health--medicine

Reconsidering Cancer's Bad Guy

Fri, 23 Nov 2012 16:26:03 +0100

Researchers at the University of Copenhagen have found that a protein, known for causing cancer cells to spread around the body, is also one of the molecules that trigger repair processes in the brain. These findings are the subject of a paper, published this week in Nature Communications. They point the way to new avenues of research into degenerative brain diseases like Alzheimer's.

How to repair brain injuries is a fundamental question facing brain researchers. Scientists have been familiar with the protein S100A4 for some time as a factor in metastasis, or how cancer spreads. However it's the first time the protein has been shown to play a role in brain protection and repair.

"This protein is not normally in the brain, only when there's trauma or degeneration. When we deleted the protein in mice we discovered that their brains were less protected and able to resist injury. We also discovered that S100A4 works by activating signalling pathways inside neurons," says Postdoc Oksana Dmytriyeva, who worked on the research in a team at the Protein Laboratory in the Department of Neuroscience and Pharmacology at the University of Copenhagen.

The villain turns out to be the hero

This research stands on the shoulders of many years of work on S100A4 in its deadlier role in cancer progression. The discovery represents a significant development for the new Neuro-Oncology Group that moved to the University of Copenhagen's Protein Laboratory Group from the Danish Cancer Society in October.

"We were surprised to find this protein in this role, as we thought it was purely a cancer protein. We are very excited about it and we're looking forward to continuing our research in a practical direction. We hope that the findings will eventually benefit people who need treatment for neurodegenerative disorders like Alzheimer's disease, although obviously we have a long way to go before we get to that point," says Oksana Dmytriyeva.

The scientific paper The metastasis-promoting S100A4 protein confers neuroprotection in brain injury can be found online in the journal Nature Communications.

Simplifying Heart Surgery With Stretchable Electronics Devices

Thu, 22 Nov 2012 14:27:27 +0100

Researchers utilized stretchable electronics to create a catheter to make cardiac ablation simpler. (Credit: Image courtesy of Northwestern University)

Researchers at the McCormick School of Engineering are part of a team that has used stretchable electronics to create a multipurpose medical catheter that can both monitor heart functions and perform corrections on heart tissue during surgery.

The device marks the first time stretchable electronics have been applied to a surgical process known as cardiac ablation, a milestone that could lead to simpler surgeries for arrhythmia and other heart conditions. The researchers had previously demonstrated the concept to apply stretchable electronics to heart surgery, but with this research improved the design's functionality to the point that it could be utilized in animal tests.

Cardiac ablation is a surgical technique that corrects heart rhythm irregularities by destroying specific heart tissue that triggers irregular heartbeats. The procedure is typically performed either with open-heart surgery or by inserting a series of long, flexible catheters through a vein in the patient's groin and into his heart.

Currently this catheter method requires the use of three different devices, which are inserted into the heart in succession: one to map the heart's signals and detect the problem area, a second to control positions of therapeutic actuators and their contact with the epicardium, and a third to burn the tissue away.

"Our catheter replaces all three devices previously needed for cardiac ablation therapy, making the surgery faster, simpler, and with a lower risk of complication," said Yonggang Huang, Joseph Cummings Professor of Civil and Environmental Engineering and Mechanical Engineering at McCormick.

Central to the design is a section of catheter that is printed with a thin layer of stretchable electronics. The catheter's exterior protects the electronics during its trip through the bloodstream; once inside the heart, the catheter is inflated like a balloon, exposing the electronics to a larger surface area inside the heart.

With the catheter is in place, the individual devices within can perform their specific tasks. A pressure sensor determines the pressure on the heart; an EKG sensor monitors the heart's condition during the procedure; and a temperature sensor controls the temperature so as not to damage surrounding tissue. The temperature can also be controlled during the procedure without removing the catheter.

These devices can deliver critical, high-quality information -- such as temperature, mechanical force, and blood flow -- to the surgeon in real time, and the system is designed to operate reliably without any changes in properties as the balloon inflates and deflates.

Researchers at McCormick led the efforts to design and optimize the system. (McCormick graduate student Shuodao Wang is a co-first author of the paper.) Device fabrications were done at the University of Illinois at Urbana-Champaign, and animal tests were conducted at University of Arizona Sarver Heart Center.

Other partners on this research include Seoul National University in the Republic of Korea; the University of Texas at Austin; Zhejiang University in China; the Harbin Institute of Technology in China; the Institute of High Performance Computing in Singapore; Massachusetts General Hospital; and Tufts University.

Chemotherapy-Resistant Cancer Stem Cell Could Be 'Achilles' Heel' of Cancer

Wed, 21 Nov 2012 14:25:35 +0100

Scientists have discovered a subpopulation of cells that display cancer stem cell properties and resistance to chemotherapy, and participate in tumor progression. (Credit: © Jezper / Fotolia)

Scientists at Mount Sinai School of Medicine have discovered a subpopulation of cells that display cancer stem cell properties and resistance to chemotherapy, and participate in tumor progression. This breakthrough could lead to the development of new tests for early cancer diagnosis, prognostic tests, and innovative therapeutic strategies, as reported in Cancer Cell.

Resistance to chemotherapy is a frequent and devastating phenomenon that occurs in cancer patients during certain treatments. Unfortunately, tumors that initially respond to chemotherapy eventually become resistant to it, contributing to tumor progression and death. The study reveals that these new cancer "stem" cells, which have not been differentiated into more specific cell types, are capable of multiplying despite being exposed to chemotherapy, while differentiated cells die.

Led by Carlos Cordon-Cardo, MD, PhD, Chair of Pathology, and Josep Domingo-Domenech, MD, PhD, Assistant Professor of Pathology at Mount Sinai, the research team generated cellular models of drug resistance by treating prostate tumor cell lines with increasing doses of the common chemotherapy drugs, including docetaxel. They identified a cell population expressing markers of embryonic development. In addition, these cells displayed cancer stem cell functions, including the capacity to initiate tumor cell growth. Next, the team evaluated human tissue samples of prostate cancer and found that patients with more aggressive or metastatic tumors had more of these cancer "stem" cells.

"This is the first time these so-called cancer stem cells of prostate have been identified as the basis for drug resistance and tumor progression, indicating that they are cancer's 'Achilles Heel,'" said Dr. Cordon-Cardo. "These findings are the culmination of more than six years of innovative research, which has led to the successful unveiling of cancer characteristics that are critical to understanding how the disease works and progresses."

The study also defines a new therapeutic strategy for patients with prostate cancer, consisting of a combination of standard chemotherapy and two pharmacological agents that inhibit key signaling pathways associated with embryonic development and cell differentiation. Results showed that chemotherapy eliminated differentiated tumor cells, whereas the signaling pathway inhibitors selectively depleted the cancer stem cell population. Some of these inhibitors are already in clinical trials, and some are FDA-approved.

"By targeting these newly identified cancer 'stem' cells, we are attacking the foundation of tumor growth, rather than treating the symptoms of it," said Dr. Domingo-Domenech. "The novel discovery of this cell population could lead to the development of new tests for early cancer diagnosis, prognostic tests, and innovative therapeutic strategies."

Ongoing studies suggest that this new cell type exist in other tumor types such as breast cancer, colon cancer, bladder cancer and lung cancer. Dr. Cordon-Cardo's team is studying these disease areas to determine the presence and impact of these cancer cells.

Nanotech Device Mimics Dog's Nose to Detect Explosives

Wed, 21 Nov 2012 14:22:24 +0100

Concept illustration of the microscale free-surface microfluidic channel as it concentrates vapor molecules that bind to nanoparticles inside a chamber. A laser beam detects the nanoparticles, which amplify a spectral signature of the detected molecules. (Credit: Image courtesy of University of California - Santa Barbara)

Portable, accurate, and highly sensitive devices that sniff out vapors from explosives and other substances could become as commonplace as smoke detectors in public places, thanks to researchers at University of California, Santa Barbara.

Researchers at UCSB, led by professors Carl Meinhart of mechanical engineering and Martin Moskovits of chemistry, have designed a detector that uses microfluidic nanotechnology to mimic the biological mechanism behind canine scent receptors. The device is both highly sensitive to trace amounts of certain vapor molecules, and able to tell a specific substance apart from similar molecules.

"Dogs are still the gold standard for scent detection of explosives. But like a person, a dog can have a good day or a bad day, get tired or distracted," said Meinhart. "We have developed a device with the same or better sensitivity as a dog's nose that feeds into a computer to report exactly what kind of molecule it's detecting." The key to their technology, explained Meinhart, is in the merging of principles from mechanical engineering and chemistry in a collaboration made possible by UCSB's Institute for Collaborative Biotechnologies.

Results published this month inAnalytical Chemistry show that their device can detect airborne molecules of a chemical called 2,4-dinitrotoluene, the primary vapor emanating from TNT-based explosives. The human nose cannot detect such minute amounts of a substance, but "sniffer" dogs have long been used to track these types of molecules. Their technology is inspired by the biological design and microscale size of the canine olfactory mucus layer, which absorbs and then concentrates airborne molecules.

"The device is capable of real-time detection and identification of certain types of molecules at concentrations of 1 ppb or below. Its specificity and sensitivity are unparalleled," said Dr. Brian Piorek, former mechanical engineering doctoral student in Meinhart's laboratory and Chief Scientist at Santa Barbara-based SpectraFluidics, Inc . The technology has been patented and exclusively licensed to SpectraFluidics, a company that Piorek co-founded in 2008 with private investors.

"Our research project not only brings different disciplines together to develop something new, but it also creates jobs for the local community and hopefully benefits society in general," commented Meinhart.

Packaged on a fingerprint-sized silicon microchip and fabricated at UCSB's state-of-the-art cleanroom facility, the underlying technology combines free-surface microfluidics and surface-enhanced Raman spectroscopy (SERS) to capture and identify molecules. A microscale channel of liquid absorbs and concentrates the molecules by up to six orders of magnitude. Once the vapor molecules are absorbed into the microchannel, they interact with nanoparticles that amplify their spectral signature when excited by laser light. A computer database of spectral signatures identifies what kind of molecule has been captured.

"The device consists of two parts," explained Moskovits. "There's a microchannel, which is like a tiny river that we use to trap the molecules and present them to the other part, a mini spectrometer powered by a laser that detects them. These microchannels are twenty times smaller than the thickness of a human hair."

"The technology could be used to detect a very wide variety of molecules," said Meinhart. "The applications could extend to certain disease diagnosis or narcotics detection, to name a few."

Moskovits added, "The paper we published focused on explosives, but it doesn't have to be explosives. It could detect molecules from someone's breath that may indicate disease, for example, or food that has spoiled."

The fundamental research was developed through an interdisciplinary collaboration between Professors Meinhart and Moskovits, and carried out by former doctoral researchers Dr. Piorek and Dr. Seung-Joon Lee. Their project was funded in part by UCSB's Institute for Collaborative Biotechnologies through the Army Research Office and DARPA.

Compound in Grapes, Red Wine Could Be Key to Fighting Prostate Cancer

Tue, 20 Nov 2012 17:08:57 +0100

Scientists at MU have found that treatment with a compound found in grape skins and red wine could increase the chances of a full recovery from all types of prostate cancer, including aggressive tumors. (Credit: Image courtesy of University of Missouri-Columbia)

Resveratrol, a compound found commonly in grape skins and red wine, has been shown to have several beneficial effects on human health, including cardiovascular health and stroke prevention. Now, a University of Missouri researcher has discovered that the compound can make prostate tumor cells more susceptible to radiation treatment, increasing the chances of a full recovery from all types of prostate cancer, including aggressive tumors.

"Other studies have noted that resveratrol made tumor cells more susceptible to chemotherapy, and we wanted to see if it had the same effect for radiation therapy," said Michael Nicholl, an assistant professor of surgical oncology in the MU School of Medicine. "We found that when exposed to the compound, the tumor cells were more susceptible to radiation treatment, but that the effect was greater than just treating with both compounds separately."

Prostate tumor cells contain very low levels of two proteins, perforin and granzyme B, which can function together to kill cells. However, both proteins need to be highly "expressed" to kill tumor cells. In his study, when Nicholl introduced resveratrol into the prostate tumor cells, the activity of the two proteins increased greatly. Following radiation treatment, Nicholl found that up to 97 percent of the tumor cells died, which is a much higher percentage than treatment with radiation alone.

"It is critical that both proteins, perforin and granzyme B, are present in order to kill the tumor cells, and we found that the resveratrol helped to increase their activity in prostate tumor cells," Nicholl said. "Following the resveratrol-radiation treatment, we realized that we were able to kill many more tumor cells when compared with treating the tumor with radiation alone. It's important to note that this killed all types of prostate tumor cells, including aggressive tumor cells."

Resveratrol is present in grape skins and red wine and available over-the-counter in many health food sections at grocery stores. However, the dosage needed to have an effect on tumor cells is so great that many people would experience uncomfortable side effects.

"We don't need a large dose at the site of the tumor, but the body processes this compound so efficiently that a person needs to ingest a lot of resveratrol to make sure enough of it ends up at the tumor site. Because of that challenge, we have to look at different delivery methods for this compound to be effective," Nicholl said. "It's very attractive as a therapeutic agent since it is a natural compound and something that most of us have consumed in our lifetimes."

Nicholl said that the next step would be to test the procedure in an animal model before any clinical trials can be initiated. Nicholl's studies were published in the Journal of Andrologyand Cancer Science. The early-stage results of this research are promising. If additional studies, including animal studies, are successful within the next few years, MU officials will request authority from the federal government to begin human drug development (this is commonly referred to as the "investigative new drug" status). After this status has been granted, researchers may conduct human clinical trials with the hope of developing new treatments for cancer.

Optogenetics Illuminates Pathways of Motivation Through Brain

Mon, 19 Nov 2012 12:12:25 +0100

Whether you are an apple tree or an antelope, survival depends on using your energy efficiently. In a difficult or dangerous situation, the key question is whether exerting effort -- sending out roots in search of nutrients in a drought or running at top speed from a predator -- will be worth the energy.

In a paper published online Nov. 18 inNature, Karl Deisseroth, MD, PhD, a professor of bioengineering and of psychiatry and behavioral sciences at Stanford University, and postdoctoral scholar Melissa Warden, PhD, describe how they have isolated the neurons that carry these split-second decisions to act from the higher brain to the brain stem. In doing so, they have provided insight into the causes of severe brain disorders such as depression.

In organisms as complex as humans, the neural mechanisms that help answer the question, "Is it worth my effort?" can fail, leading to debilitating mental illnesses. Major depressive disorder, for instance, which affects nearly 20 percent of people at some point in life, is correlated with underperformance in the parts of the brain involved in motivation. But researchers have struggled to work out the exact cause and effect.

"It's challenging because we do not have a fundamental understanding of the circuitry that controls this sort of behavioral pattern selection. We don't understand what the brain is doing wrong when these behaviors become dysfunctional, or even what the brain is supposed to be doing when things are working right," Deisseroth said. "This is the level of the mystery we face in this field."

Clinicians refer to this slowing down of motivation in depressed patients as "psychomotor retardation." According to Deisseroth, who is also a practicing psychiatrist, patients may experience this symptom mentally, finding it hard to envision the positive results of an action, or, he said, they may feel physically heavy, like their limbs just do not want to move.

"This is one of the most debilitating aspects of depression, and motivation to take action is something that we can model in animals. That's the exciting opportunity for us as researchers," said Deisseroth, who also holds the D.H. Chen Professorship.

Light coercion

Psychiatrists, Deisseroth included, believe the will to act may be born in the prefrontal cortex -- the foremost part of the brain that helps plan and coordinate action. It then zips through the brain as a series of electrical signals, passing from neuron to neuron along countless branching pathways until it reaches the nerves that directly implement movement. Until this study, however, it was not clear which of these pathways might control the willingness to meet challenges, or the anticipation that action might be worthwhile in a difficult situation.

To isolate these pathways relevant to depression, Deisseroth's team needed to stimulate specific brain cells in rodents and observe changes in their behavior. They used optogenetics, a technique Deisseroth developed at Stanford in 2005, which has since revolutionized the fields of bioengineering and neuroscience.

The secret is as old as green algae. These single-celled organisms produce a protein called channelrhodopsin that makes them sensitive to sunlight. Borrowing and engineering the gene for this protein, Deisseroth has been able to create neurons that respond to light delivered from fiber-optic cables. He can turn the neurons on and off by sending bursts of light to activate different areas of the brain and then observe the effects on behavior.

Working backward

Surprisingly, the researchers found that simply stimulating the prefrontal cortices of rodents didn't motivate them to try any harder in a laboratory challenge. It turns out that motivation is not as simple as stimulating a region of the brain. Instead of one switch in the prefrontal cortex that turns motivation on, multiple switches work in concert. Some neurons excite motivated activity and others inhibit it. Broadly stimulating the executive part of the brain will not generate a simple effect on behavior.

"It's one step more subtle," said Deisseroth, "but this is something that optogenetics was very well-suited to resolve."

An optogenetic method called projection targeting allowed the scientists to work backward from the brain stem and find the exact pathway from neurons in the prefrontal cortex that signal motivation.

The researchers first introduced their light-sensitive protein into cells in the prefrontal cortex. The light sensitivity then spread out like the branches of a tree through all the outgoing connections and eventually made its way to the brain stem, making those regions light sensitive, too.

Then, illuminating the newly light-sensitive regions of the brain stem thought to control motivational movement, Deisseroth and Warden watched the behavioral effects as a subgroup of neurons in the prefrontal cortex that sent connections to the brain stem were activated. They could see not only which cells are possibly involved in motivation, but the way motivation moves from one brain region to another.

Mapping motivation

The researchers suspected that one part of the brain stem in particular, the dorsal raphe nucleus, might be crucial to behaviors that control effort. This cluster of cells is a production hub for serotonin -- a chemical messenger that changes the firing behavior of other cells. Serotonin is associated with mood modulation; many antidepressant drugs, for instance, may act by increasing serotonin concentration in the brain.

When the pathway between the prefrontal cortex and the dorsal raphe nucleus was stimulated, rodents facing a challenge in the lab showed an immediate and dramatic surge in motivation.

Curiously, however, when the rodents were relaxing in their home environment, the same stimulation had no effect. The pathway was not merely linked to any action, or to agitation; it was, more specifically, helping to "set the effort that the organism was willing to put forth to meet a challenge," Deisseroth said.

Researchers were also able to produce the opposite effect -- reduced effort in response to challenge -- by stimulating prefrontal neurons that project to the lateral habenula, a region perched atop the brain stem that is thought to play a role in depression. When this region was getting signals driven optogenetically from the prefrontal cortex, rodents put forward less effort.

Larger puzzles

These findings are part of a larger puzzle that Deisseroth and his team have pieced together by using optogenetics to model human behavior in animal subjects. The work has already helped clinicians and researchers to better understand what is going on in a patient's brain.

Connecting depressive symptoms with brain pathways may be helpful in the development of drugs, but according to Deisseroth, the most important part of this research is its insight into how motivation works in both depressed and healthy people.

He has observed that this insight alone can be helpful to those dealing with mental illness and seeking an explanation for troubling symptoms that feel deeply personal. For those patients, he said, simply knowing that a biological reality underlies their experience can be a motivational force in itself.

Other Stanford co-authors include graduate students Aslihan Selimbeyoglu and Sung-Yon Kim; research assistant Julie Mirzabekov; lab manager Maisie Lo; postdoctoral scholars Kimberly Thompson, PhD, and Avishek Adhikari, PhD; and former postdoctoral scholar Kay Tye. They also collaborated with Loren Frank, PhD, a faculty member at UC-San Francisco.

This research was supported by the Wiegers Family Fund, the Brain & Behavior Research Foundation, a Stanford graduate fellowship, a Samsung scholarship, a Berry Foundation fellowship, the National Institute of Mental Health, the National Institute on Drug Abuse, the U.S. Department of Defense, the Keck Foundation, the McKnight Foundation, the Yu, Snyder, Tarlton, and Woo Foundations, and the Gatsby Charitable Foundation.

The work was also supported by Stanford's Department of Bioengineering, which is jointly operated by the School of Engineering and the School of Medicine.

Vitamin D May Prevent Clogged Arteries in Diabetics

Sat, 17 Nov 2012 03:26:04 +0100

Low levels of vitamin D in people with diabetes appear to encourage cholesterol to build up in arteries, eventually blocking the flow of blood. In mice, immune cells adhering to the wall of a major blood vessel near the heart are loaded with cholesterol (shown in red). (Credit: Bernal-Mizrachi lab)

People with diabetes often develop clogged arteries that cause heart disease, and new research at Washington University School of Medicine in St. Louis suggests that low vitamin D levels are to blame.

In a study published Nov. 9 in theJournal of Biological Chemistry, the researchers report that blood vessels are less like to clog in people with diabetes who get adequate vitamin D. But in patients with insufficient vitamin D, immune cells bind to blood vessels near the heart, then trap cholesterol to block those blood vessels.

"About 26 million Americans now have type 2 diabetes," says principal investigator Carlos Bernal-Mizrachi, MD. "And as obesity rates rise, we expect even more people will develop diabetes. Those patients are more likely to experience heart problems due to an increase in vascular inflammation, so we have been investigating why this occurs."

In earlier research, Bernal-Mizrachi, an assistant professor of medicine and of cell biology and physiology, and his colleagues found that vitamin D appears to play a key role in heart disease. This new study takes their work a step further, suggesting that when vitamin D levels are low, a particular class of white blood cell is more likely to adhere to cells in the walls of blood vessels.

Vitamin D conspires with immune cells called macrophages either to keep arteries clear or to clog them. The macrophages begin their existence as white blood cells called monocytes that circulate in the bloodstream. But when monocytes encounter inflammation, they are transformed into macrophages, which no longer circulate.

In the new study, researchers looked at vitamin D levels in 43 people with type 2 diabetes and in 25 others who were similar in age, sex and body weight but didn't have diabetes.

They found that in diabetes patients with low vitamin D -- less than 30 nanograms per milliliter of blood -- the macrophage cells were more likely to adhere to the walls of blood vessels, which triggers cells to get loaded with cholesterol, eventually causing the vessels to stiffen and block blood flow.

"We took everything into account," says first author Amy E. Riek, MD, instructor in medicine. "We looked at blood pressure, cholesterol, diabetes control, body weight and race. But only vitamin D levels correlated to whether these cells stuck to the blood vessel wall."

Riek and Bernal-Mizrachi say what's not yet clear is whether giving vitamin D to people with diabetes will reverse their risk of developing clogged arteries, a condition called atherosclerosis. They now are treating mice with vitamin D to see whether it can prevent monocytes from adhering to the walls of blood vessels near the heart, and they also are conducting two clinical trials in patients.

In one of those studies, the researchers are giving vitamin D to people with diabetes and hypertension to see whether the treatment may lower blood pressure. In the second study, African Americans with type 2 diabetes are getting vitamin D along with their other daily medications, and the research team is evaluating whether vitamin D supplements can slow or reverse the progression of heart disease.

Sometime in the next several months, the scientists hope to determine whether vitamin D treatment can reverse some of the risk factors associated with cardiovascular disease.

"In the future, we hope to generate medications, potentially even vitamin D itself, that help prevent the deposit of cholesterol in the blood vessels," Bernal-Mizrachi explains. "Previous studies have linked vitamin D deficiency in these patients to increases in cardiovascular disease and in mortality. Other work has suggested that vitamin D may improve insulin release from the pancreas and insulin sensitivity. Our ultimate goal is to intervene in people with diabetes and to see whether vitamin D might decrease inflammation, reduce blood pressure and lessen the likelihood that they will develop atherosclerosis or other vascular complications."

Funding for this research comes from the National Heart, Lung and Blood Institute (NHLBI), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Center for Research Resources (NCRR), National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research of the National Institutes of Health (NIH). Support also comes from the American Diabetes Association, the Endocrine Society, the Endocrine Fellows Foundation and the Ruth L. Kirchstein National Research Service Award 2. NIH grant numbers are RO1 HO094818-0, P30DK079333, T32 HD043010, and UL1TRR000448/Sub-Award KL2TR000450.

Shape Matters in DNA Nanoparticle Therapy: Particles Could Become a Safer, More Effective ...

Wed, 14 Nov 2012 14:26:54 +0100

Researchers from Johns Hopkins and Northwestern universities have discovered how to control the shape of nanoparticles that move DNA through the body and have shown that the shapes of these carriers may make a big difference in how well they work in treating cancer and other diseases.

This study, to be published in the Oct. 12 online edition of the journalAdvanced Materials, is also noteworthy because this gene therapy technique does not use a virus to carry DNA into cells. Some gene therapy efforts that rely on viruses have posed health risks.

"These nanoparticles could become a safer and more effective delivery vehicle for gene therapy, targeting genetic diseases, cancer and other illnesses that can be treated with gene medicine," said Hai-Quan Mao, an associate professor of materials science and engineering in Johns Hopkins' Whiting School of Engineering.

Mao, co-corresponding author of theAdvanced Materials article, has been developing nonviral nanoparticles for gene therapy for a decade. His approach involves compressing healthy snippets of DNA within protective polymer coatings. The particles are designed to deliver their genetic payload only after they have moved through the bloodstream and entered the target cells. Within the cells, the polymer degrades and releases DNA. Using this DNA as a template, the cells can produce functional proteins that combat disease.

A major advance in this work is that Mao and his colleagues reported that they were able to "tune" these particles in three shapes, resembling rods, worms and spheres, which mimic the shapes and sizes of viral particles. "We could observe these shapes in the lab, but we did not fully understand why they assumed these shapes and how to control the process well," Mao said. These questions were important because the DNA delivery system he envisions may require specific, uniform shapes.

To solve this problem, Mao sought help about three years ago from colleagues at Northwestern. While Mao works in a traditional wet lab, the Northwestern researchers are experts in conducting similar experiments with powerful computer models.

Erik Luijten, associate professor of materials science and engineering and of applied mathematics at Northwestern's McCormick School of Engineering and Applied Science and co-corresponding author of the paper, led the computational analysis of the findings to determine why the nanoparticles formed into different shapes.

"Our computer simulations and theoretical model have provided a mechanistic understanding, identifying what is responsible for this shape change," Luijten said. "We now can predict precisely how to choose the nanoparticle components if one wants to obtain a certain shape."

The use of computer models allowed Luijten's team to mimic traditional lab experiments at a far faster pace. These molecular dynamic simulations were performed on Quest, Northwestern's high-performance computing system. The computations were so complex that some of them required 96 computer processors working simultaneously for one month.

In their paper, the researchers also wanted to show the importance of particle shapes in delivering gene therapy. Team members conducted animal tests, all using the same particle materials and the same DNA. The only difference was in the shape of the particles: rods, worms and spheres.

"The worm-shaped particles resulted in 1,600 times more gene expression in the liver cells than the other shapes," Mao said. "This means that producing nanoparticles in this particular shape could be the more efficient way to deliver gene therapy to these cells."

The particle shapes used in this research are formed by packaging the DNA with polymers and exposing them to various dilutions of an organic solvent. DNA's aversion to the solvent, with the help of the team's designed polymer, causes the nanoparticles to contract into a certain shape with a "shield" around the genetic material to protect it from being cleared by immune cells.

Lead authors of the Advanced Materials paper are Wei Qu, a graduate student in Luijten's research group at Northwestern, and Xuan Jiang, who was a doctoral student in Mao's lab. Along with Mao and Luijten, the remaining co-authors of the paper, all from Johns Hopkins, are Deng Pan, who worked on the project as an undergraduate; Yong Ren, a postdoctoral fellow; John-Michael Williford, a biomedical engineering doctoral student; and Honggang Cui, an assistant professor in the department of chemical and biomolecular engineering.

This illustration depicts DNA molecules (light green), packaged into nanoparticles by using a polymer with two different segments. One segment (teal) carries a positive charge that binds it to the DNA, and the other (brown) forms a protective coating on the particle surface. By adjusting the solvent surrounding these molecules, the Johns Hopkins and Northwestern researchers were able to control the shape of the nanoparticles. The team’s animal tests showed that a nanoparticle’s shape could dramatically affect how effectively it delivers gene therapy to the cells. The cartoon images in the foreground, obtained though computational modeling, matched closely with the gray background images, which were collected through transmission electron microscopy. (Credit: Wei Qu, Northwestern University, simulation cartoons; Xuan Jiang, Johns Hopkins University, microscopic images)

New Research: Limiting Carbs to Dinner-Time Increases Satiety, Reduces Risk for Diabetes and ...

Mon, 12 Nov 2012 14:35:05 +0100

An experimental diet with carbohydrates eaten mostly at dinner could benefit people suffering from severe and morbid obesity, according to new research at the Hebrew University of Jerusalem.

The diet influences secretion patters of hormones responsible for hunger and satiety, as well as hormones associated with metabolic syndrome. In this way the diet can help dieters persist over the long run, and reduce risk factors for diabetes and cardiovascular disease.

The research was carried out by research student Sigal Sofer under the auspices of Prof. (Emeritus) Zecharia Madar, at the Institute of Biochemistry, Food Science and Nutrition at the Hebrew University's Robert H. Smith Faculty of Agriculture, Food and Environment. (Prof. Madar is now Chief Scientist at Israel's Ministry of Education.)

Sofer randomly assigned 78 police officers to either the experimental diet (carbohydrates at dinner) or a control weight loss diet (carbohydrates throughout the day). 63 subjects finished the six-month program.

The researchers examined the experimental diet's effect on the secretion of three hormones: leptin, considered to be the satiety hormone, whose level in the blood is usually low during the day and high during the night; ghrelin, considered the hunger hormone, whose level in the blood is usually high during the day and low during the night; and adiponectin, considered the link between obesity, insulin resistance and the metabolic syndrome, whose curve is low and flat in obese people.

"The idea came about from studies on Muslims during Ramadan, when they fast during the day and eat high-carbohydrate meals in the evening, that showed the secretion curve of leptin was changed," explained Prof. Madar.

The researchers found that the innovative dietary manipulation led to changes in daylight hormonal profiles in favor of the dieters: the satiety hormone leptin's secretion curve became convex during daylight hours with a nadir in the late day; the hunger hormone ghrelin's secretion curve became concave, peaking only in the evening hours; and the curve of adiponectin, considered the link between obesity, insulin resistance and the metabolic syndrome, was elevated. At the same time this dietary pattern led to lower hunger scores, and better anthropometric (weight, abdominal circumference and body fat), biochemical (blood sugar, blood lipids) and inflammatory outcomes compared to the control group.

The findings suggest there is an advantage in concentrating carbohydrate intake in the evening, especially for people at risk of developing diabetes or cardiovascular disease due to obesity. "The findings lay the basis for a more appropriate dietary alternative for those people who have difficulty persisting in diets over time," said Prof. Madar. "The next step is to understand the mechanisms that led to the results obtained."

The study was published in two continuous papers: "Greater weight loss and hormonal changes after 6 months diet with carbohydrates eaten mostly at dinner" (published in Obesity) and "Changes in daily leptin, ghrelin and adiponectin profiles following a diet with carbohydrates eaten at dinner in obese subjects" (published in Nutrition, Metabolism & Cardiovascular Diseases).

Sources of support for the study include Meuhedet Medical Services, Israel; the Israeli Police Force; the Kaplan Medical Center in Rehovot, Israel (for Dr. Fink); the Israel Diabetes Association; and the Israel Lung and Tuberculosis Association (for Prof. Eliraz).

An experimental diet with carbohydrates eaten mostly at dinner could benefit people suffering from severe and morbid obesity. (Credit: © fairith / Fotolia)

Increased Risk of Prematurity and Low Birth Weight in Babies Born After Three or More Abortions

Thu, 08 Nov 2012 15:15:34 +0100

One of the largest studies to look at the effect of induced abortions on a subsequent first birth has found that women who have had three or more abortions have a higher risk of some adverse birth outcomes, such as delivering a baby prematurely and with a low birth weight.

The research, which is published online in Europe's leading reproductive medicine journal Human Reproduction Aug. 29, found that among 300,858 Finnish mothers, 31,083 (10.3%) had had one induced abortion between 1996-2008, 4,417 (1.5%) had two, and 942 (0.3%) had three or more induced abortions before a first birth (excluding twins and triplets). Those who had had three or more induced abortions had a small, but statistically significant increased risk of having a baby with very low birth weight (less than 1500g), low birth weight (less than 2500g), or of a preterm birth (before 37 weeks), or very preterm birth (before 28 weeks), compared to women who had had no abortions. There was a slightly increased risk of a very preterm birth for women who had had two induced abortions.

Dr Reija Klemetti, an associate professor and senior researcher in public health at the National Institute for Health and Welfare in Helsinki, Finland, who led the research, said: "Our results suggest that induced abortions before the first birth, particularly three or more abortions, are associated with a marginally increased risk during the first birth. However, the increased risk is very small, particularly after only one or even two abortions, and women should not be alarmed by our findings."

Most of the induced abortions (88%) were surgically performed and nearly all (91%) were performed before 12 weeks gestation. The researchers adjusted their findings to take account of various factors that could affect birth outcomes, such as social background, marital status, age, smoking, previous ectopic pregnancies and miscarriages. Multiple births (twins and triplets) were excluded.

The risk of having a baby born very preterm appeared to increase slightly with each induced abortion, but only the risk from two abortions or more was statistically significant.

"To put these risks into perspective, for every 1000 women, three who have had no abortion will have a baby born under 28 weeks," said Dr Klemetti. "This rises to four women among those who have had one abortion, six women who have had two abortions, and 11 women who have had three or more."

Among women who had had three or more abortions, there was a statistically significant increased risk of a third (35%) of having a baby born preterm (before 37 weeks), a two-fold (225%) increased risk of very low birth weight, and a two-fifths (43%) increased risk of low birth weight.

The study also showed a small increased risk of a baby's death around the time of birth. However, the numbers for this finding were very low (1498 births or five per 1000 babies) and so should be treated with caution. In addition, the authors say they might not have been able to fully adjust for all the factors that could affect this result and perinatal deaths are sensitive to social factors such as poverty.

"Our study is the first large study to look at a broad set of perinatal outcomes and to control, at least partly, for the most important confounding factors such as smoking and socioeconomic position," said Dr Klemetti. "However, it is important to say that even though we adjusted for these factors, and also ectopic pregnancies and miscarriages, there might be some confounding for social class that we could not control for. Most probably, this may be related to women's (or some of these women's) way of life, life habits, and sexual and reproductive health.

"Furthermore, this is an observational study and, however large and well-controlled, it only shows there is a link between abortion and some adverse birth outcomes -- it cannot prove that abortions are the cause.

"Finland has one of the lowest rates of induced abortion in Europe*, but even so, a large number are carried out every year. In addition, Finland has good quality abortion and maternity care, and in other contexts, particularly in poorer countries, the situation may be different. For these reasons, even a very small increase in the risk of poor birth outcomes could have significant health implications, as preterm births and low birth weight can have serious, adverse effects on the health and well-being of both babies and mothers.

"We suggest that the potential for increased risks for subsequent births should be included in sex education, especially as there are other, good reasons to avoid induced abortions. Health professionals should also be informed about the potential risks of repeat abortions."

* In 2011 there were 10,108 induced abortions in Finland, which translates to 8.7 per 1000 women aged between 15-49.