pathway where it's going to be much more precocious," he said. "The next steps in this research lay in finding out what exact stimuli causes this atypical brain development."

Journal Reference:

1. Martin Mrazik, Stefan Dombrowski. The Neurobiological Foundations of Giftedness. Roeper Review, 2010; 32 (4): 224 DOI: 10.1080/02783193.2010.508154

Courtesy: ScienceDaily

Prostate Cancer: Targeted Therapy Shrank Tumors Up to 74 Percent in Cells in Mice

Researchers at the University of Michigan Comprehensive Cancer Center have identified a potential target to treat an aggressive type of prostate cancer. The target, a gene called SPINK1, could be to prostate cancer what HER2 has become for breast cancer.

Like HER2, SPINK1 occurs in only a small subset of prostate cancers -- about 10 percent. But the gene is an ideal target for a monoclonal antibody, the same type of drug as Herceptin, which is aimed at HER2 and has dramatically improved treatment for this aggressive type of breast cancer.

"Since SPINK1 can be made on the surface of cells, it attracted our attention as a therapeutic target. Here we show that a 'blocking' antibody to SPINK1 could slow the growth of prostate tumors in mice that were positive for the SPINK protein," says study author Arul Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology and a Howard Hughes Medical Institute Investigator.

The study appears in the March 2 issue of Science Translational Medicine.

The researchers additionally found that SPINK1 can bind to a receptor called EGFR. They tested a drug that blocks EGFR, cetuximab, which is already approved by the U.S. Food and Drug Administration, and found that this also reduced the cancerous effects of SPINK1.

Using mice, researchers first tested a monoclonal antibody -- a type of targeted treatment designed to go after a specific molecule (in this case, SPINK1). They then tested cetuximab. Tumors treated with the SPINK1 antibody shrunk 60 percent, while tumors treated with cetuximab shrunk 40 percent. By combining the two drugs, tumors were 74 percent smaller.

The effect was seen only in tumors that expressed SPINK1 and was not seen in tumors that did not express SPINK1.

Previous studies that looked at cetuximab for metastatic prostate cancer have been disappointing, with only 8 percent of patients showing some benefit. The researchers suggest that the poor results may be because the treatment is appropriate only for patients with SPINK1-positive tumors.

"About 10 percent of prostate cancer patients are SPINK1-positive and strategies to block SPINK1 signaling may have utility in this subset of patients. These studies should stimulate the development of antibody-based therapies against SPINK1 or targeting of EGFR in SPINK1-positive cancer patients," says study author Bushra Ateeq, a research fellow at the U-M Medical School.

SPINK1 is associated with a more aggressive form of prostate cancer. It can be detected in the urine of prostate cancer patients, making it an easy test for urologists to perform routinely.

"This non-invasive form of screening could be helpful in the molecular categorization of prostate cancer patients and administering therapies in a molecularly guided fashion," says Chinnaiyan, S.P. Hicks Endowed Professor of Pathology at the U-M Medical School and an American Cancer Society Research Professor.

The study suggests that side effects were limited in mice. Future studies will need to determine whether targeting SPINK1 in humans would affect normal tissue. The researchers will also look to further understand why SPINK1 is elevated in a subset of prostate cancers. Clinical trials testing SPINK1 therapies are not available at this time.

Prostate cancer statistics: 217,730 Americans will be diagnosed with prostate cancer this year and 32,050 will die from the disease, according to the American Cancer Society

Additional authors: Scott A. Tomlins, Bharathi Laxman, Irfan A. Asangani, Qi Cao, Xuhong Cao, Yong Li, Felix Y. Feng, Kenneth J. Pienta and Sooryanarayana Varambally

Funding U.S. Department of Defense, Early Detection Research Network, Prostate SPORE, National Institutes of Health, Prostate Cancer Foundation

Reference: Science Translational Medicine, Vol. 3, No. 72, March 2, 2011

Journal Reference:

1. Bushra Ateeq, Scott A. Tomlins, Bharathi Laxman, Irfan A. Asangani, Qi Cao, Xuhong Cao, Yong Li, Xiaoju Wang, Felix Y. Feng, Kenneth J. Pienta, Sooryanarayana Varambally and Arul M. Chinnaiyan. Therapeutic Targeting of SPINK1-Positive Prostate Cancer. Sci Transl Med, 2 March 2011 3:72ra17 DOI: 10.1126/scitranslmed.3001498

Courtesy: ScienceDaily

Invasive Species Widespread, but Not More Than at Home Range

Invasive plant species have long had a reputation as being bad for a new ecosystem when they are introduced.Stan Harpole, assistant professor of ecology, evolution and organismal biology at Iowa State University, is founding organizer of a team of more than 70 researchers working at 65 sites worldwide that tested that assumption.

They wanted to know if it is true that problematic invasive species often spread widely in their new habitats because they don't encounter predators or diseases that help keep them in check in their home ranges.

"There is this assumption that when plants invade a new area that they become much more abundant in the new area than they were in the native areas," said Harpole. "It turns out that, on average, they aren't any more abundant away from home than they are at home."

Harpole says there is a "rule of 10s" that can apply to invasive species.

"Of, say, 100 plants that arrive in a new area, only about 10 percent of those will survive without being in a greenhouse or some other controlled area," said Harpole. "Of those 10 that can survive, only about 10 percent of those really cause problems.

"When you think about all the species we've brought over from other areas, relatively few have become serious pest species. The problem is we've brought over so many that quite a few have become major problems and they get a lot of attention."

Harpole points to the kudzu plant as an example.

Kudzu was introduced from Asia as a soil erosion plant more than a century ago. It now chokes out native species from Texas to Maine to Florida, according to the U.S. Department of Agriculture.

Problem plants like this are uncommon when compared to all the exotic species in a region, but they do get the most interest and may give the impression that species that escape their home range often spread and take over new habitats and become more abundant than before, says Harpole.

Invasion can also be thought of more generally as a process in which new species enter new habitats. Even plants now considered native were once invaders, says Harpole.

When glaciers receded from the Midwest 10,000 years ago, there were no native species in the area -- the retreating ice left bare ground open for invasion.

"All the plants that are now seen as native were invasive in the past in the sense that they had to spread across the landscape," he said.

"What's different today is that we move plants so much faster than they would move by themselves. Now a species can become global in a matter of years, where it may have taken tens of thousands of years in the past," said Harpole.

Harpole is coauthor of a research paper led by Jennifer Firn of Queensland University of Technology, Australia, and is published in the journal Ecology Letters. Coordination of the study was funded by the National Science Foundation.

Journal Reference:

1. Jennifer Firn, Joslin L. Moore, Andrew S. MacDougall, Elizabeth T. Borer, Eric W. Seabloom, Janneke HilleRisLambers, W. Stanley Harpole, Elsa E. Cleland, Cynthia S. Brown, Johannes M. H. Knops, Suzanne M. Prober, David A. Pyke, Kelly A. Farrell, John D. Bakker, Lydia R. O’Halloran, Peter B. Adler, Scott L. Collins, Carla M. D’Antonio, Michael J. Crawley, Elizabeth M. Wolkovich, Kimberly J. La Pierre, Brett A. Melbourne, Yann Hautier, John W. Morgan, Andrew D. B. Leakey, Adam Kay, Rebecca McCulley, Kendi F. Davies, Carly J. Stevens, Cheng-Jin Chu, Karen D. Holl, Julia A. Klein, Philip A. Fay, Nicole Hagenah, Kevin P. Kirkman, Yvonne M. Buckley. Abundance of introduced species at home predicts abundance away in herbaceous communities. Ecology Letters, 2011; 14 (3): 274 DOI: 10.1111/j.1461-0248.2010.01584.x

Courtesy: ScienceDaily

Scientists Create Cell Assembly Line: New Technology Synthesizes Cellular Structures from Simple Starting Materials

Borrowing a page from modern manufacturing, scientists from the Florida campus of The Scripps Research Institute have built a microscopic assembly line that mass produces synthetic cell-like compartments.

The new computer-controlled system represents a technological leap forward in the race to create the complex membrane structures of biological cells from simple chemical starting materials.

"Biology is full of synthetic targets that have inspired chemists for more than a century," said Brian Paegel, Scripps Research assistant professor and lead author of a new study published in the Journal of the American Chemical Society. "The lipid membrane assemblies of cells and their organelles pose a daunting challenge to the chemist who wants to synthesize these structures with the same rational approaches used in the preparation of small molecules."

While most cellular components such as genes or proteins are easily prepared in the laboratory, little has been done to develop a method of synthesizing cell membranes in a uniform, automated way. Current approaches are capricious in nature, yielding complex mixtures of products and inefficient cargo loading into the resultant cell-like structures.

The new technology transforms the previously difficult synthesis of cell membranes into a controlled process, customizable over a range of cell sizes, and highly efficient in terms of cargo encapsulation.

The membrane that surrounds all cells, organelles and vesicles -- small subcellular compartments -- consists of a phospholipid bilayer that serves as a barrier, separating an internal space from the external medium.

The new process creates a laboratory version of this bilayer that is formed into small, cell-sized compartments.

How It Works

"The assembly-line process is simple and, from a chemistry standpoint, mechanistically clear," said Sandro Matosevic, research associate and co-author of the study.

A microfluidic circuit generates water droplets in lipid-containing oil. The lipid-coated droplets travel down one branch of a Y-shaped circuit and merge with a second water stream at the Y-junction. The combined flows of droplets in oil and water travel in parallel streams toward a triangular guidepost.

Then, the triangular guide diverts the lipid-coated droplets into the parallel water stream as a wing dam might divert a line of small boats into another part of a river. As the droplets cross the oil-water interface, a second layer of lipids deposits on the droplet, forming a bilayer.

The end result is a continuous stream of uniformly shaped cell-like compartments.

The newly created vesicles range from 20 to 70 micrometers in diameter -- from about the size of a skin cell to that of a human hair. The entire circuit fits on a glass chip roughly the size of a poker chip.

The researchers also tested the synthetic bilayers for their ability to house a prototypical membrane protein. The proteins correctly inserted into the synthetic membrane, proving that they resemble membranes found in biological cells.

"Membranes and compartmentalization are ubiquitous themes in biology," noted Paegel. "We are constructing these synthetic systems to understand why compartmentalized chemistry is a hallmark of life, and how it might be leveraged in therapeutic delivery."

Journal Reference:

1. Sandro Matosevic, Brian M. Paegel. Stepwise Synthesis of Giant Unilamellar Vesicles on a Microfluidic Assembly Line. Journal of the American Chemical Society, 2011; 110210133308021 DOI: 10.1021/ja109137s

Courtesy: ScienceDaily