#Scientists dramatically improve method for finding common genetic alterations in tumors St jude Children's Research Hospital scientists have developed a significantly better computer tool for finding genetic alterations that play an important role in many cancers
but were difficult to identify with whole-genome sequencing. The findings appear in the scientific journal Nature Methods.
The tool is called an algorithm CONSERTING, short for Copy Number Segmentation by Regression Tree in Next Generation Sequencing.
St jude researchers created CONSERTING to improve identification of copy number alterations (CNAS) in the billions of pieces of genetic information generated by next-generation
whole-genome sequencing techniques. CNAS involve the gain or loss of DNA segments. The alterations affect just a few
or many hundreds of genes depending on the size of the DNA segments. In this study, researchers showed CONSERTING identified such alterations with dramatically better accuracy
and sensitivity than other techniques, including four published algorithms used to recognize CNA in whole-genome sequencing data.
The comparison involved the normal and tumor genomes from 43 children and adults with brain tumors, leukemia, melanoma and the pediatric eye tumor retinoblastoma."
whole-genome sequencing to better understand the genetic landscape of cancer genomes and lay the foundation for the next era of cancer therapy,
"said corresponding author Jinghui Zhang, Ph d.,a member of the St jude Department of Computational biology.""In this study of the tumor and normal genomes of 43 patients, CONSERTING identified copy number alterations in children with 100 times greater precision and 10 times greater precision in adults."
"First author Xiang Chen, Ph d.,a St jude senior research scientist, added:""CONSERTING helped us identify alterations that other algorithms missed,
including previously undetected chromosomal rearrangements and copy number alterations present in a small percentage of tumor cells."
"Using CONSERTING, researchers discovered genetic alterations driving pediatric leukemia, the pediatric brain tumor low-grade glioma, the adult brain tumor glioblastoma and retinoblastoma.
The algorithm also helped identify genetic changes that are present in a small percentage of a tumor's cells.
The alterations may be the key to understanding why tumors sometimes return after treatment. In addition, Zhang said CONSERTING should make it easier to track the evolution of tumors with complex genetic rearrangements,
sometimes involving multiple chromosomes that swap pieces when they break and reassemble. St jude has made CONSERTING available for free to researchers worldwide.
The software user manual and related data can be downloaded from http://www. stjuderesearch. org/site/lab/zhang.
St jude researchers have developed also a cloud version of CONSERTING and related tools that can be accessed through Amazon web services.
Instead of downloading CONSERTING, scientists can upload data for analysis. Work on CONSERTING began in 2010 shortly after the St jude Children's Research Hospital--Washington University Pediatric Cancer Genome Project was launched.
The Pediatric Cancer Genome Project used next-generation, whole-genome sequencing to study some of the most aggressive and least understood childhood cancers.
Early in the project researchers realized that existing analytic methods often missed duplications or deletions of DNA segments
particularly small changes that involve a handful of genes and provide insight into the origins of a patient's cancer.
CONSERTING has now been used to analyze next-generation, whole-genome sequencing data for the Pediatric Cancer Genome Project.
The project includes the normal and cancer genomes of 700 pediatric cancer patients with 21 different cancer subtypes.
CONSERTING combines a method of data analysis called regression tree, which is a machine learning algorithm, with next-generation,
whole-genome sequencing. Machine learning capitalizes on advances in computing to design algorithms that repeatedly and rapidly analyze large,
complex sets of data sets and unearth unexpected insights.""This combination has provided us with a powerful tool for recognizing copy number alterations,
even those present in relatively few cells or in tumor samples that include normal cells along with tumor cells,
"Zhang said. Next-generation, whole-genome sequencing involves breaking the human genome into about 1 billion pieces that are copied
and reassembled using the normal genome as a template. CONSERTING software compensates for gaps and variations in sequencing data.
The sequencing data is integrated with information about the chromosomal rearrangements to find CNAS and identify their origins in the genome e
#Cellular bubbles used to deliver Parkinson's meds directly to brain And what's the best way of getting her drug-packed exosomes to the brain?
It looks like a simple nasal spray will do the trick, say Elena Batrakova and her colleagues at the UNC Eshelman School of Pharmacy's Center for Nanotechnology in Drug Delivery.
Batrakova and her colleagues extracted exosomes from immune cells and successfully loaded them with the enzyme catalase, a potent antioxidant that counters the neuron-killing inflammation responsible for Parkinson's and other degenerative neurological disorders.
Their work was published in the Journal of Controlled Release. This is the first time a large therapeutic protein like catalase has been delivered to the brain using exosomes.
Getting drugs into the brain is extremely difficult in general because it is protected and isolated from the rest of the body by the blood-brain barrier,
which is extremely selective about what is allowed to pass through. Batrakova and her team at the pharmacy school harvested exosomes from macrophages,
white blood cells that are responsible for clearing foreign material from the body. Exosomes are produced tiny spheres by cells to carry chemical messages.
They are made of the same material that makes up cell membranes. Diseases like cancer and AIDS propagate throughout the body by hijacking exosomes."
"Exosomes are engineered by nature to be the perfect delivery vehicles for proteins and genetic material, "Batrakova says."
"Catalase is a huge protein, and it is almost impossible to deliver across the blood-brain barrier alone.
We use exosomes from white blood cells, which are invisible to the immune system and easily interact and fuse with the blood-brain barrier to deliver their cargo across it."
"Catalase counteracts the effects of free radicals, destructive molecules that are byproducts of cellular activity and especially prevalent in areas of chronic inflammation."
"Catalase is one of the most potent antioxidants in nature, "Batrakova says.""One molecule of catalase can deactivate about one million free radicals per second,
and it never stops because the enzyme is consumed not in the reaction. No small molecule drug even comes close to matching it in speed or efficiency."
"Traditional drugs--from cold medicine to chemotherapy--are composed of small molecules of a few dozen atoms, typically.
Biopharmaceuticals, or biologics, are produced proteins by living cells. Proteins such as catalase are tens of thousands of times larger than the small molecules that make up traditional drugs.
These packages of medicine will be ignored by the patient's immune system, which works against unknown proteins as well as many synthetic delivery vehicles s
#New centimeter-accurate GPS SYSTEM could transform virtual reality and mobile devices The researchers'new system could allow unmanned aerial vehicles to deliver packages to a specific spot on a consumer's back porch,
enable collision avoidance technologies on cars and allow virtual reality (VR) headsets to be used outdoors. The researchers'new centimeter-accurate GPS coupled with a smartphone camera could be used to quickly build a globally referenced 3-D map of one's surroundings that would greatly expand the radius of a VR game.
Currently, VR does not use GPS, which limits its use to indoors and usually a two-to three-foot radius."Imagine games where,
rather than sit in front of a monitor and play, you are in your backyard actually running around with other players,
"said Todd Humphreys, assistant professor in the Department of Aerospace engineering and Engineering Mechanics and lead researcher."
"To be able to do this type of outdoor, multiplayer virtual reality game, you need highly accurate position
and orientation that is tied to a global reference frame.""Humphreys and his team in the Radionavigation Lab have built a low-cost system that reduces location errors from the size of a large car to the size of a nickel--a more than 100 times increase in accuracy.
Humphreys collaborated with Professor Robert W. Heath from the Department of Electrical and Computer engineering and graduate students on the new technology,
which they describe in a recent issue of GPS World. Centimeter-accurate positioning systems are used already in geology, surveying and mapping,
but the survey-grade antennas these systems employ are too large and costly for use in mobile devices.
The breakthrough by Humphreys and his team is a powerful and sensitive software-defined GPS RECEIVER that can extract centimeter accuracies from the inexpensive antennas found in mobile devices--such precise measurements were not previously possible.
The researchers anticipate that their software's ability to leverage low-cost antennas will reduce the overall cost of centimeter accuracy,
making it economically feasible for mobile devices. Humphreys and his team have spent six years building a specialized receiver, called GRID,
to extract so-called carrier phase measurements from low-cost antennas. GRID currently operates outside the phone,
but it will eventually run on the phone's internal processor. To further develop this technology, Humphreys and his students recently co-founded a startup,
called Radiosense. Humphreys and his team are working with Samsung to develop a snap-on accessory that will tell smartphones, tablets and virtual reality headsets their precise position and orientation.
The researchers designed their system to deliver precise position and orientation information--how one's head rotates
or tilts--to less than one degree of measurement accuracy. This level of accuracy could enhance VR environments that are based on real-world settings,
as well as improve other applications, including visualization and 3-D mapping. Additionally, the researchers believe their technology could make a significant difference in people's daily lives
including transportation, where centimeter-accurate GPS could lead to better vehicle-to-vehicle communication technology."
"If your car knows in real time the precise position and velocity of an approaching car that is blocked from view by other traffic,
your car can plan ahead to avoid a collision, "Humphreys said. Further information: http://gpsworld. com/accuracy-in-the-palm-of-your-hand d
#'Microcombing'creates stronger, more conductive carbon nanotube films"It's a simple process and can create a lightweight CNT film,
or'bucky paper,'that is a meter wide and twice as strong as previous such films--it's even stronger than CNT FIBERS,
"says Yuntian Zhu, Distinguished Professor of Materials science and engineering at NC State and corresponding author of a paper describing the work.
The researchers begin by growing the CNTS on a conventional substrate in a closely packed array.
The CNTS are tangled together, so when researchers pull on one end of the array the CNTS form a continuous ribbon that is only nanometers thick.
This ribbon is attached to a spool which begins winding the ribbon up. As the spool pulls, the CNT ribbon is dragged between two surgical blades.
While the blades appear straight to the naked eye, they actually have micrometer-scale fissures on their cutting edge.
These fissures create a kind of"microcomb"that pulls the CNTS into alignment--just as a regular comb sorts through tangled hair.
When the ribbon of aligned CNTS is being wound onto the spool, the researchers apply an alcohol solution.
This pulls the CNTS closer together, strengthening the bonds between CNTS. The CNT ribbon wraps around itself as it winds around the spool
creating a layered film of pure CNTS. Researchers can control the thickness of the film by controlling the number of layers.
The CNT films made using the microcombing technique had more than twice the tensile strength of the uncombed CNT films--greater than 3 gigapascals for the microcombed material,
versus less than 1. 5 gigapascals for the uncombed material. The microcombed CNT film also had 80 percent higher electrical conductivity than the uncombed film."
"This is a significant advance, but we want to find ways to make CNT alignment even straighter,
"Zhu says.""It's still not perfect.""In addition, the technique would theoretically be easy to scale up for large-scale production.
We'd like to find an industry partner to help us scale this up and create a material for the marketplace
#Breast cancer vaccines may work better with silicon microparticles Model studies showed that microparticles loaded with an antigen, HER2,
not only protected the antigen from premature destruction, but also stimulated the immune system to recognize and relentlessly attack cancer cells overexpressing the HER2 antigen."
"We could completely inhibit tumor growth after just one dose of the cancer vaccine in the animal model,
"said principal investigator Haifa Shen, M d, . Ph d."This is the most amazing result we have seen ever in a tumor treatment study."
"The success of the treatment, Shen and his team learned, appears to be the porous silicon microparticles (PSMS) themselves.
In vivo and in vitro studies confirmed the microparticles stimulated a strong, sustained innate immune response at local sites of tumor activity and growth--with or without any antigen loaded."
"We have shown for the first time that a microparticle can serve as a carrier for sustained release and processing of tumor antigens,
"Shen said.""But just as importantly, we learned the microparticles themselves appear to be enough to stimulate a type I interferon response,
and were transferred even from one antigen-presenting cell to another to maintain a long-lasting antigen-releasing effect."
"Cancer vaccines are designed to turn a patient's own immune system more strongly against cancer cells, and have been an area of recent and intense interest among oncologists.
Since 2010, the FDA has approved vaccines and other immunotherapy drugs for melanoma, prostate cancer, and lung cancer.
There are currently dozens of active clinical trials evaluating vaccines for cancer therapy. Approximately 235,000 new diagnoses of breast cancer were made last year,
and over 40,000 patients died from the disease. As yet, there are no FDA-approved vaccines for breast cancer.
Such a vaccine might target HER2 a cell surface hormone receptor that is overexpressed in the tumor cells of 15 to 30 percent of breast cancer patients.
Such cells are called HER2+or HER2 positive. In this case, HER2 is both a naturally occurring hormone receptor and an antigen target for therapy.
A vaccine against HER2 would train the immune system's more destructive agents to recognize the cancer cells overproducing HER2
and destroy them, leaving healthy cells more or less alone. But so far, vaccines against HER2 have seen only moderate success."Vaccines targeting the HER2 oncoprotein have been tried,
"Shen said.""But these vaccines have mostly not been very potent because of inefficient vaccine delivery, a poor immune response at the site of the tumor,
and other factors. We have shown that the PSM-mediated vaccine is not only potent enough to trigger tumor cell killing,
but also modifies the tumor microenvironment in a way that favors tumor treatment.""An important aspect of PSM function is stimulating the body's own immune system to fight cancer,
Shen said.""PSMS persistently challenge the antigen-presenting cells to activate the T cells, "he said."
"And the PSMS modify the tumor microenvironment so that the cytotoxic T cells maintain their activity.""Shen said the use of PSMS could work for any variety of cancer antigens and cancers,
and that the PSMS could be loaded with multiple antigens for a single vaccine target, or multiple antigens for several targets, possibly enhancing the approach's effectiveness further."
"Besides developing a highly potent breast cancer vaccine, we have demonstrated also that PSMS are said versatile, "Shen."
"This is a technology platform that can be applied by other scientists to develop vaccines for other types of cancers, ultimately helping,
we hope, more types of cancer patients.""Before human clinical trials can begin, Shen said the researchers must evaluate the toxicity of antigen-loaded PSMS s
#Enzyme responsible for obesity-related high blood pressure identified"Hypertension is a condition in which arterial blood vessels are exposed to persistently elevated blood pressure,
making the heart work harder to pump blood to the body, "said William Durante, a professor of medical pharmacology and physiology at the MU School of medicine and lead author of the study."
"Hypertension can lead to severe health issues such as heart attacks, kidney failure, organ damage, and weakened or ruptured blood vessels.
By comparing genetically obese rats to lean rats, we discovered that obese animals were deficient in the amino acid arginine due to elevated activity of the enzyme arginase,
which breaks down this molecule.""Although arginase is present throughout the body, it is primarily found in the liver.
Its role is to assist in the breakdown of ammonia, which is flushed eventually out during urination.
However, Durante's team found significantly increased arginase activity within blood vessels and in the blood of obese rats compared to lean animals."
"The problem with this development is that arginase depletes arteries and blood of arginine, which is needed to generate nitric oxide,
"Durante said.""Nitric oxide is formed a gas from arginine that relaxes blood vessels and lowers arterial blood pressure.
The destruction of arginine by arginase reduces nitric oxide levels, leading to the constriction of blood vessels and high blood pressure."
"Using two methods to correct the arginine deficiency, Durante's team first supplemented the diet of obese animals with the amino acid L-arginine.
The second method involved using drugs that block the activity of arginase. Although both approaches restored nitric oxide production and reversed hypertension in obese rats, the use of arginase-inhibiting drugs may be a better solution."
"Blocking arginase activity offers a more specific approach in treating hypertension, because you are directly targeting the underlying biochemical defect in obesity,
"Durante said.""L-arginine is a natural amino acid commonly found in red meat, poultry, fish and dairy products.
It is manufactured also and used as a nutritional supplement or medication. However, a dietary approach using L-arginine may not be the best treatment option.
Yes, arginine increases nitric oxide, but it also exerts other biological effects, and it can be converted by arginase to alternative compounds that counteract its benefits to the circulation."
"In future studies, researchers plan to investigate what causes the increase in arginase activity in blood vessels and in the blood of obese animals.
However, Durante feels that identifying the role of arginase in the development of obesity-related hypertension will ultimately benefit obese patients."
"Obesity is a significant health issue not only in this country, but worldwide,"Durante said.""The key to reversing the effects of obesity-related hypertension will be to effectively block arginase activity.
This new knowledge may help in the discovery of treatment options for obese patients with high blood pressure
#Researchers observe the moment when a mind is changed Researchers studying how the brain makes decisions have recorded,
for the first time the moment-by-moment fluctuations in brain signals that occur when a monkey making free choices has a change of mind.
The findings result from experiments led by electrical engineering Professor Krishna Shenoy, whose Stanford lab focuses on movement control and neural prostheses--such as artificial arms--controlled by the user's brain."
"This basic neuroscience discovery will help create neural prostheses that can withhold moving a prosthetic arm until the user is certain of their decision,
thereby averting premature or inopportune movements, "Shenoy said. The experiments are described in the journal elife.
while he was a graduate student in Shenoy's lab. Kaufman taught laboratory monkeys to perform a decision-making task.
This improvement on what's called the"single trial decoder"algorithm revealed the neural signals that occurred during a momentary hesitation
who is now a postdoctoral scholar at Cold Spring Harbor Laboratory.""The most critical result of our work here is that we can track a single decision
and see how the monkey arrived there: whether he decided quickly, slowly, or changed his mind halfway through."
"The experiments The experiments involved monkeys that were trained to reach for either of two targets on a computer screen.
while two jittering targets were positioned on either side of a computer screen. Colored barriers on the screen created a simple maze.
When the targets stopped jittering the monkeys were trained to move to one or the other target by sweeping his fingertip through the maze until he touched one of the targets.
During the experiments, 192 electrodes in each monkey's motor and premotor cortex began measuring brain activity the moment that the targets appeared on screen.
The single-trial advantage Using his single-trial decoder algorithm, Kaufman could analyze moment-by-moment brain activity during each individual decision.
"This deeper understanding of decision-making will help researchers to fine-tune the control algorithms of neural prostheses to enable people with paralysis to drive a brain-controlled prosthetic arm or guide a neurally-activated cursor on a computer screen.
Mark M. Churchland, now an assistant professor at Columbia University, and Stephen I. Ryu, now a consulting professor of electrical engineering at Stanford and a neurosurgeon at the Palo alto Medical Foundation.
The philosophical implications Kaufman said the team's findings also bear on a longstanding philosophical debate about human consciousness.
In the early 1980s, University of California, San francisco neuroscientist Benjamin Libet conducted an experiment to assess the nature of free will.
Subjects hooked up to an electroencephalogram (EEG) were asked to push a button whenever they liked. They were asked also to note the precise time that they first became aware of the wish or urge to move.
The scientists studied for the first time native defects and dielectric properties of an emerging semiconductor compound called thallium sulfide iodide (Tl6si4.
the researchers demonstrated the material's potential for creating high-performance, low-cost, room-temperature semiconductor radiation detectors. In a paper published this week in the Journal of Applied Physics, from AIP Publishing,
"A detailed understanding of the fundamental charge transport properties of the material is essential for detector developments."
"Native defects, a type of structural flaw in which the regular pattern of atoms is altered naturally during crystal growth, play an important role in charge carrier trapping and recombination in semiconductors.
Du's research established a theoretical foundation for the development of thallium sulfide iodide radiation detectors, opening doors for a new generation of room-temperature semiconductor radiation detectors.
The Limits of Conventional Radiation Detectorssemiconductor radiation detectors are devices that measure ionizing radiation by collecting radiation-generated charge carriers in the semiconductor between electrodes under a bias voltage.
Conventional semiconductor detectors such as germanium and silicon require low temperatures to operate which limits their applications outside of laboratories.
For example, germanium detectors must be cooled to liquid nitrogen temperature (about 77 Kelvin or-196 degrees Celsius) to produce spectroscopic data.
In recent years, scientists have been seeking new materials for room-temperature radiation detectors. A semiconductor material called cadmium zinc telluride (Cdznte) has been found to be the best candidate to date,
but it suffers from the difficulty of growing large-size high-quality single crystals, making it difficult and expensive to incorporate in commercial detectors.
Researchers are still searching for a material with improved performance and lower cost that is suitable for commercial production,
Du said. Thallium Sulfide Iodide: A Promising Candidateaccording to Du, a good semiconductor candidate should be a dense material
and contain heavy chemical elements so that it can effectively stop and absorb high-energy radiation. Also, in order to work properly at room temperature,
the material should have a reasonably large band gap (the energy difference between the top of the valence band
and the bottom of the conduction band in semiconductors) and high resistivity to suppress thermally generated charge carriers for precisely detecting radiation-generated carriers.
Moreover, the detector materials need to have excellent carrier transport efficiency to make sure radiation-generated charges effectively diffuse through the crystal
and reach the electrodes. Enter thallium sulfide iodide. Thallium sulfide iodide is an emerging semiconductor compound that has attracted attention in recent years for room-temperature radiation detection,
Du said. Previous experimental studies have shown the material's good carrier transport properties, indicating great potential for future development.
Compared to cadmium zinc telluride, thallium sulfide iodide has higher density, heavier chemical elements and much lower growth temperature,
Native defects, the natural structure flaws in a semiconductor, can interact with charge carriers, causing carrier trapping and scattering,
thus harming the carrier transport process. Studying the native defects and their effects on charge transport in a material are hence essential for the performance improvement of a radiation detector.
thus reducing carrier scattering and trapping.""The defect and dielectric properties, combined with other good properties such as large band gap, high density,
low melting temperature and so on, suggest that thallium sulfide iodide is a good candidate for fabricating new generation room-temperature radiation detectors with improved performance and lower cost than previous detectors,
"Du said. The researchers'next step is to study impurities, impurity-defect complexes and their effects on carrier transport in thallium sulfide iodide e
#Compact light source improves CT SCANS With its ability to image cross sections of the human body, X-ray computer tomography (CT) has become an important diagnostic tool in medicine.
Conventional CT SCANS are very detailed when it comes to bones and other dense body parts that strongly absorb X-rays.
However, the technique struggles with the visualization and distinction of"soft tissues"such as organs, which are more transparent to X-rays."
"Our work demonstrates that we can achieve better results with the Compact Light source, "says Professor for Biomedical Physics Franz Pfeiffer of the Technical University of Munich in Germany, who led the new study published April 20 in the Proceedings of the National Academy of Sciences."
"The CLS allows us to do multimodal tomography scans--a more advanced approach to X-ray imaging."
"More than One Kind of Contrastthe amount of detail in a CT SCAN depends on the difference in brightness,
or contrast, which makes one type of tissue distinguishable from another. The absorption of X-rays--the basis for standard CT--is only one way to create contrast.
but they become visible in phase-contrast tomography, "says the study's lead author, Elena Eggl, a researcher at the Technical University of Munich."
"The dark-field method, on the other hand, is particularly sensitive to structures like vertebrae and the lung's alveoli."
these methods require X-ray light with a well-defined wavelength aligned in a particular way--properties that conventional CT SCANNERS in hospitals do not deliver sufficiently.
--but these are large and expensive machines that cannot simply be implemented at every research institute and clinic.
"It turns out that the properties of the CLS are perfect for applications like tomography."
"More Modes, Finer Detailin the recent study, the researchers reported the first"multimodal"CT SCAN with the CLS:
which is not possible with absorption-based CT SCANS.""Using a standard sample of chemically well-defined liquids,
when combining all three tomography modes. Implications for Cancer, Materialsthe success of this research, which was done on a CLS prototype,
has led to the commissioning of the first commercial device. The researchers'next goal is to use the CLS for phase-contrast
and dark-field CT in preclinical studies--an approach that could help visualize cancer.""We work closely together with two clinics to study tumors,
"Eggl says.""One of our plans is to image breast tissue samples and also entire breasts after mastectomy to better understand the clinical picture of breast cancer."
"Besides medical applications, multimodal tomography could also open up new possibilities in materials science, for instance, in studies of extremely durable and lightweight carbon fibers and other fibrous materials,
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