Drug Destroys Human Cancer Stem Cells but Not Healthy Ones

A team of scientists at McMaster University has discovered a drug, thioridazine, successfully kills cancer stem cells in the human while avoiding the toxic side-effects of conventional cancer treatments.

"The unusual aspect of our finding is the way this human-ready drug actually kills cancer stem cells; by changing them into cells that are non-cancerous," said Mick Bhatia, the principal investigator for the study and scientific director of McMaster's Stem Cell and Cancer Research Institute in the Michael G. DeGroote School of Medicine.

Unlike chemotherapy and radiation, thioridazine appears to have no effect on normal stem cells.

The research, published May 24 in the science journal Cell, holds the promise of a new strategy and discovery pipeline for the development of anticancer drugs in the treatment of various cancers. The research team has identified another dozen drugs that have good potential for the same response.

For 15 years, some researchers have believed stem cells are the source of many cancers. In 1997, Canadian researchers first identified cancer stem cells in certain types of leukemia. Cancer stem cells have since been identified in blood, breast, brain, lung, gastrointestinal, prostate and ovarian cancer.

To test more than a dozen different compounds, McMaster researchers pioneered a fully automated robotic system to identify several drugs, including thioridazine.

"Now we can test thousands of compounds, eventually defining a candidate drug that has little effect on normal stem cells but kills the cells that start the tumor," said Bhatia.

The next step is to test thioridazine in clinical trials, focusing on patients with acute myeloid leukemia whose disease has relapsed after chemotherapy. Bhatia wants to find out if the drug can put their cancer into remission, and by targeting the root of the cancer (cancer stem cells) prevent the cancer from coming back. Researchers at McMaster have already designed how these trials would be done.

Bhatia's team found thioridazine works through the dopamine receptor on the surface of the cancer cells in both leukemia and breast cancer patients. This means it may be possible to use it as a biomarker that would allow early detection and treatment of breast cancer and early signs of leukemia progression, he said.

The research team's next step is to investigate the effectiveness of the drug in other types of cancer. In addition, the team will explore several drugs identified along with thioridazine. In the future, thousands of other compounds will be analyzed with McMaster robotic stem cell screening system in partnership with collaborations that include academic groups as well as industry.

"The goal for all of the partners is the same -- to find unique drugs to change the way we tackle and treat cancer," he said.

The research was supported by grants from the Canadian Institute of Health Research (CIHR), the Canadian Cancer Society Research Institute (CCSRI) and the Ontario Ministry of Economic Development and Innovation (MEDI)'s Ontario Consortium of Regenerating inducing Therapeutics (OCRiT).

Source: McMaster University [May 24, 2012]

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New twist on ancient math problem could improve medicine, microelectronics

A hidden facet of a math problem that goes back to Sanskrit scrolls has just been exposed by nanotechnology researchers at the University of Michigan and the University of Connecticut.

A hidden facet of a math problem that goes back to Sanskrit scrolls has just been exposed by nanotechnology researchers [Credit: © bivainis/Fotolia]

It turns out we've been missing a version of the famous "packing problem," and its new guise could have implications for cancer treatment, secure wireless networks, microelectronics and demolitions, the researchers say.

Called the "filling problem," it seeks the best way to cover the inside of an object with a particular shape, such as filling a triangle with discs of varying sizes. Unlike the traditional packing problem, the discs can overlap. It also differs from the "covering problem" because the discs can't extend beyond the triangle's boundaries.

"Besides introducing the problem, we also provided a solution in two dimensions," said Sharon Glotzer, U-M professor of chemical engineering.

That solution makes it immediately applicable to treating tumors using fewer shots with radiation beams or speeding up the manufacturing of silicon chips for microprocessors.

The key to solutions in any dimension is to find a shape's "skeleton," said Carolyn Phillips, a postdoctoral fellow at Argonne National Laboratory who recently completed her Ph.D. in Glotzer's group and solved the problem as part of her dissertation.

"Every shape you want to fill has a backbone that goes through the center of the shape, like a spine," she said.

For a pentagon, the skeleton looks like a stick-drawing of a starfish. The discs that fill the pentagon best will always have their centers on one of those lines.

Junctions between lines in the skeleton are special points that Glotzer's team refers to as "traps." The pentagon only has one trap, right at its center, but more complicated shapes can contain multiple traps. In most optimal solutions, each trap has a disc centered over it, Phillips said.

Other discs in the pattern change size and move around, depending on how many discs are allowed, but those over the traps are always the same. Phillips suspects that if a design uses enough discs, every trap will have a disc centered over it.

In their paper, published online today in Physical Review Letters, the researchers report the rules for how to find the ideal size and spacing of the discs that fill a shape. In the future, they expect to reveal an algorithm that can take the desired shape and the number of discs, or the shape and percentage of the area to be filled, and spit out the best pattern to fill it.

Extending the approach into three dimensions, Glotzer proposes that it could decide the placement of wireless routers in a building where the signal must not be available to a potential hacker in the parking lot. Alternatively, it could help demolition workers to set off precision explosions, ensuring that the blast covers the desired region but doesn't extend beyond a building's outer walls.

Phillips expects filling solutions to be scientifically useful as well. Glotzer's team developed the new problem by trying to find a way to represent many-sided shapes for their computer models of nanoparticles. In addition to nanotechnology, biology and medicine often need models for complex shapes, such as those of proteins.

"You don't want to model every single one of the thousands of atoms that make up this protein," Phillips said. "You want a minimal model that gives the shape, allowing the proteins to interact in a lock-and-key way, as they do in nature."

The filling approach may prove a perfect fit for a variety of fields.

Author: Katherine McAlpine | Source: University of Michigan [May 10, 2012]

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Transplanted gene-modified blood stem cells protect brain cancer patients from toxic side effects of chemotherapy

For the first time, scientists at Fred Hutchinson Cancer Research Center have transplanted brain cancer patients' own gene-modified blood stem cells in order to protect their bone marrow against the toxic side effects of chemotherapy. Initial results of the ongoing, small clinical trial of three patients with glioblastoma showed that two patients survived longer than predicted if they had not been given the transplants, and a third patient remains alive with no disease progression almost three years after treatment.

"We found that patients were able to tolerate the chemotherapy better and without negative side effects after transplantation of the gene-modified stem cells than patients in previous studies who received the same type of chemotherapy without a transplant of gene-modified stem cells," said Hans-Peter Kiem, M.D., senior and corresponding author of the study published in the May 9 issue of Science Translational Medicine.

Kiem, a member of the Clinical Research Division at the Hutchinson Center, said that a major barrier to effective use of chemotherapy to treat cancers like glioblastoma has been the toxicity of chemotherapy drugs to other organs, primarily bone marrow. This results in decreased blood cell counts, increased susceptibility to infections and other side effects. Discontinuing or delaying treatment or reducing the chemotherapy dose is generally required, but that often results in less effective treatment.

In the current study, Kiem and colleagues focused on patients with glioblastoma, an invariably fatal cancer. Many of these patients have a gene called MGMT (O6-methylguanine-DNA-methyltransferase) that is turned on because the promoter for this gene is unmethylated. MGMT is a DNA repair enzyme that counteracts the toxic effect of some chemotherapy agents like temozolomide. Patients with such an unmethylated promoter status have a particularly poor prognosis.

A drug called benzylguanine can block the MGMT gene and make tumor cells sensitive to chemotherapy again, but when given with chemotherapy, the toxic effects of this combination are too much for bone marrow cells, which results in marrow suppression.

By giving bone marrow stem cells P140K, which is a modified version of MGMT, those cells are protected from the toxic effects of benzylguanine and chemotherapy, while the tumor cells are still sensitive to chemotherapy. "P140K can repair the damage caused by chemotherapy and is impervious to the effects of benzylguanine," Kiem said.

"This therapy is analogous to firing at both tumor cells and bone marrow cells, but giving the bone marrow cells protective shields while the tumor cells are unshielded," said Jennifer Adair, Ph.D., who shares first authorship of the study with Brian Beard, Ph.D., both members of Kiem's lab.

The three patients in this study survived an average of 22 months after receiving transplants of their own circulating blood stem cells. One, an Alaskan man, remains alive 34 months after treatment. Median survival for patients with this type of high-risk glioblastoma without a transplant is just over a year.

"Glioblastoma remains one of the most devastating cancers with a median survival of only 12 to 15 months for patients with unmethylated MGMT," said Maciej Mrugala, M.D., the lead neuro oncologist for this study.

As many as 50 percent to 60 percent of glioblastoma patients harbor such chemotherapy-resistant tumors, which makes gene-modified stem cell transplant therapy applicable to a large number of these patients. In addition, there are also other brain tumors such as neuroblastoma or other solid tumors with MGMT-mediated chemo resistance that might benefit from this approach.

The researchers also found that chemotherapy increased the number of gene-modified blood and bone marrow cells in these patients. Kiem said this finding will have implications for other stem cell gene therapy applications where defective bone marrow stem cells can be corrected by gene therapy but their numbers need to be increased to produce a therapeutic benefit, or for patients with HIV/AIDS to increase the number of HIV-resistant stem and T cells.

The clinical trial is open and is recruiting more patients. For more information go to: http://clinicaltrials.gov/ct2/show/NCT00669669.

Source: Fred Hutchinson Cancer Research Center [May 09, 2012]

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Breathalyzer Device Reveals Signs of Disease

This invention could give new meaning to the term "bad breath!" It's the Single Breath Disease Diagnostics Breathalyzer, and when you blow into it, you get tested for a biomarker—a sign of disease. As amazing as that sounds, the process is actually very simple thanks to ceramics nanotechnology. All it takes is a single exhale.

You blow into a small valve attached to a box that is about half the size of your typical shoebox and weighs less than one pound. Once you blow into it, the lights on top of the box will give you an instant readout. A green light means you pass (and your bad breath is not indicative of an underlying disease; perhaps it’s just a result of the raw onions you ingested recently); however, a red light means you might need to take a trip to the doctor’s office to check if something more serious is an issue.

With support from the National Science Foundation (NSF), Professor Perena Gouma and her team at Stony Brook University in New York developed a sensor chip that you might say is the "brain" of the breathalyzer. It's coated with tiny nanowires that look like microscopic spaghetti and are able to detect minute amounts of chemical compounds in the breath. "These nanowires enable the sensor to detect just a few molecules of the disease marker gas in a 'sea' of billions of molecules of other compounds that the breath consists of," Gouma explains. This is what nanotechnology is all about.

You can't buy this in the stores just yet--individual tests such as an acetone-detecting breathalyzer for monitoring diabetes and an ammonia-detecting breathalyzer to determine when to end a home-based hemodialysis treatment--are still being evaluated clinically. However, researchers envision developing the technology such that a number of these tests can be performed with a single device. Within a couple of years, you might be able to self-detect a whole range of diseases and disorders, including lung cancer, by just exhaling into a handheld breathalyzer.

Handheld breath tests to estimate blood alcohol content and nitric oxide detectors used in hospitals to monitor pulmonary infections have been around for a while, but there is no consumer-based technology like this currently available. The research team envisions the cost of the final product being under $20, just one of many reasons Gouma thinks the Single Breath Disease Diagnostics Breathalyzer has the potential to empower individuals to take care of their own health like never before. "People can get something over the counter and it's going to be a first response or first detection type of device. This is really a nanomedicine application that is affordable because it is based on inexpensive ceramic materials that can be mass produced at low cost," she notes.

The manufacturing process that creates the single crystal nanowires is called "electrospinning." It starts with a liquid compound being shot from a syringe into an electrical field. The electric field crystallizes the inserted liquid into a tiny thread or "wire" that collects onto an aluminum backing. Gouma says enough nanowire can be produced in one syringe to stretch from her lab in Stony Brook, N.Y. to the moon and still be a single grain (monocrystal).

"There can be different types of nanowires, each with a tailored arrangement of metal and oxygen atoms along their configuration, so as to capture a particular compound," explains Gouma. "For example, some nanowires might be able to capture ammonia molecules, while others capture just acetone and others just the nitric oxide. Each of these biomarkers signal a specific disease or metabolic malfunction so a distinct diagnostic breathalyzer can be designed."

"This concept could not have been realized without a fundamental understanding of the material used to create the miniaturized gas detectors," said Janice Hicks, a deputy division director in the Mathematical and Physical Sciences Directorate at NSF. "The research transcends traditional scientific and engineering disciplines and may lead to new applications or diagnostics."

Gouma also says the nanowires can be rigged to detect infectious viruses and microbes like Salmonella, E. coli or even anthrax. "There will be so many other applications we haven't envisioned. It's very exciting; it's a whole new world," she says.

Authors: Miles O' Brien and Jon Baime | Source: National Science Foundation [May 08, 2012, 2012]

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Study reveals huge genetic diversity in cells shed by tumors

The cells that slough off from a cancerous tumor into the bloodstream are a genetically diverse bunch, Stanford University School of Medicine researchers have found. Some have genes turned on that give them the potential to lodge themselves in new places, helping a cancer spread between organs. Others have completely different patterns of gene expression and might be more benign, or less likely to survive in a new tissue. Some cells may even express genes that could predict their response to a specific therapy. Even within one patient, the tumor cells that make it into circulating blood vary drastically.

The finding underscores how multiple types of treatment may be required to cure what appears outwardly as a single type of cancer, the researchers say. And it hints that the current cell-line models of human cancers, which showed patterns that differed from the tumor cells shed from human patients, need to be improved upon.

The new study, which will be published online May 7 in PLoS ONE, is the first to look at so-called circulating tumor cells one by one, rather than taking the average of many of the cells. And it's the first to show the extent of the genetic differences between such cells.

"Within a single blood draw from a single patient, we're seeing heterogeneous populations of circulating tumor cells," said senior study author Stefanie Jeffrey, MD, professor of surgery and chief of surgical oncology research.

For over a century, scientists have known that circulating tumor cells, or CTCs, are shed from tumors and move through the bloodstreams of cancer patients. And over the past five years, there's been a growing sense among many cancer researchers that these cells — accessible by a quick blood draw — could be the key to tracking tumors non-invasively. But separating CTCs from blood cells is hard; there can be as few as one or two CTCs in every milliliter of a person's blood, mixed among billions of other blood cells.

To make their latest discovery, Jeffrey, along with an interdisciplinary team of engineers, quantitative biologists, genome scientists and clinicians, relied on a technology they developed in 2008. Called the MagSweeper, it's a device that lets them isolate live CTCs with very high purity from patient blood samples, based on the presence of a particular protein — EpCAM — that's on the surface of cancer cells but not healthy blood cells.

With the goal of studying CTCs from breast cancer patients, the team first tested whether they could accurately detect the expression levels of 95 different genes in single cells from seven different cell-line models of breast cancer — a proof of principle since they already knew the genetics of these tumors. These included four cell lines generally used by breast cancer researchers and pharmaceutical scientists worldwide and three cell lines specially generated from patients' primary tumors.

"Most researchers look at just a few genes or proteins at a time in CTCs, usually by adding fluorescent antibodies to their samples consisting of many cells," said Jeffrey. "We wanted to measure the expression of 95 genes at once and didn't want to pool our cells together, so that we could detect differences between individual tumor cells."

So once Jeffrey and her collaborators isolated CTCs using the MagSweeper, they turned to a different kind of technology: real-time PCR microfluidic chips, invented by a Stanford collaborator, Stephen Quake, PhD, professor of bioengineering. They purified genetic material from each CTC and used the high-throughput technology to measure the levels of all 95 genes at once. The results on the cell-line-derived cells were a success; the genes in the CTCs reflected the known properties of the mouse cell-line models. So the team moved on to testing the 95 genes in CTCs from 50 human breast cancer patients — 30 with cancer that had spread to other organs, 20 with only primary breast tumors.

"In the patients, we ended up with 32 of the genes that were most dominantly expressed," said Jeffrey. "And by looking at levels of those genes, we could see at least two distinct groups of circulating tumors cells." Depending on which genes they used to divide the CTCs into groups, there were as many as five groups, she said, each with different combinations of genes turned on and off. And if they'd chosen genes other than the 95 they'd picked, they likely would have seen different patterns of grouping. However, because the same individual CTCs tended to group together in multiple different analyses, these cells likely represent different types of spreading cancer cells.

The diversity, Jeffrey said, means that tumors may contain multiple types of cancer cells that may get into the bloodstream, and a single biopsy from a patient's tumor doesn't necessarily reflect all the molecular changes that are driving a cancer forward and helping it spread. Moreover, different cells may require different therapies. One breast cancer patient studied, for example, had some CTCs positive for the marker HER2 and others lacked the marker. When the patient was treated with a drug designed to target HER2-positive cancers, the CTCs lacking the molecule remained in her bloodstream.

When the team went on to compare the diverse genetic profiles of the breast cancer patients' CTCs with the cells they'd studied from the cell lines, they were in for another surprise: None of the human CTCs had the same gene patterns as any of the cell-line models.

"These models are what people are using for drug discovery and initial drug testing," said Jeffrey, "but our finding suggests that perhaps they're not that helpful as models of spreading cancers." While the human cell-line cells did show diversity between each of the seven cell lines, they didn't fall into any of the same genetic profiles as the CTCs from human blood samples.

These results don't have immediate impacts for cancer patients in the clinic because more work is needed to discover whether different types of CTCs respond to different therapies and whether that will be clinically useful for guiding treatment decisions. But the finding is a step forward in understanding the basic science behind the bits of tumors that circulate in the blood. It's the first time that scientists have used high-throughput gene analysis to study individual CTCs, and opens the door for future experiments that delve even more into the cell diversity. The Stanford team is now working on different methods of using CTCs for drug testing as well as studying the relationship between CTC genetic profiles and cancer treatment outcomes. They've also expanded their work to include primary lung and pancreatic cancers as well as breast tumors.

Source: Stanford University Medical Center [May 07, 2012]

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Regular jogging shows dramatic increase in life expectancy

Undertaking regular jogging increases the life expectancy of men by 6.2 years and women by 5.6 years, reveals the latest data from the Copenhagen City Heart study presented at the EuroPRevent2012 meeting. Reviewing the evidence of whether jogging is healthy or hazardous, Peter Schnohr told delegates that the study's most recent analysis (unpublished) shows that between one and two-and-a-half hours of jogging per week at a "slow or average" pace delivers optimum benefits for longevity. The EuroPRevent2012 meeting, held 3 May to 5 May 2012, in Dublin, Ireland, was organised by the European Association for Cardiovascular Prevention and Rehabilitation (EACPR), a registered branch of the European Society of Cardiology (ESC).

"The results of our research allow us to definitively answer the question of whether jogging is good for your health," said Schnohr, who is chief cardiologist of the Copenhagen City Heart Study, speaking in the "Assessing prognosis: a glimpse of the future" symposium on Saturday. "We can say with certainty that regular jogging increases longevity. The good news is that you don't actually need to do that much to reap the benefits."

The debate over jogging first kicked off in the 1970s when middle aged men took an interest in the past-time. "After a few men died while out on a run, various newspapers suggested that jogging might be too strenuous for ordinary middle aged people," recalled Schnohr.

The Copenhagen City Heart study, which started 1976, is a prospective cardiovascular population study of around 20,000 men and women aged between 20 to 93 years. The study, which made use of the Copenhagen Population Register, set out to increase knowledge about prevention of cardiovascular disease and stroke. Since then the study, which has resulted in publication of over 750 papers, has expanded to include other diseases such as heart failure, pulmonary diseases, allergy, epilepsy, dementia, sleep-apnea and genetics. The investigators have explored the associations for longevity with different forms of exercise and other factors.

For the jogging sub study, the mortality of 1,116 male joggers and 762 female joggers was compared to the non joggers in the main study population. All participants were asked to answer questions about the amount of time they spent jogging each week, and to rate their own perceptions of pace (defined as slow, average, and fast). "With participants having such a wide age span we felt that a subjective scale of intensity was the most appropriate approach," explained Schnohr, who is based at Bispebjerg University Hospital, Copenhagen.

The first data was collected between 1976 to 1978, the second from 1981 to 1983, the third from 1991 to 1994, and the fourth from 2001 to 2003. For the analysis participants from all the different data collections were followed using a unique personal identification number in the Danish Central Person Register. "These numbers have been key to the success of the study since they've allowed us to trace participants wherever they go," said Schnohr.

Results show that in the follow-up period involving a maximum of 35 years, 10,158 deaths were registered among the non-joggers and 122 deaths among the joggers. Analysis showed that risk of death was reduced by 44% for male joggers (age-adjusted hazard ratio 0.56) and 44% for female joggers (age-adjusted hazard ratio 0.56). Furthermore the data showed jogging produced an age adjusted survival benefit of 6.2 years in men and 5.6 years in women.

Further analysis exploring the amounts of exercise undertaken by joggers in the study has revealed a U-shaped curve for the relationship between the time spent exercising and mortality. The investigators found that between one hour and two and a half hours a week, undertaken over two to three sessions, delivered the optimum benefits, especially when performed at a slow or average pace. "The relationship appears much like alcohol intakes. Mortality is lower in people reporting moderate jogging, than in non-joggers or those undertaking extreme levels of exercise," said Schnohr.

The ideal pace can be achieved by striving to feel a little breathless. "You should aim to feel a little breathless, but not very breathless," he advised.

Jogging, said Schnohr, delivers multiple health benefits. It improves oxygen uptake, increases insulin sensitivity, improves lipid profiles (raising HDL and lowering triglycerides), lowers blood pressure, reduces platelet aggregation, increases fibrinolytic activity, improves cardiac function, bone density, immune function, reduces inflammation markers, prevents obesity, and improves psychological function. "The improved psychological wellbeing may be down to fact that people have more social interactions when they're out jogging," said Schnohr.

Source: European Society of Cardiology [May 03, 2012]

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Genetic Pathway Impacting the Spread of Cancer Cells Discovered

In a new study from Lawson Health Research Institute, Dr. Joseph Torchia has identified a new genetic pathway influencing the spread of cancer cells. The discovery of this mechanism could lead to new avenues for treatment. Regular cell division is regulated by methylation, a series of chemical changes. Methylation modifies DNA to ensure cells divide at a healthy, balanced rate. In cancer, the methylation process is unbalanced, causing cells to resist regulation and divide uncontrollably.

Research suggests changes in genetics play a role in this process, yet little is known about the mechanism. In a new study led by Dr. Torchia and his colleagues, a hormone called Transforming Growth Factor Beta (TGF-β) is starting to show the answers. Using genetic sequencing, they analyzed the effects of TGF-β on DNA methylation to reveal a never-before- seen pathway.

When TGF-β comes into contact with a cell it activates the tumor-suppressing gene, which stops the cells from dividing. According to Dr. Torchia's group, ZNF217, a cancer-causing gene, can interfere with this process by binding to the DNA. This prevents the tumour-suppressing genes from activating, and the cells continue to divide.

These results characterize the dynamic processes underlying cell division, suggesting genetic influencers must be balanced to keep cell division under control. Most importantly, they provide hope for new cancer therapies. "This link between methylation and TGF-β has never been shown before," Dr. Torchia says. "If we understand how methylation is regulated, and identify the machinery that's involved, we may be able to target some of the machinery therapeutically and turn these genes back on to fight the cancer."

Source: Lawson Health Research Institute [May 03, 2012]

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Dynamic Changes in Gene Regulation in Human Stem Cells Revealed

A team led by scientists at The Scripps Research Institute and the University of California (UC) San Diego has discovered a new type of dynamic change in human stem cells. Last year, this team reported recurrent changes in the genomes of human pluripotent stem cells as they are expanded in culture. The current report, which appears in the May 4, 2012 issue of the journal Cell Stem Cell, shows that these cells can also change their epigenomes, the patterns of DNA modifications that regulate the activity of specific genes -- sometimes radically. These changes may influence the cells' abilities to serve as models of human disease and development.

"Our results show that human pluripotent stem cells change during expansion and differentiation in ways that are not easily detected, but that have important implications in using these cells for basic and clinical research," said team leader Louise Laurent, assistant professor in the UC San Diego School of Medicine.

Human pluripotent stem cells can give rise to virtually every type of cell in the body. Because of this remarkable quality, they hold huge potential for cell replacement therapies and drug development.

Many avenues of stem cell research focus on determining how genes are turned on and off during the course of normal development or at the onset of a disease transformation. It is widely accepted that gene activation and silencing play important roles in transforming all-purpose stem cells into the specific adult cell types that make up the specialized tissues of organs such as the heart and brain.

In the new study, Laurent and her collaborator, Professor Jeanne Loring of Scripps Research, and their colleagues focused on understanding gene silencing via DNA methylation, a process whereby bits of DNA are chemically marked with tags that prevent the genes from being expressed, effectively switching them off. Errors in gene silencing via DNA methylation are known contributors to serious developmental defects and cancer.

Specifically, the team assessed the state of both DNA methylation and gene expression in the most comprehensive set of human stem cell samples to date, composed of more than 200 human pluripotent stem cell samples from more than 100 cell lines, along with 80 adult cell samples representing 17 distinct tissue types. The researchers used a new global DNA methylation array, developed in collaboration with Illumina, Inc, which detects the methylation state of 450,000 sites in the human genome. The results showed surprising changes in patterns of DNA methylation in the stem cells. Because of the unprecedented breadth of the study, the researchers were able to determine the frequency of different types of changes.

One of the anomalies highlighted by the study centers on X chromosomes. Since female cells contain two X chromosomes and males only one, one of the X chromosomes in females is normally silenced by DNA methylation through a process called X-chromosome inactivation (XCI). The new study demonstrated that a majority of female human pluripotent stem cells cultured in the lab lost their X chromosome inactivation over time, resulting in cells with two active X chromosomes.

This phenomenon could affect stem cell-based models of diseases caused by mutations of the X chromosome, such as Lesch-Nyhan disease, the researchers note. These cell-based models require that only the diseased copy of an X-linked gene be expressed, with the normal copy of the gene in females silenced via XCI. As the originally inactive X chromosome becomes active, the normal copy of the gene is expressed, changing the phenotype of the cells from diseased to normal.

"If an X chromosome that was assumed to be inactive is actually active, scientists may find that their cells perplexingly change from mutant to normal over time in culture," Loring said.

Another epigenomic aberration noted in pluripotent cells was in imprinted genes. Human cells contain two copies of most genes: one inherited from the mother and one from the father. In most cases, both the maternal and paternal copies of a gene are expressed equally. This is not the case, however, for imprinted genes, some of which are only expressed from the paternal chromosomes and others expressed only from the maternal chromosomes. This parent-of-origin specific gene expression involves silencing of one of the copies of the gene. Abnormalities in this selective silencing of genes can lead to serious developmental diseases.

The study found that, while the patterns of DNA methylation required to maintain imprinted gene silencing were stable in all of the somatic tissues, surprisingly, frequent aberrations in the patterns of DNA methylation existed in imprinted genes in the stem cells. Some of these aberrations arose very early in the establishment of the cell lines, while others crept in with the passage of time.

Interestingly, the team was able to link at least some of these aberrations to the conditions under which the stem cells were cultured in the lab. This suggests that researchers who use stem cells to study diseases linked to genomic imprinting will need to use conditions that best maintain imprinted gene silencing.

The researchers found another surprise -- this one having to do with the basic process by which stem cells become specialized adult cells. Scientists have assumed that most genes are active at the earliest stages of human development, and that unnecessary ones are switched off as the cells developed specialized functions.

"For example, during the process of differentiation from a stem cell into a neuron, you might expect to observe silencing of all the genes that are important for the kidney, the pancreas, and the liver," said Kristopher Nazor, a Scripps Research Kellogg School of Science and Technology graduate student who is lead author of the study. "But we found something quite different."

When the team compared stem cells with adult cells taken from tissue samples, rather than seeing mostly active genes in the stem cells and selectively silenced genes in the adult ones, they saw the opposite: in the stem cells, the researchers found that genes linked to the development of specialized tissue cells were silent and methylated, while in the adult cells regions of DNA involved in cell type specification were active and unmethylated. The scientists could reproduce some aspects of the developmental changes in culture: when stem cells were differentiated into neural cells in the culture dish, the patterns of DNA methylation became similar to those seen in human brain tissue.

This implies that, contrary to conventional wisdom, the genes responsible for transforming stem cells into tissue cells were initially silent, and were switched on during the process of differentiation.

Source: The Scripps Research Institute [May 03, 2012]

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Keep aging brains sharp

Exercising, eating a healthy diet and playing brain games may help you keep your wits about you well into your 80s and even 90s, advises a new book by researchers at George Mason University. 

"These are all cheap, easy things to do," says Pamela Greenwood, an associate professor in the Department of Psychology on Mason's Fairfax, Va. campus. "We should all be doing them anyway. You should do them for your heart and health, so why not do them for your brain as well?" 

For the past 20 years, Greenwood and Raja Parasuraman, University Professor of Psychology, have studied how the mind and brain age, focusing on Alzheimer's disease. Their book, "Nurturing the Older Brain and Mind" published by MIT Press, came out in March. The cognitive neuroscientists geared the book to middle-aged readers who want to keep their mental snap. 

"We know that if we can put off dementing illnesses even by a year or two through lifestyle changes, that will reduce the number of people with Alzheimer's disease, which is reaching epidemic proportions," Parasuraman says. 

Not everyone's brain declines when retirement age hits. "You can look at a group of 65-year-olds — some are in nursing homes, and some are running the world," Greenwood says. 

Now that more workers are staying on the job longer for economic reasons and because countries are upping the retirement age, keeping the mind agile becomes paramount, Parasuraman says. 

For the book, Parasuraman and Greenwood examined only scientific studies, theirs and others, ranging from neurological to physiological. A few surprises leaped out of the data. 

"Several old dogmas were overturned," Parasuraman says. "There's the tired old joke that we're losing brain cells as we age — maybe starting as young as 20 or 30 — and it's all downhill after that." 

Not so, new research reveals. Not only are some 60-year-olds as sharp as 20-year-olds, but their brains still create new cells. Brain cells may not grow as fast as bone or skin cells, but grow they do, particularly in the hippocampus. "It's the area of the brain that's very important to memory and is affected by Alzheimer's disease," Parasuraman says. 

Novel experiences and new learning help new brain cells become part of the circuitry. Parasuraman points to a study of terminally ill cancer patients whose brains were still forming new neurons. "If a person who's in a terminally ill state can generate new neurons, then surely healthy people can," Parasuraman says. 

Brain games and new experiences may build up "white matter," which insulates neurons as they carry signals, Greenwood says. In older brains, this white matter insulation develops holes and signals go awry. 

Older adult gamers are winning skills to help them move through life, Parasuraman says. "We are looking at everyday problem solving," he says. "Are you better at balancing a checkbook? Are you better at making decisions in a grocery store? We're finding you get better at those tasks (after playing the video games in the study)." 

Moving large muscle groups also builds brain matter. In one study detailed in the book, older, sedentary people began walking or did stretching exercises for 45 minutes, three times a week. "Those people actually became smarter over time," Greenwood says. "You don't have to be running Ironman marathons. You can just walk briskly three or four times a week." 

Another best bet for an active mind is a nutritious diet that limits calories to the minimum amount needed to keep a body healthy. No starvation diets, though. "The strongest evidence we have is not very pleasant, which is dietary restriction, reducing calories," Parasuraman says. "That clearly improves longevity and cognition. The evidence in animals is very strong. Such dietary restriction may never be popular. But perhaps every-other-day fasting as an approximation to it is something people would tolerate: You eat normally one day, and the next day you don't." 

Popping supplements won't fill a nutritionally deficient diet, Parasuraman says. "A lot of people think, 'I can eat junk food and then take a pill.' No. You have to eat fruits and vegetables, leafy vegetables. It has to be part of the regular diet because otherwise it's not absorbed." 

Fat cells help make up cell membranes. The unsaturated fats found in fish and olive oils may boost flexibility in these membranes. The more flexible membranes are, the better they may work, scientists theorize. Saturated fats such as butter have to go because these fats vie with healthy fats for a place in the cell membrane, Greenwood explains. 

Greenwood and Parasuraman want people to know that getting old doesn't mean getting senile. "The bottom line message of the book is really a hopeful one," Greenwood says. "There are lots of things that you can do (to keep your brain healthy)." 

Source: George Mason University [April 04, 2012]

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DNA sequencing lays foundation for personalized cancer treatment

Scientists at Washington University School of Medicine in St. Louis are using powerful DNA sequencing technology not only to identify mutations at the root of a patient's tumor – considered key to personalizing cancer treatment – but to map the genetic evolution of disease and monitor response to treatment. 

The Genomics of Drug Sensitivity in Cancer project released its first results on July 15th. Researchers released a first dataset from a study that will expose 1,000 cancer cell lines (including ovarian) to 400 anticancer treatments [Washington University]

"We're finding clinically relevant information in the tumor samples we're sequencing for discovery-oriented research studies," says Elaine Mardis, PhD, co-director of The Genome Institute at the School of Medicine. "Genome analysis can play a role at multiple time points during a patient's treatment, to identify 'driver' mutations in the tumor genome and to determine whether cells carrying those mutations have been eliminated by treatment." 

This work is helping to guide the design of future cancer clinical trials in which treatment decisions are based on results of sequencing, says Mardis, who is speaking April 1 at the opening plenary session of the American Association for Cancer Research annual meeting in Chicago. She also is affiliated with the Siteman Cancer Center at the School of Medicine and Barnes-Jewish Hospital. 

To date, Mardis and her colleagues have sequenced all the DNA – the genome – of tumor cells from more than 700 cancer patients. By comparing the genetic sequences in the tumor cells to healthy cells from the same patient, they can identify mutations underlying each patient's cancer. 

Already, information gleaned through whole-genome sequencing is pushing researchers to reclassify tumors based on their genetic makeup rather than their location in the body. In patients with breast cancer, for example, Mardis and her colleagues have found numerous driver mutations in genes that have not previously been associated with breast tumors. 

A number of these genes have been identified in prostate, colorectal, lung or skin cancer, as well as leukemia and other cancers. Drugs that target mutations in these genes, including imatinib, ruxolitinib and sunitinib, while not approved for breast cancer, are already on the market for other cancers. 

"We are finding genetic mutations in multiple tumor types that could potentially be targeted with drugs that are already available," Mardis says. 

She predicts, however, that it may require a paradigm change for oncologists to evaluate the potential benefits of individualized cancer therapy. While clinical trials typically involve randomly assigning patients to a particular treatment regimen, a personalized medicine approach calls for choosing drugs based on the underlying mutations in each patient's tumor. 

"Having all treatment options available for every patient doesn't fit neatly into the confines of a carefully designed clinical trial," Mardis acknowledges. "We're going to need more flexibility." 

When during the course of cancer mutations develop also is likely to be important in decisions about treatment. In a recent study, Mardis and her team mapped the genetic evolution of leukemia and found clues to suggest that targeted cancer drugs should be aimed at mutations that develop early in the course of the disease. 

Using "deep digital sequencing," a technique developed at The Genome Institute, they sequenced individual mutations in patients' tumor samples more than 1,000 times each. This provides a read-out of the frequency of each mutation in a patient's tumor genome and allowed the researchers to map the genetic evolution of cancer cells as the disease progressed. 

They found that as cancer evolves, tumors acquire new mutations but always retain the original cluster of mutations that made the cells cancerous in the first place. Their discovery suggests that drugs targeted to cancer may be more effective if they are directed toward genetic changes that occur early in the course of cancer. Drugs that target mutations found exclusively in later-evolving cancer cells likely may not have much effect on the disease because they would not kill all the tumor cells. 

Mardis says that sequencing the entire genome of cancer cells is essential to piecing together an accurate picture of the way cancer cells evolve. If the researchers had sequenced only the small portion of the genome that involves genes, they would not have had the statistical power to track the frequency of mutations over time. (Only 1 to 2 percent of the genome consists of genes.) 

In another study, a phase III clinical trial of post-menopausal women with estrogen-receptor positive breast cancer, the Washington University researchers have shown that sequencing can help to predict which women will respond to treatment with aromatase inhibitors. These estrogen-lowering drugs are often prescribed to shrink breast tumors before surgery. But only about half of women with estrogen-receptor positive breast cancer respond to these drugs, and doctors have not been able to predict which patients will benefit. 

Interestingly, by sequencing patients' breast tumors before and after aromatase inhibitor therapy, the researchers identified substantive genomic changes that had occurred in responsive patients, whereas the genomes of unresponsive patients remained largely unchanged by the therapy. 

"No one has ever looked at treatment response at this level of resolution," Mardis says. "It's so obvious who is responding." 

In addition, the researchers have identified a series of mutations in the breast tumors that have corresponding small-molecule inhibitor drugs that target defective proteins. This finding indicates that for women who are not responding to aromatase inhibitors, treatment options may include combining conventional chemotherapy with the indicated small-molecule inhibitor. 

"We felt it was important to show there could be therapeutic options available to patients who are resistant to aromatase inhibitors," Mardis says. "As we move forward, we think sequencing will contribute crucial information to determining the best treatment options for patients."  

Source: Washington University School of Medicine [April 01, 2012]

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'Backpacking' bacteria help ferry nano-medicines inside humans

To the ranks of horses, donkeys, camels and other animals that have served humanity as pack animals or beasts of burden, scientists are now enlisting bacteria to ferry nano-medicine cargos throughout the human body. They reported on progress in developing these "backpacking" bacteria -- so small that a million would fit on the head of a pin -- in San Diego on March 29 at the 243rd National Meeting & Exposition of the American Chemical Society (ACS). 

Bacterial cells could deliver diagnostics, therapeutics or sensors to where they are needed most in the body ]Credit:Sean Parsons, ACS]

"Cargo-carrying bacteria may be an answer to a major roadblock in using nano-medicine to prevent, diagnose and treat disease," David H. Gracias, Ph.D., leader of the research team said. Gracias explained that nanotechnology is the engineering of ultra-small machines and other devices. These devices generally lack practical self-sustaining motors to move particles of medication, sensors and other material to diseased parts of the body. So why not attach such cargo to bacteria, which have self-propulsion systems, and have them hike around the human body? 

"Currently, it is hard to engineer microparticles or nanoparticles capable of self-propelled motion in well-defined trajectories under biologically relevant conditions," Gracias said. He is with Johns Hopkins University in Baltimore, Maryland. "Bacteria can do this easily, and we have established that bacteria can carry cargo." 

In addition, bacteria can respond to specific biochemical signals in ways that make it possible to steer them to desired parts of the body. Once there, bacteria can settle down, deposit their cargo and grow naturally. Bacteria already live all over the body, particularly in the large intestine, with bacterial cells outnumbering human cells 10-to-1. Despite their popular reputation as disease-causers, there are bacteria in the human body, especially in the intestinal tract, that are not harmful, and the backpackers fall into that category. 

Gracias' bacteria don't really carry little nylon or canvas backpacks. Their "backpacks" are micro- or nano-sized molecules or devices that have useful optical, electrical, magnetic, electrical or medicinal properties. The cargos that the team tested also varied in size, shape and material. So far, the team has loaded beads, nanowires and lithographically fabricated nanostructures onto bacteria. 

Other scientists are seeking to enlist bacteria in transporting nano-cargo. They already have established, for instance, that large numbers of bacteria -- so-called "bacterial carpets" -- can move tiny objects. Gracias' research focuses on attaching one piece of cargo to an individual bacterium, rather than many bacteria to much larger cargo. The bacteria, termed "biohybrid devices," can still move freely, even with the cargo stuck to them. 

"This is very early-stage exploratory research to try and enable new functionalities for medicine at the micro- and nanoscale by leveraging traits from bacteria," explained Gracias. "Our next steps would be to test the feasibility of the backpacking bacteria for diagnosing and treating disease in laboratory experiments. If that proves possible, we would move on to tests in laboratory mice. This could take a few years to complete." 

Source: American Chemical Society [March 29, 2012]

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Gene sequencing at warp speed

One million vocalists singing the same song will sound cacophonous to an audience member if the singers belt out the tune at different tempos. 

“But if you’re listening to one person sing, and he changes his tempo, you’re still going to stay in tune with him,” said Meni Wanunu, an assistant professor of physics in Northeastern’s College of Science. 

Wanunu used the analogy to explain the difference between older and newer gene sequencing techniques. Old techniques, he said, analyzed millions of DNA molecules at a time. But new techniques take a single-molecule approach, a strategy that has the potential to revolutionize the field — once a few significant challenges are overcome. 

By obtaining the sequence of an organism’s genetic material with ease, scientists can explore a range of research areas, from correlating genes with functions to answering evolutionary mysteries. Doctors can use gene sequencing to test for specific genes that are related to specific diseases, such as breast and ovarian cancers. Patients could learn in their home what foods to avoid and which drugs would be most effective for them. 

Older and current commercial sequencing technologies are too expensive for realizing personalized health and medicine applications. By studying DNA motion through nanopores, Wanunu’s team and others in the field hope to provide simple and straightforward approaches that could reduce sequencing costs by a thousand times, making it available for all. 

In an article published on Sunday in the journal Nature Methods, Wanunu and colleagues at University of Pennsylvania and Columbia University unveiled a device that speeds up the rate at which DNA molecules can be detected, a significant step toward reading their sequence. 

Wanunu, who joined the Northeastern faculty in September, designs nanoscale membranes that contain pores through which charged particles, such as DNA molecules and salt ions, can pass when exposed to an electric field. 

When a long DNA molecule passes through a pore, the membrane’s current momentarily subsides, yielding a negative spike in voltage signal. DNA consists of many repeating subunits called bases, each of which has previously been shown to exhibit a characteristic signal spike. 

Existing state-of-the-art techniques can’t measure current changes though a nanopore fast enough to allow reading each base. “You can show that DNA was there, but not what the sequence is,” Wanunu explained. 

Slowing down DNA movement by lowering the voltage is not a practical solution, Wanunu said. “If you lower the voltage too much, at some point DNA will not want to enter and if it doesn’t enter you won’t be able to read it. If it enters too fast, you’re not going to know the sequence.” 

Armed with this information, the team focused their efforts on speeding up the rate of measurement. By thinking outside the box (literally), Wanunu's colleagues Jacob Rosenstein and Ken Shepard from Columbia University designed a miniature "patch-clamp amplifier" that is 10 times smaller than traditional amplifiers. More importantly, it is 10 times faster, being able to read current through the nanopore about every half microsecond — just about the time it takes for a DNA base to move through. 

Sequencing DNA is one of many applications for this amplifier. It could also be useful for neuroscientists in reading cell currents, analyzing RNA structures and probing proteins. Wanunu plans to optimize the system, by focusing on the speed of DNA movement, on minimizing the capacity for pores to clog and on identifying stronger, thinner membrane materials like graphene. 

Author: Angela Herring | Source: Northeastern University [March 19, 2012]

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Permafrost bacteria may slow down aging

A hardy type of bacteria recently discovered in the permafrost of Siberia could help slow down the ageing process, Russian scientists claimed on Tuesday. 

The species of bacteria -- given the name Bacillius F -- was found in laboratory tests to have shown signs of slowing down the process of ageing on mice, the Russian Academy of Sciences (RAN) said. 

The Siberian branch of the RAN said Bacillius F lags 3 million years behind similar bacteria in evolutionary terms, according to the characteristics of proteins and some other factors. 

"Taking into consideration the unusual living environment, one can only marvel at the resilience of these bacteria," it said. 

It added that the organisms found in Russia's northern region of Yakutia -- home to the coldest inhabited area on the planet -- reproduce at just 5 degrees Celsius. 

"We just thought: since the bacteria were found in the permafrost where they were successfully preserved they will possibly have mechanisms of retaining viability," added Nadezhda Mironova, senior research scientist at the Institute of Chemical Biology and Fundamental Medicine of the Russian Academy of Sciences. 

"This is what happened," she was quoted as saying. 

Injections of the bacteria into mice have helped boost the natural defences of the animals as they grew older. 

"Bacillius F injections have favourably affected the quality of being of the aging animals," the Russian scientists said. 

"First and foremost, this concerns immunity and the speed of its activation." 

Experiments have shown that metabolism in the tested mice have increased by 20 to 30 percent, the scientists said, adding that the bacterium may also reduce instances of senile blindness but not the emergence of tumours. 

The Russian Academy of Sciences did not say how many mice were tested, adding more animals were needed for the experiments to be more reliable. The mice from a test group lived longer than those in a control group however, it said, calling the results "impressive." 

Source: AFP [January 17, 2012]

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Opioids Erase Memory Traces of Pain

A team of researchers at the MedUni Vienna's Department of Neurophysiology (Centre for Brain Research) has discovered a previously unknown effect of opioids: the study, which has now been published in the journal Science and was led by Ruth Drdla-Schutting and Jurgen Sandkuhler, shows that opioids not only temporarily relieve pain, but at the right dose can also erase memory traces of pain in the spinal cord and therefore eliminate a key cause of chronic pain. 

The scientists recreated a surgical procedure in vivo in which pain fibres were stimulated under controlled conditions. 

Says Sandkuhler: "Although deep anaesthesia prevents any sensations of pain, we were able to reserve long-term synaptic potentiation in the spinal cord. Despite anaesthesia, there appears to be a memory trace for pain and a pain amplifier has engaged." High doses of intravenous opioids over the course of an hour -- normally opioids are delivered at moderate doses over a longer period -- were able to completely resolve the potentiation. Says Sandkuhler: "The memory trace for pain was therefore deleted again and the pain amplifier switched off." 

The memory trace, as it is termed, is triggered by a variety of mechanisms, including the potentiation of signal transmission at the contact points (synapses) between the nerve cells. This is known as long-term synaptic potentiation. This pain memory can result in the sensation of amplified pain lasting much longer than the actual cause of the pain, even leading to a condition known as chronic pain syndrome. 

A paradigm shift in pain therapy? 

The project, which is sponsored by the Vienna Fund for Science, Research and Technology (WWTF), is currently investigating how this discovery can be put to use in clinical settings. To this end, test subjects or patients with pain syndrome are being given a high dose of an opioid over a period of 60 minutes. 

"If our approach turns out to be effective under clinical conditions, this would herald a paradigm shift in pain therapy. It would mean moving away from the temporary, purely symptom-based pain therapy to a long-term removal of the cause of pain based on pain mechanisms using opioids." 

The effect of opioids (morphine or morphine-like substances) is based on their ability to bind to specific binding sites, known as µ-opiate receptors (MOR) which are found on nerve cells and which process pain-related information. Until now, it has been assumed that opioids are only able to alleviate pain while they are bound to the MOR and therefore suppress stimulation in the pain-processing system. Says Drdla-Schutting: "As soon as the medication is stopped, the pain-relieving effect disappears too." In clinical practice, opioids are therefore given continuously in moderate doses in order to achieve permanent binding to the MOR. This may relieve pain very effectively, but its cause cannot be eliminated. The new, high-dose, short-term therapy with opioids, on the other hand, causes a reversal of cellular changes that play an important role in pain memories, therefore possibly eliminating one of the causes of chronic pain. 

Source: Medical University of Vienna [January 12, 2012]

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Studies identify risk factors in rising trend of liver cancer

Doctors have known for years that the incidence of deadly liver cancer is on the rise, but what is causing that trend has remained a mystery. Two recent Mayo Clinic studies published in the January issue of Mayo Clinic Proceedings offer a clearer picture of the rise of hepatocellular carcinoma (HCC), or liver cancer, which has tripled in the U.S. in the last three decades and has a 10 to 12 percent five-year survival rate when detected in later stages.

"The studies illuminate the importance of identifying people with risk factors in certain populations to help catch the disease in its early, treatable stages," said W. Ray Kim, M.D., a specialist in Gastroenterology and Hepatology and principal investigator of one study.

Dr. Kim's research group looked at several decades of records in the Rochester Epidemiology Project, a database that accounts for an entire county's inpatient and outpatient care. The study found the overall incidence of HCC in the population (6.9 per 100,000) is higher than has been estimated for the nation based on data from the National Cancer Institute (5.1 per 100,000). The study also found that HCC, which two decades ago tended to be caused by liver-scarring diseases such as cirrhosis from alcohol consumption, is now occurring as a consequence of hepatitis C infection.

"The liver scarring from hepatitis C can take 20 to 30 years to develop into cancer," Dr. Kim says. "We're now seeing cancer patients in their 50s and 60s who contracted hepatitis C 30 years ago and didn't even know they were infected."

Eleven percent of cases were linked to obesity, in particular fatty liver disease.

"It's a small percentage of cases overall," Dr. Kim says. "But with the nationwide obesity epidemic, we believe the rates of liver cancer may dramatically increase in the foreseeable future."

Another study looked exclusively at the Somali population, which is growing in the U.S., particularly in Minnesota, where as many as 50,000 Somalis have settled in the last two decades. The East African country is known to have a high prevalence of hepatitis B, a risk factor for HCC.

Researchers investigating records in the Mayo Clinic Life Sciences System confirmed that hepatitis B remains a risk factor, but they were surprised to find that a significant percentage of liver cancer cases in the population are attributable to hepatitis C, which had not been known to be significantly prevalent.

"The study suggests that screening for hepatitis C would be helpful for the Somali population and would enable close surveillance of liver cancer among those at risk," says lead author Abdirashid Shire, Ph.D., a Mayo Clinic researcher. "That would greatly improve treatment and survival of Somalis with this type of cancer."

Source: Mayo Clinic [January 03, 2012]

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Deep brain stimulation shows promising results for unipolar and bipolar depression

A new study shows that deep brain stimulation (DBS) is a safe and effective intervention for treatment-resistant depression in patients with either unipolar major depressive disorder (MDD) or bipolar ll disorder (BP). The study was published Online First by Archives of General Psychiatry, one of the JAMA/Archives journals. 

The study was led by Helen S. Mayberg, MD, professor in the Departments of Psychiatry and Behavioral Sciences and Neurology at Emory University School of Medicine, with co-investigators Paul E. Holtzheimer, MD, lead psychiatrist and now associate professor and director of the Mood Disorders Service, Dartmouth Medical School, and neurosurgeon Robert E. Gross, MD, PhD, associate professor in the Departments of Neurosurgery and Neurology at Emory. Gross served as chief neurosurgeon for the study. 

"Depression is a serious and debilitating medical illness," says Mayberg. "When we found that the potential for effective and sustained antidepressant response with DBS for patients with otherwise treatment resistant major depressive disorder was high, the next step was to determine if patients with intractable bipolar depression could also be successfully treated." 

An earlier study by Mayberg done in Toronto in collaboration with scientists at Toronto Western Hospital, University Health Network and Emory, was the first to show such results for patients with treatment-resistant major depressive disorder. Mayberg conducted this new expanded trial at Emory to include patients with bipolar ll disorder. 

Bipolar spectrum disorder, sometimes referred to as manic-depression, is characterized by bouts of mania or hypomania alternating between episodes of depression. Although people with bipolar ll disorder do not have full manic episodes, depressive episodes are frequent and intense, and there is a high risk of suicide. A major challenge in treating bipolar depression is that many antidepressant medications may cause patients to "switch" into a hypomanic or manic episode. 

DBS uses high-frequency electrical stimulation targeted to a predefined area of the brain specific to the particular neuropsychiatric disorder. Here, each study participant was implanted with two thin wire electrodes, one on each side of the brain. The other end of each wire was connected under the skin of the patient's neck to a pulse generator implanted in the chest – similar to a pacemaker – that directs the electrical current. 

Study participants received single-blind stimulation for four weeks (patients did not know if the DBS system was on or off), followed by active stimulation for 24 weeks. Patients were evaluated for up to two years following onset of active stimulation. Seventeen patients were enrolled in the study. 

A significant decrease in depression and increase in function were associated with continuing stimulation. Remission and response rates were 18 percent and 41 percent after 24 weeks; 36 percent and 36 percent after one year and 58 percent and 92 percent after two years of active stimulation. Patients who achieved remission did not experience a spontaneous relapse. Efficacy was similar for Major Depressive Disorder and Bi-Polar patients, and no participant experienced a manic or hypomanic episode. 

Mayberg and her colleagues continue to refine this intervention. Current studies include demographic, clinical and imaging predictors of response and remission, and introduction of psychotherapeutic rehabilitation. Why and how this treatment works is the primary focus of ongoing research. 

"Most of these patients have been in a depressed state for many years and are disabled and isolated," says Holtzheimer. "As their depression improves, they need a process to help them achieve full recovery that includes integration back into society. 

"We hope to optimize the rate of improvement for these patients by using a model of care that provides psychotherapeutic rehabilitation built on evidence-based psychotherapy but tailored to the specific individual's situation."  

Source: Emory University [January 02, 2012]

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