Showing posts with label Approach. Show all posts
Showing posts with label Approach. Show all posts

Sunday, 28 July 2013

New approach for studying deadly brain cancer

Main Category: Cancer / Oncology
Also Included In: Neurology / Neuroscience
Article Date: 25 Jul 2013 - 1:00 PDT Current ratings for:
New approach for studying deadly brain cancer
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Human glioblastoma multiforme, one of the most common, aggressive and deadly forms of brain cancer, is notoriously difficult to study. Scientists have traditionally studied cancer cells in petri dishes, which have none of the properties of the brain tissues in which these cancers grow, or in expensive animal models.

Now a team of engineers has developed a three-dimensional hydrogel that more closely mimics conditions in the brain. In a paper in the journal Biomaterials, the researchers describe the new material and their approach, which allows them to selectively tune up or down the malignancy of the cancer cells they study.

The new hydrogel is more versatile than other 3-D gels used for growing glioma (brain cancer) cells in part because it allows researchers to change individual parameters - the gel's stiffness, for example, or the presence of molecular signals that can influence cancer growth - while minimally altering its other characteristics, such as porosity.

Being able to adjust these traits individually will help researchers tease out important features associated with the initial growth of a tumor as well as its response to clinical therapies, said University of Illinois chemical and biomolecular engineering professor Brendan Harley, who led the study with postdoctoral researcher Sara Pedron and undergraduate student Eftalda Becka. Harley is an affiliate of the Institute for Genomic Biology at Illinois.

The researchers found that they could increase or decrease the malignancy of glioma cells in their hydrogel simply by adding hyaluronic acid, a naturally occurring carbohydrate found in many tissues, especially the brain.

Hyaluronic acid (HA) is a key component of the extracellular matrix that provides structural and chemical support to cells throughout the body. HA contributes to cell proliferation and cell migration, and local changes in HA levels have been implicated in tumor growth.

"Hyaluronic acid is one of the major building blocks in the brain," Harley said. "The structure of a newly forming brain tumor has some of this HA within it, but there's also a lot of the HA in the brain surrounding the tumor."

Previous studies have used hydrogels made out of nothing but hyaluronic acid to study gliomas, Harley said. "The problem there is that HA is structurally not very strong." It also is difficult to adjust the amount of HA that the glioma cells are exposed to if their environment is 100 percent HA, he said.

In the new study, Pedron observed how glioma cells behaved in two different hydrogels - one based on methacrylated gelatin (GelMA) and the other using a more conventional polyethylene glycol (PEG) biomaterial. These two materials vary in one important trait: GelMA is a naturally derived material that contains adhesive sites that allow cells to latch onto it; synthetic PEG does not.

"The purpose of having these two systems was to isolate the effect of HA on glioma cells," Pedron said. If changing HA levels produced different effects in different gels, that would indicate that the gels were contributing to those effects, she said.

Instead, Harley and Pedron found that additions of HA to glioma cells had "very similar" effects in both materials. Adding too little or too much HA led to reduced malignancy, while incorporating just enough HA led to significantly enhanced malignancy. This held true for multiple types of glioblastoma multiforme cells. This suggests that "it's the HA itself that is likely the cause for this malignant change," Harley said.

"If you have a material that allows you to selectively tune up or down malignancy, that will allow you to ask lots of questions about treatment methods for more malignant or less malignant forms of glioma. It also will allow scientists to try to get a response that's closer to what you see in the body," he said.

"If you talk to pathologists, they'll say a biomaterial will never allow you to grow a full brain tumor, which is probably true," Harley said. "But it's realistic to think that a well-designed biomaterial will allow you to study aspects of glioma growth and treatment in a way that's much richer than simply looking in a petri dish and much more accessible than trying to study tumor development within the brain itself."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our cancer / oncology section for the latest news on this subject.

The U. of I. department of chemical and biomolecular engineering, the Institute for Genomic Biology and the Campus Research Board supported this research.

University of Illinois at Urbana-Champaign

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New idea and approach in the treatment of vascular dementia

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our alzheimer's / dementia section for the latest news on this subject.

Article: " A ginkgo biloba extract promotes proliferation of endogenous neural stem cells in vascular dementia rats " by Jiwei Wang2, Wen Chen1, Yuliang Wang1 (1 Department of Physiology, Weifang Medical University, Weifang 261042, Shandong Province, China; 2 School of Medicine, Shandong University, Jinan 250012, Shandong Province, China).

Wang JW, Chen W, Wang YL. A ginkgo biloba extract promotes proliferation of endogenous neural stem cells in vascular dementia rats. Neural Regen Res. 2013;8(18):1655-1662.

Full text: http://www.sjzsyj.org:8080/Jweb_sjzs/CN/article/downloadArticleFile.do?attachType=PDF&id=634

Neural Regeneration Research

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Saturday, 27 July 2013

Research approach highlights potential therapeutic targets for Alzheimer's disease

Main Category: Alzheimer's / Dementia
Article Date: 26 Jul 2013 - 1:00 PDT Current ratings for:
Research approach highlights potential therapeutic targets for Alzheimer's disease
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Key molecular pathways that ultimately lead to late-onset Alzheimer's disease, the most common form of the disorder, have been identified by researchers at Columbia University Medical Center (CUMC). The study, which used a combination of systems biology and cell biology tools, presents a new approach to Alzheimer's disease research and highlights several new potential drug targets. The paper was published in the journal Nature.

Much of what is known about Alzheimer's comes from laboratory studies of rare, early-onset, familial (inherited) forms of the disease. "Such studies have provided important clues as to the underlying disease process, but it's unclear how these rare familial forms of Alzheimer's relate to the common form of the disease," said study leader Asa Abeliovich, MD, PhD, associate professor of pathology and cell biology and of neurology in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at CUMC. "Most important, dozens of drugs that 'work' in mouse models of familial disease have ultimately failed when tested in patients with late-onset Alzheimer's. This has driven us, and other laboratories, to pursue mechanisms of the common form of the disease."

Non-familial Alzheimer's is complex; it is thought to be caused by a combination of genetic and environmental risk factors, each having a modest effect individually. Using so-called genome-wide association studies (GWAS), prior reports have identified a handful of common genetic variants that increase the likelihood of Alzheimer's. A key goal has been to understand how such common genetic variants function to impact the likelihood of Alzheimer's.

In the current study, the CUMC researchers identified key molecular pathways that link such genetic risk factors to Alzheimer's disease. The work combined cell biology studies with systems biology tools, which are based on computational analysis of the complex network of changes in the expression of genes in the at-risk human brain.

More specifically, the researchers first focused on the single most significant genetic factor that puts people at high risk for Alzheimer's, called APOE4 (found in about a third of all individuals). People with one copy of this genetic variant have a three-fold increased risk of developing late-onset Alzheimer's, while those with two copies have a ten-fold increased risk. "In this study," said Dr. Abeliovich, "we initially asked: If we look at autopsy brain tissue from individuals at high risk for Alzheimer's, is there a consistent pattern?"

Surprisingly, even in the absence of Alzheimer's disease, brain tissue from individuals at high risk (who carried APOE4 in their genes) harbored certain changes reminiscent of those seen in full-blown Alzheimer's disease," said Dr. Abeliovich. "We therefore focused on trying to understand these changes, which seem to put people at risk. The brain changes we considered were based on 'transcriptomics' - a broad molecular survey of the expression levels of the thousands of genes expressed in brain."

Using the network analysis tools mentioned above, the researchers then identified a dozen candidate "master regulator" factors that link APOE4 to the cascade of destructive events that culminates in Alzheimer's dementia. Subsequent cell biology studies revealed that a number of these master regulators are involved in the processing and trafficking of amyloid precursor protein (APP) within brain neurons. APP gives rise to amyloid beta, the protein that accumulates in the brain cells of patients with Alzheimer's. In sum, the work ultimately connected the dots between a common genetic factor that puts individuals at high risk for Alzheimer's, APOE4, and the disease pathology.

Among the candidate "master regulators" identified, the team further analyzed two genes, SV2A and RFN219. "We were particularly interested in SV2A, as it is the target of a commonly used anti-epileptic drug, levetiracetam. This suggested a therapeutic strategy. But more research is needed before we can develop clinical trials of levetiracetam for patients with signs of late-onset Alzheimer's disease."

The researchers evaluated the role of SV2A, using human-induced neurons that carry the APOE4 genetic variant. (The neurons were generated by directed conversion of skin fibroblasts from individuals at high risk for Alzheimer's, using a technology developed in the Abeliovich laboratory.) Treating neurons that harbor the APOE4 at-risk genetic variant with levetiracetam (which inhibits SV2A) led to reduced production of amyloid beta. The study also showed that RFN219 appears to play a role in APP-processing in cells with the APOE4 variant.

"Our findings suggest that both SV2A and RFN219 are candidate drug targets," said Dr. Abeliovich. "What's exciting to us is that these approaches may play a role in the development of drugs for the common non-familial form of Alzheimer's disease. This has been an enormous challenge."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our alzheimer's / dementia section for the latest news on this subject.

The paper is titled, "Integrative genomics identifies APOE ?4 effectors in Alzheimer's disease." The other contributors are all members of CUMC's Taub Institute for Research on Alzheimer's Disease and the Aging Brain: Herve Rhinn, Ryousuke Fujita, Liang Qiang, Rong Chen, and Joseph H. Lee. Dr. Lee is also a member of CUMC's Gertrude H. Sergievsky Center.

The authors declare no financial or other conflicts of interest. Subsequent to the acceptance of this paper, Dr. Abeliovich received a grant from UCB, Inc. for an unrelated study.

The study was supported by grants from the National Institutes of Health (R01AG042317 and RO1NS064433).

Columbia University Medical Center

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Sunday, 14 July 2013

New Approach Could Enhance Cancer Drug Delivery

Main Category: Cancer / Oncology
Article Date: 13 Jul 2013 - 0:00 PDT Current ratings for:
New Approach Could Enhance Cancer Drug Delivery
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Researchers have developed a concept to potentially improve delivery of drugs for cancer treatment using nanoparticles that concentrate and expand in the presence of higher acidity found in tumor cells.

The concept involves using nanoparticles made of "weak polybases," compounds that expand when transported into environments mimicking tumor cells, which have a higher acidity than surrounding tissues. The researchers used sophisticated modeling to show how the particles would accumulate in regions of higher acidity and remain there long enough to delivery anticancer drugs.

"This phenomenon, which we term pH phoresis, may provide a useful mechanism for improving the delivery of drugs to cancer cells in solid tumor tissues," said You-Yeon Won, an associate professor of chemical engineering at Purdue University.

Solutions with a pH less than 7 are said to be acidic, and those with a higher pH are basic or alkaline. The pH phoresis concept hinges on using synthetic "polymer micelles," tiny drug-delivery spheres that harbor medications in their inner core and contain an outer shell made of a material that has been shown to expand dramatically as the pH changes from alkaline to acidic.

A twofold size increase could result in a similar increase in the efficiency of drug delivery to tumors.

"Such an effect would be a game changer by delivering the proper dose of anticancer drugs inside tumor cells," Won said. "This pH phoresis concept also could be combined readily within other established drug-delivery methodologies, making it potentially practical for medical application."

The concept is described in a research paper that will appear in the Journal of Controlled Release on July 15, and an unedited version appeared online June 19. The paper was written by Won and doctoral student Hoyoung Lee. Findings showed how the micelles' expansion is optimized in the specific pH in tumor cells.

The researchers demonstrated that the highest degree of micelle swelling in tumors needs to occur when there is a pH of about 7.0, plus or minus 0.5, for optimal delivery of drugs to tumor tissue.

"Solid tumors have a significantly lower extracellular pH, about 6.5-6.9, compared to normal tissue, which has an average pH of 7.4," Won said.

The weak polybases in the micelles contain molecules called amines, which are made of nitrogen and hydrogen atoms. The micelles swell at lower pH due to the increased "protonation," or the addition of protons to nitrogen atoms in the amines. Because the protons are positively charged, the like-charged amines repel each other, causing the nanoparticles to expand.

The positive charge slows the movement of micelles out of tumor tissue, which would cause the nanoparticles to accumulate inside the tumor mass long enough to enter tumor cells and release anticancer drugs.

"This concept is straightforward to understand, yet no one recognized it previously," Won said. "And it took us a while to put this description on a mathematical footing. To do that, we had to modify the famous Fick's first law diffusion equation."

The law, derived by physician and physiologist Adolf Fick in 1855, describes how molecules diffuse from regions of high concentration to regions of low concentration.

The micelles also are coated with protective varnish so that they might remain intact long enough to reach tumor sites, where they would expand and then biodegrade.

More research is needed to determine how well the approach could enhance drug delivery, but the pH phoresis concept developed by Won and his student represents a step in developing nanomedicine techniques in drug delivery, he said.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our cancer / oncology section for the latest news on this subject.

Writer: Emil Venere

The research has been funded by the National Science Foundation and Purdue's School of Chemical Engineering. Support also came from the Global RNAi Carrier Initiative Program Fellowship from the Biomedical Research Institute of the Korea Institute of Science and Technology (KIST) and also the Research Fellowship from Purdue’s Bindley Bioscience Center.

ABSTRACT

pH Phoresis": A New Concept That Can Be Used for Improving Drug Delivery to Tumor Cells

You-Yeon Won,1,2,3,* and Hoyoung Lee1

1 School of Chemical Engineering and 2Bindley Bioscience Center, Purdue University

3Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology

* To whom correspondence should be addressed. E-mail: yywon@ecn.purdue.edu

We propose a new concept describing how nanoparticles composed of weak polybases (such as polyamines) would behave when they are exposed to a pH gradient; weak polybase-containing particles will tend to accumulate preferentially in low pH regions under a pH gradient environment. This phenomenon, which we term pH phoresis, may provide a useful mechanism for improving the delivery of drugs to cancer cells in solid tumor tissues.

Purdue University

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