Gene Therapy Boosts Brain Repair for Demyelinating Diseases

Our bodies are full of tiny superheroes -- antibodies that fight foreign invaders, cells that regenerate, and structures that ensure our systems run smoothly. One such structure is myelin -- a material that forms a protective, insulating cape around the axons of our nerve cells so that they can send signals quickly and efficiently. But myelin, and the specialized cells called oligodendrocytes that make it, become damaged in demyelinating diseases like multiple sclerosis (MS), leaving neurons without their myelin sheaths. As a consequence, the affected neurons can no longer communicate correctly and are prone to damage. Researchers from the California Institute of Technology (Caltech) now believe they have found a way to help the brain replace damaged oligodendrocytes and myelin. The therapy, which has been successful in promoting remyelination in a mouse model of MS, is outlined in a paper published February 8 in The Journal of Neuroscience. "We've developed a gene therapy to stimulate production of new oligodendrocytes from stem and progenitor cells -- both of which can become more specialized cell types -- that are resident in the adult central nervous system," says Benjamin Deverman, a postdoctoral fellow in biology at Caltech and lead author of the paper. "In other words, we're using the brain's own progenitor cells as a way to boost repair." The therapy uses leukemia inhibitory factor (LIF), a naturally occurring protein that was known to promote the self-renewal of neural stem cells and to reduce immune-cell attacks to myelin in other MS mouse models. "What hadn't been done before our study was to use gene therapy in the brain to stimulate these cells to remyelinate," says Paul Patterson, the Biaggini Professor of Biological Sciences at Caltech and senior author of the study. According to the researchers, LIF enables remyelination by stimulating oligodendrocyte progenitor cells to proliferate and make new oligodendrocytes. The brain has the capacity to produce oligodendrocytes, but often fails to prompt a high enough repair response after demyelination. "Researchers had been skeptical that a single factor could lead to remyelination of damaged cells," says Deverman. "It was thought that you could use factors to stimulate the division and expansion of the progenitor population, and then add additional factors to direct those progenitors to turn into the mature myelin-forming cells. But in our mouse model, when we give our LIF therapy, it both stimulates the proliferation of the progenitor cells and allows them to differentiate into mature oligodendrocytes." In other words, once the researchers stimulated the proliferation of the progenitor cells, it appeared that the progenitors knew just what was needed -- the team did not have to instruct the cells at each stage of development. And they found that LIF elicited such a strong response that the treated brain's levels of myelin-producing oligodendrocytes were restored to those found in healthy populations. The researchers note, too, that by placing LIF directly in the brain, one avoids potential side effects of the treatment that may arise when the therapy is infused into the bloodstream. "This new application of LIF is an avenue of therapy that has not been explored in human patients with MS," says Deverman, who points out that LIF's benefits might also be good for spinal-cord injury patients since the demyelination of spared neurons may contribute to disability in that disorder. To move the research closer to human clinical trials, the team will work to build better viral vectors for the delivery of LIF. "The way this gene therapy works is to use a virus that can deliver the genetic material -- LIF -- into cells," explains Patterson. "This kind of delivery has been used before in humans, but the worry is that you can't control the virus. You can't necessarily target the right place, and you can't control how much of the protein is being made." Which is why he and Deverman are developing viruses that can target LIF production to specific cell types and can turn it on and off externally, providing a means to regulate LIF levels. They also plan to test the therapy in additional MS mouse models. "For MS, the current therapies all work by modulating or suppressing the immune system, because it's thought to be a disease in which inflammation leads to immune-associated loss of oligodendrocytes and damage to the neurons," says Deverman. "Those therapies can reduce the relapse rate in patients, but they haven't shown much of an effect on the long-term progression of the disease. What are needed are therapies that promote repair. We hope this may one day be such a therapy." The work done in this study, "Exogenous Leukemia Inhibitory Factor Stimulates Oligodendrocyte Progenitor Cell Proliferation and Enhances Hippocampal Remyelination," was funded by the California Institute for Regenerative Medicine, the National Institutes of Neurological Disorders and Stroke, and the McGrath Foundation.

Targeting HIV's Sugar Coating: New Microbicide May Block AIDS Virus from Infecting Cells

University of Utah researchers have discovered a new class of compounds that stick to the sugary coating of the AIDS virus and inhibit it from infecting cells -- an early step toward a new treatment to prevent sexual transmission of the virus. Development and laboratory testing of the potential new microbicide to prevent human immunodeficiency virus infection is outlined in a study set for online publication in the journal Molecular Pharmaceutics. Despite years of research, there is only one effective microbicide to prevent sexual transmission of HIV, which causes AIDS, or acquired immune deficiency syndrome. Microbicide development has focused on gels and other treatments that would be applied vaginally by women, particularly in Africa and other developing regions. To establish infection, HIV must first enter the cells of a host organism and then take control of the cells' replication machinery to make copies of itself. Those HIV copies in turn infect other cells. These two steps of the HIV life cycle, known as viral entry and viral replication, each provide a potential target for anti-AIDS medicines. "Most of the anti-HIV drugs in clinical trials target the machinery involved in viral replication," says the study's senior author, Patrick F. Kiser, associate professor of bioengineering and adjunct associate professor of pharmaceutics and pharmaceutical chemistry at the University of Utah. "There is a gap in the HIV treatment pipeline for cost-effective and mass-producible viral entry inhibitors that can inactivate the virus before it has a chance to interact with target cells," he says. Kiser conducted the study with Alamelu Mahalingham, a University of Utah graduate student in pharmaceutics and pharmaceutical chemistry; Anthony Geonnotti of Duke University Medical Center in Durham, N.C.; and Jan Balzarini of Catholic University of Leuven in Belgium. The research was funded by the National Institutes of Health, the Bill and Melinda Gates Foundation, the Catholic University of Leuven, Belgium, and the Fund for Scientific Research, also in Belgium. Synthetic Lectins Inhibit HIV from Entering Cells Lectins are a group of molecules found throughout nature that interact and bind with specific sugars. HIV is coated with sugars that help to hide it from the immune system. Previous research has shown that lectins derived from plants and bacteria inhibit the entry of HIV into cells by binding to sugars found on the envelope coating the virus. However, the cost of producing and purifying natural lectins is prohibitively high. So Kiser and his colleagues developed and evaluated the anti-HIV activity of synthetic lectins based on a compound called benzoboroxole, or BzB, which sticks to sugars found on the HIV envelope. Kiser and his colleagues found that these BzB-based lectins were capable of binding to sugar residues on HIV, but the bond was too weak to be useful. To improve binding, they developed polymers of the synthetic lectins. The polymers are larger molecules made up of repeating subunits, which contained multiple BzB binding sites. The researchers discovered that increasing the number and density of BzB binding sites on the synthetic lectins made the substances better able to bind to the AIDS virus and thus have increased antiviral activity. "The polymers we made are so active against HIV that dissolving about one sugar cube's weight of the benzoboroxole polymer in a bath tub of water would be enough to inhibit HIV infection in cells," says Kiser. Depending on the strain, HIV displays significant variations in its viral envelope, so it is important to evaluate the efficacy of any potential new treatment against many different HIV strains. Kiser and his colleagues found that their synthetic lectins not only showed similar activity across a broad spectrum of HIV strains, but also were specific to HIV and didn't affect other viruses with envelopes. The scientists also tested the anti-HIV activity of the synthetic lectins in the presence of fructose, a sugar present in semen, which could potentially compromise the activity of lectin-based drugs because it presents an alternative binding site. However, the researchers found that the antiviral activity of the synthetic lectins was fully preserved in the presence of fructose. "The characteristics of an ideal anti-HIV microbicide include potency, broad-spectrum activity, selective inhibition, mass producibility and biocompatibility," says Kiser. "These benzoboroxole-based synthetic lectins seem to meet all of those criteria and present an affordable and scalable potential intervention for preventing sexual transmission in regions where HIV is pandemic." Kiser says future research will focus on evaluating the ability of synthetic lectins to prevent HIV transmission in tissues taken from the human body, with later testing in primates. Kiser and his colleagues are also developing a gel form of the polymers, which could be used as a topical treatment for preventing sexual HIV transmission.

New Sensor Glove May Help Stroke Patients Recover Mobility

A new sensor glove may help stroke patients recover hand mobility by playing video games. 

People who have strokes are often left with moderate to severe physical impairments. Now, thanks to a glove developed at McGill, stroke patients may be able to recover hand motion by playing video games. The Biomedical Sensor Glove was developed by four final-year McGill Mechanical Engineering undergrads under the supervision of Professor Rosaire Mongrain.

It is designed to allow patients to exercise in their own homes with minimal supervision, while at the same time permitting doctors to monitor their progress from a distance, thus cutting down on hospital visits and costs.
Patients can monitor their progress thanks to software, which will generate 3D models and display them on the screen, while at the same time sending the information to the treating physician.
The glove was developed by the students in response to a design request from the startup company Jintronix Inc. The students met with company representatives once a week for several months to develop the glove, which can track the movements of the wrist, the palm and the index finger using several Inertial Measurement Units. Although similar gloves currently exist, they costs approximately $30,000. By using more accurate and less expensive sensors, the students were able to develop a glove that currently costs $1000 to produce.
Jintronix, Inc. has submitted the project to Grand Challenges Canada, which is an independent not-for-profit organization dedicated to improving the health and well-being of people in developing countries, in the hopes that they will receive funding for further development.

Oldest Fossils of Large Seaweeds, Possible Animals Tell Story About Oxygen in an Ancient Ocean

These images are part and counterpart of a macroscopic Lantian fossil, probably a seaweed, with differentiated morphologies including a distinct root-like holdfast to secure the organism on sea bottom, a conical stem, and a crown of ribbon-like structures. Scale bar is 1 centimeter. 

Almost 600 million years ago, before the rampant evolution of diverse life forms known as the Cambrian explosion, a community of seaweeds and worm-like animals lived in a quiet deep-water niche under the sea near what is now Lantian, a small village in Anhui Province of South China. Then they simply died, leaving some 3,000 nearly pristine fossils preserved between beds of black shale deposited in oxygen-free waters.

Scientists from the Chinese Academy of Sciences, Virginia Tech in the U.S., and Northwest University in Xi'an, China report the discovery of the fossils and the mystery in the Feb. 17 issue of Nature.
In addition to perhaps ancient versions of algae and worms, the Lantian biota -- named for its location -- included macrofossils with complex and puzzling structures. In all, scientists identified about 15 different species at the site.
The fossils suggest that morphological diversification of macroscopic eukaryotes -- the earliest versions of organisms with complex cell structures -- may have occurred only tens of millions of years after the snowball earth event that ended 635 million years ago, just before the Ediacaran Period. And their presence in the highly organic-rich black shale suggests that, despite the overall oxygen-free conditions, brief oxygenation of the oceans did come and go.
"So there are two questions," said Shuhai Xiao, professor of geobiology in the College of Science at Virginia Tech. "Why did this community evolve when and where it did? It is clearly different in terms of the number of species compared to biotas preserved in older rocks. There are more species here and they are more complex and larger than what evolved before. These rocks were formed shortly after the largest ice age ever, when much of the global ocean was frozen. By 635 million years ago, the snowball earth event ended and oceans were clear of ice. Perhaps that prepared the ground for the evolution of complex eukaryotes."
The team was examining the black shale rocks because, although they were laid down in waters that were not good for oxygen-dependent organisms, "they are known to be able to preserve fossils very well," said Shuhai. "In most cases, dead organisms were washed in and preserved in black shales. In this case, we discovered fossils that were preserved in pristine condition where they had lived -- some seaweeds still rooted."
The conclusion that the environment would have been poisonous is derived from geochemical data, "but the bedding surfaces where these fossils were found represent moments of geological time during which free oxygen was available and conditions were favorable. They are very brief moments to a geologist," said Xiao. "but long enough for the oxygen-demanding organisms to colonize the Lantian basin and capture the rare opportunities."
The research team suggests in the article in Nature that the Lantian basin was largely without oxygen but was punctuated by brief oxic episodes that were opportunistically populated by complex new life forms, which were subsequently killed and preserved when the oxygen disappeared. "Such brief oxic intervals demand high-resolution sampling for geochemical analysis to capture the dynamic and complex nature of oxygen history in the Ediacaran Period," said lead author Xunlai Yuan, professor of palaeontology with the Chinese Academy of Sciences.
Proving that hypothesis awaits further study. The rocks in the study region are deposited in layered beds. The nature of the rock changes subtly and there are finer and finer layers that can be recognized within each bed. "We will need to sample each layer to see whether there is any difference in oxygen contents between layers with fossils and those without" said co-author Chuanming Zhou, professor of palaeontology with the Chinese Academy of Sciences.
The research was supported by Chinese Academy of Sciences, National Natural Science Foundation of China, Chinese Ministry of Science and Technology, National Science Foundation, NASA Exobiology and Evolutionary Biology Program, and a Guggenheim fellowship to Xiao

Primates' Unique Gene Regulation Mechanism

Three baby orangutans from Tanjung Putting Orangutan Rehab Center in Borneo Indonesia. Scientists have discovered a new way genes are regulated that is unique to primates, including humans and monkeys. 

Scientists have discovered a new way genes are regulated that is unique to primates, including humans and monkeys. Though the human genome -- all the genes that an individual possesses -- was sequenced 10 years ago, greater understanding of how genes function and are regulated is needed to make advances in medicine, including changing the way we diagnose, treat and prevent a wide range of diseases.
"It's extremely valuable that we've sequenced a large bulk of the human genome, but sequence without function doesn't get us very far, which is why our finding is so important," said Lynne E. Maquat, Ph.D., lead author of the new study published February 9 in the journal Nature.
When our genes go awry, many diseases, such as cancer, Alzheimer's and cystic fibrosis can result. The study introduces a unique regulatory mechanism that could prove to be a valuable treatment target as researchers seek to manipulate gene expression -- the conversion of genetic information into proteins that make up the body and perform most life functions -- to improve human health.
The newly identified mechanism involves Alu elements, repetitive DNA elements that spread throughout the genome as primates evolved. While scientists have known about the existence of Alu elements for many years, their function, if any, was largely unknown.
Maquat discovered that Alu elements team up with molecules called long noncoding RNAs (lncRNAs) to regulate protein production. They do this by ensuring messenger RNAs (mRNAs), which take genetic instructions from DNA and use it to create proteins, stay on track and create the right number of proteins. If left unchecked, protein production can spiral out of control, leading to the proliferation or multiplication of cells, which is characteristic of diseases such as cancer.
"Previously, no one knew what Alu elements and long noncoding RNAs did, whether they were junk or if they had any purpose. Now, we've shown that they actually have important roles in regulating protein production," said Maquat, the J. Lowell Orbison Chair, professor of Biochemistry and Biophysics and director of the Center for RNA Biology at the University of Rochester Medical Center.
The expression of genes that call for the development of proteins involves numerous steps, all of which are required to occur in a precise order to achieve the appropriate timing and amount of protein production. Each of these steps is regulated, and the pathway discovered is one of only a few pathways known to regulate mRNAs directly in the midst of the protein production process.
Regulating mRNAs is one of several ways cells control gene expression, and researchers from institutions and companies around the world are honing in on this regulatory landscape in search of new ways to manage and treat disease.
According to Maquat, "This new mechanism is really a surprise. We continue to be amazed by all the different ways mRNAs can be regulated."
Maquat and the study's first author, Chenguang Gong, a graduate student in the Department of Biochemistry and Biophysics at the Medical Center, found that long noncoding RNAs and Alu elements work together to trigger a process known as SMD (Staufen 1-mediated mRNA decay). SMD conditionally destroys mRNAs after they orchestrate the production of a certain amount of proteins, preventing the creation of excessive, unwanted proteins in the body that can disrupt normal processes and initiate disease.
Specifically, long noncoding RNAs and Alu elements recruit the protein Staufen-1 to bind to numerous mRNAs. Once an mRNA finishes directing a round of protein production, Staufen-1 works with another regulatory protein previously identified by Maquat, UPF1, to initiate the degradation or decay of the mRNA so that it cannot create any more proteins.
While the research fills in a piece of the puzzle as to how our genes operate, it also accentuates the overwhelming complexity of how our DNA shapes us and the many known and unknown players involved. Maquat and Gong plan on exploring the newly identified pathway in future research.
This research was supported by a grant from the General Medical Sciences Division of the National Institutes of Health and an Elon Huntington Hooker Graduate Student Fellowship.

Portable Breast Scanner Allows Cancer Detection in the Blink of an Eye

A new portable scanner based on radio frequency technology can show in a second the presence of tumors -- malignant and benign -- in the breast on a computer. The red dot indicates the presence of a tumor.

Women could have a fast test for breast cancer and instantly identify the presence of a tumor in the comfort of their own home thanks to groundbreaking new research from the University of Manchester.
Professor Zhipeng Wu has invented a portable scanner based on radio frequency technology, which is able to show in a second the presence of tumours -- malignant and benign -- in the breast on a computer.
Using radio frequency or microwave technology for breast cancer detection has been proven by researchers in the US, Canada and UK. However, up to now, it can take a few minutes for an image to be produced, and this had to be done in a hospital or specialist care centre.
Now Professor Wu, from the University's School of Electrical and Electronic Engineering, says concerned patients can receive real-time video images in using the radio frequency scanner which would clearly and simply show the presence of a tumour.
Not only is this a quicker and less-intrusive means of testing, it also means women can be tested at GP surgeries, which could help dramatically reduce waiting times and in some cases avoid unnecessary X-ray mammography. The scanner could also be used at home for continuous monitoring of breast health.
The patented real-time radio frequency scanner uses computer tomography and works by using the same technology as a mobile phone, but with only a tiny fraction of its power.
This makes it both safe and low-cost and the electronics can be housed in a case the size of a lunch box for compactness and portability. Other existing systems are much larger.
Breast cancer is the second biggest killer in women, accounting for 8.2% of all cancer deaths. October is National Breast Cancer Awareness month.
The usual way of detecting breast cancer up to now is mammography, which works well for women over the age of 50 and can give results of up to 95% accuracy.
But it is far less effective for younger women. The detection rate could be as low as 60% for women under the age of 50, which accounts for 20% of all breast cancer cases.
At that stage it is even more important get accurate diagnosis. Early diagnosis and treatment could save thousands of lives.
The main difference between the two methods is that mammography works on density, while radio frequency technique works on dielectric contrasts between normal and diseased breast tissues.
In Professor Wu's design, as soon as the breast enters the cup an image appears on screen.
The presence of a tumour or other abnormality will show up in red as the sensor detects the difference in tissue contrasts at radio frequencies. Malignant tissues have higher permittivity and conductivity and therefore appear differently than normal ones to a screen.
Up to 30 images are generated every second, meaning a breast scan could be over in a far shorter time than they are currently.
Professor Wu said: "The system we have is portable and as soon as you lie down you can get a scan -- it's real-time.
"The real-time imaging minimises the chance of missing a breast tumour during scanning.
"Other systems also need to use a liquid or gel as a matching substance, such as in an ultrasound, to work but with our system you don't need that -- it can be done simply in oil, milk, water or even with a bra on.
"Although there is still research to be done, the system has great potential to bring a new way for breast cancer diagnosis.
"This will benefit millions of women in both developed and developing countries bearing in mind that one in nine women may develop breast cancer in their lifetime."
Professor Wu submitted his innovation of the sensor system to the IET Innovation Awards. The technology has been shortlisted in both Electronics and Measurement in Action categories. The winners will be announced in November.

Gene Therapy for Metastatic Melanoma in Mice Produces Complete Remission

A potent anti-tumor gene introduced into mice with metastatic melanoma has resulted in permanent immune reconfiguration and produced a complete remission of their cancer, according to an article to be published in the December 2010 issue of the Journal of Clinical Investigation.
Indiana University School of Medicine researchers used a modified lentivirus to introduce a potent anti-melanoma T cell receptor gene into the hematopoietic stem cells of mice. Hematopoietic stem cells are the bone marrow cells that produce all blood and immune system cells.
The T cell gene, which recognizes a specific protein found on the surface of melanoma, was isolated and cloned from a patient with melanoma. The gene-modified stems cells were then transplanted back into hosts and found to eradicate metastatic melanoma for the lifetime of the mice.
"We found that the transplantation of gene-modified hematopoietic stem cells results in a new host immune system and the complete elimination of tumor," reported Christopher E. Touloukian, M.D., an assistant professor of surgery and immunology at the IU School of Medicine and a member of the Indiana University Melvin and Bren Simon Cancer Center. "To date, cancer immunotherapies have been hampered by limited and diminishing immune responses over time. We believe this type of translational model opens new doors for patients with melanoma and potentially other cancers by taking advantage of the potent regenerative capacity of hematopoietic stem cells and new advances in gene therapy."
This research was funded by a National Institutes of Health grant.
It has paved the way for a new clinical trial in humans funded by the V Foundation for Cancer Research. The pilot phase I trial will involve treatment of 12 patients and focus primarily on the safety and efficacy of the therapy, said Dr. Touloukian, who is the senior author on the JCI paper and the principal investigator for the clinical study. The clinical trial is expected to begin accruing patients by late 2011.
In 2010, more than 68,000 patients will be diagnosed with melanoma and the disease will be associated with approximately 9,000 deaths. The state of Indiana has the 11th highest rate of melanoma incidence of all 50 states. Current treatments for metastatic melanoma, though exciting and innovative, have been highly toxic and largely unsuccessful with the most patients dying within 6 to 12 months after diagnosis.

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.

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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